Symphony Ntawm Nanomaterials Thiab Immunotherapy Raws Li Cov Kab Mob Cancereimmunity

Abstract

Lub cev tiv thaiv kab mob koom nrog hauv kev pib thiab kev loj hlob ntawm mob qog noj ntshav. Kev tshawb fawb txog kev mob qog noj ntshav thiab kev tiv thaiv kab mob tau ua rau muaj kev txhim kho ntawm ntau qhov kev kho mob zoo immunotherapy. Cov tshuaj tiv thaiv kab mob no feem ntau ua rau ib kauj ruam ntawm kev tiv thaiv kab mob qog noj ntshav. Nyob rau hauv xyoo tas los no, kev tshawb pom ntawm nanomaterials tshiab tau nthuav dav ua haujlwm thiab muaj peev xwm siv tau ntawm nanomaterials. Ntxiv nrog rau kev ua yeeb yam hauv kev xa tshuaj, qee cov khoom siv nano tuaj yeem ua rau cov kab mob immunogenic cell tuag (ICD) ntawm cov qog nqaij hlav cancer lossis tswj cov profile thiab lub zog ntawm lub cev tiv thaiv kab mob raws li immunomodulators. Raws li lawv cov versatility, nanomaterials yuav ua hauj lwm raws li ib tug kev platform rau ntau yam tshuaj los yog kho cov tswv yim, ib txhij tsom rau ob peb kauj ruam ntawm kev tiv thaiv kab mob qog noj ntshav los txhim kho cov txiaj ntsig ntawm kev tiv thaiv kab mob tiv thaiv kab mob. Txhawm rau qhia txog lub luag haujlwm tseem ceeb ntawm nanomaterials hauv kev tiv thaiv kab mob qog noj ntshav raws li lub voj voog tiv thaiv kab mob qog noj ntshav, qhov kev tshuaj xyuas no yuav piav qhia meej txog kev sib tham ntawm lub cev tiv thaiv kab mob thiab mob qog noj ntshav, thiab cov ntawv thov tam sim no ntawm nanomaterials, suav nrog cov neeg nqa tshuaj, ICD inducers, thiab immunomodulators. Ntxiv mus, qhov kev tshuaj xyuas no yuav muab cov ncauj lus kom ntxaws txog kev paub txog kev txhim kho kev tiv thaiv kab mob qog noj ntshav ua ke raws li kev tiv thaiv kab mob qog noj ntshav, vam tias yuav ua kom muaj txiaj ntsig zoo ntawm cov kev kho mob no pab los ntawm nanomaterials.

cistanche ntxiv cov txiaj ntsig-nce kev tiv thaiv

1. Taw qhia

Mob qog noj ntshav, ib qho ntawm cov kab mob ua rau tuag taus, hem lub neej ntawm kwv yees li 20 lab tus tib neeg thoob ntiaj teb tam sim no1. Kev lig kev cai, kev phais, kws khomob, thiab kev siv hluav taws xob yog qhov tseem ceeb theranostics rau cov neeg mob qog noj ntshav. Txawm li cas los xij, kev mob toxicity, mob qog noj ntshav, thiab metastasis cuam tshuam rau cov neeg mob cov tsos mob 2. Raws li peb txoj kev nkag siab ntawm kev sib cuam tshuam ntawm oncology thiab kev tiv thaiv kab mob tau nce ntxiv, nws tau dhau los ua qhov ua tau los siv cov neeg mob lub cev tiv thaiv kab mob los tiv thaiv qog noj ntshav. Cov tshuaj tiv thaiv kab mob qog noj ntshav uas tuaj yeem ua rau lub cev tsis muaj zog tau pom tias muaj kev cuam tshuam ntev rau kev loj hlob ntawm qog noj ntshav, rov ua dua, thiab metastasis3. Cov tshuaj tiv thaiv kab mob qog noj ntshav, xws li kev tiv thaiv kab mob tiv thaiv kab mob (ICB) 4e7 thiab chimeric antigen receptor T (CAR-T) 8e10 cell therapy, tau txhim kho tag nrho cov ciaj sia nyob rau hauv ib pawg ntawm cov neeg mob, tshwj xeeb tshaj yog cov neeg mob qog nqaij hlav hematological. Txawm li cas los xij, cov kev kho mob no ua rau muaj cov lus teb tsawg hauv cov qog nqaij hlav 11 thiab cuam tshuam nrog cov kab mob o 12. Tom qab kev kho mob tau zoo ntawm ICB thiab CAR-T txoj kev kho, ntau cov tshuaj tiv thaiv kab mob thiab cov tswv yim sib txuas tau tsim. Immunotherapy yog redefining cancer theranostics thiab tsis txwv rau kev kho mob ntawm situ los yog cov qog nqaij hlav uas twb muaj lawm. Txawm li cas los xij, kev paub txog kev tiv thaiv kab mob tsis tiav nrog rau cov kev txwv tsis pub muaj kev txwv tseem txwv txoj kev loj hlob ntawm kev siv tshuaj tiv thaiv kab mob cancer ntau dua. Novel immunological lub hom phiaj, txoj kev xa tshuaj, thiab kev kho mob sib koom ua ke yuav ua rau muaj kev cuam tshuam hauv kev kho mob qog noj ntshav.

Tsis ntev los no, kev tshawb pom hauv kev tiv thaiv kab mob qog noj ntshav tau nthuav dav lub qab ntug ntawm kev kho mob qog noj ntshav. Neoantigens, muab tau los ntawm kev hloov pauv tshwm sim thaum lub sij hawm loj hlob sai ntawm cov qog nqaij hlav cancer, ua rau muaj kev tiv thaiv kab mob ntawm cov qog antigens13. Cov tshuaj tiv thaiv Neoantigen tau pom tias ua kom muaj cytotoxic T (CD8þ T) cells14. Tsis tas li ntawd, lub nra hnyav ntawm kev hloov pauv qog noj ntshav yog ib qho tseem ceeb prognostic qhia txog kev kho mob cancer immunotherapy15,16. Thaum lub sij hawm ICB kho, tus nqi ntawm cov qog-infiltrating CD8þ T hlwb raug txuas ncaj qha rau cov nyhuv kho17. "Cov qog kub", nrog cov lej ntau dua ntawm kev nkag mus rau CD8þ T hlwb tawm tsam qog antigens, nthuav tawm cov lus teb ntau dua rau ICB therapy18. Ntxiv nrog rau kev ua kom lub cev tiv thaiv kab mob tiv thaiv kab mob qog noj ntshav, kev tswj hwm cov qog noj ntshav microenvironment kuj tseem tsim nyog. Ntau yam cytokines thiab lub cev tiv thaiv kab mob koom nrog hauv kev txhim kho thiab kho cov qog immunosuppressive microenvironments. Cov no suav nrog interleukin (IL)-10, transforming growth factor (TGF)-b, immune checkpoints overexpressed on the surface of cancer cells, regulatory T (Treg) cells, and M2-type tumor-associated macrophages (TWS) 19. Tsis ntev los no, lub voj voog tiv thaiv kab mob qog noj ntshav uas piav qhia txog kev sib cuam tshuam ntawm cov ntaub so ntswg qog noj ntshav thiab lub cev tiv thaiv kab mob tau tshwm sim, thiab lub tswv yim no tau hloov kho tas li thiab txhim kho. Lub voj voog tiv thaiv kab mob qog noj ntshav piav qhia txog cov txheej txheem ntawm yuav ua li cas qog antigens uas tau tso tawm los ntawm cov qog nqaij hlav puas tsuaj raug ntes los ntawm APC hlwb thiab ua rau CD8þ T hlwb, thiab CD8þ T cells infiltrate li cas rau hauv cov ntaub so ntswg thiab tua cov qog nqaij hlav cancer. Rau kev kho mob qog noj ntshav, txhua kauj ruam ntawm kev tiv thaiv kab mob qog noj ntshav yuav tsum tau txiav txim siab zoo. Ntxiv mus, optimizing lub cev nqaij daim tawv thiab spatial activation ntawm lub cev tiv thaiv kab mob yog lub hauv paus rau kev ua kom muaj kev nyab xeeb thiab ntev-ntev anticancer nyhuv20.

Kev tiv thaiv kab mob qog noj ntshav feem ntau yog siv los ua haujlwm kom ntseeg tau tias nws mus txog tag nrho cov qog nqaij hlav. Txawm li cas los xij, qhov no tuaj yeem ua rau muaj kev tiv thaiv kab mob hnyav, xws li mob plab, raws plab, thiab endocrinopathy23,24. Yog li ntawd, lub hom phiaj thiab tshwj xeeb ua kom cov kab mob qog noj ntshav muaj feem xyuam rau lub cev yog qhov tseem ceeb.

Vim muaj kev sib koom tes ntawm cov kws kho mob, biologists, chemists, thiab cov kws tshawb fawb cov ntaub ntawv, nanomaterials tam sim no ua lub luag haujlwm tseem ceeb thiab muaj ntau yam hauv kev kho mob qog noj ntshav25e28. Nanomaterials tuaj yeem ua rau cov ntaub so ntswg mob qog noj ntshav piv rau cov tshuaj dawb me me, uas yog hu ua kev txhim kho permeability thiab khaws cia (EPR) effect29. Cov nyhuv EPR yog thawj zaug ntseeg tau los ntawm hyperpermeable qog vasculature thiab impaired lymphatic drainage30. Cov ntawv ceeb toom tsis ntev los no tau qhia tias feem ntau cov nanomaterials nkag mus rau cov ntaub so ntswg ntawm cov kab mob trans-endothelial active 31,32. Kev tshawb fawb ntxaws ntxiv ntawm cov txheej txheem ntawm EPR yuav ua rau cov khoom siv nano kom zoo rau kev ua kom muaj txiaj ntsig zoo hauv cov ntaub so ntswg. Raws li lub platform zoo tshaj plaws, nanomaterials tuaj yeem sib xyaw ua ke ntau yam tshuaj rau kev sib xyaw ua ke lossis cov tswv yim kho mob sib koom ua ke33,34, lub sijhawm no, ib feem ntawm lawv muaj lawv cov haujlwm, suav nrog photothermal35, photodynamic36, thiab sib nqus teb muaj peev xwm37. Tsis tas li ntawd, qee cov khoom siv nano tuaj yeem txhawb lub cev tiv thaiv kab mob, ib feem los ntawm kev txhawb nqa antigen thiab nthuav tawm los ntawm APCs38. Cov khoom ntawm nanomaterials no ua rau nws muaj peev xwm ua tau ib txhij qhib ob peb kauj ruam hauv kev tiv thaiv kab mob qog noj ntshav nrog qhov tseeb ntawm lub cev thiab lub cev, uas pab tswj kev tiv thaiv kab mob tiv thaiv kab mob thiab ua kom muaj zog tiv thaiv kab mob tiv thaiv kab mob los ntawm kev sib koom ua ke sib txawv ntawm cov txheej txheem tiv thaiv kab mob. Cov ntawv thov tam sim no ntawm nanomaterials hauv kev tiv thaiv kab mob qog noj ntshav suav nrog kev siv tshuaj yeeb (kev xa tawm ntawm apoptosis inducer, immunostimulants, photothermal lossis photodynamic molecules, ICB antibodies), cov ntaub ntawv ua haujlwm (induction ntawm photothermal lossis photodynamic txheej txheem), thiab immunomodulators. Qhov kev tshuaj xyuas no tau sau tseg cov txheej txheem tiv thaiv kab mob thiab kev paub txog kev tiv thaiv kab mob qog noj ntshav, lub sijhawm no tham txog kev nthuav dav ntawm kev siv nanomaterials los txhawb kev tiv thaiv kab mob qog noj ntshav raws li kev tiv thaiv kab mob qog noj ntshav. Thaum kawg, peb cia siab tias yuav txheeb xyuas qhov kev ua tiav los txhawb kev sib xyaw ua ke thiab siv cov khoom siv nano hauv kev kho mob qog noj ntshav.

2. Kev ua si ntawm kev mob qog noj ntshav thiab kev tiv thaiv kab mob

Cancer immunotherapy yog ib qho nyuaj interdisciplinary teb, koom nrog kev sib cuam tshuam thiab crosstalk ntawm cov qog thiab lub cev tiv thaiv kab mob ntawm ntau theem ntawm kev loj hlob qog noj ntshav. Nws tau pib ntseeg tias tsis muaj kev sib raug zoo ntawm kev tiv thaiv kab mob thiab kev txhim kho qog noj ntshav. Hauv ob peb lub xyoo dhau los, cov ntaub ntawv pov thawj ntau ntxiv tau tshaj tawm los txhawb kev koom tes ntawm kev tiv thaiv kab mob qog noj ntshav 39,40. Tsis tas li ntawd, mob qog noj ntshav tau pom tias muaj kev cuam tshuam rau kev tiv thaiv kab mob thiab ua rau lub cev tiv thaiv kab mob los yog tiv thaiv kab mob 41. Raws li cov kev tshawb pom no, ntau cov kev tshawb fawb tau tsom mus rau kev ua kom cov neeg mob lub cev tiv thaiv kab mob los yog siv lub zog tiv thaiv kab mob los saib xyuas, inhibit, thiab rov qab mob qog noj ntshav. Txawm li cas los xij, qhov cuam tshuam ntawm kev tiv thaiv kab mob qog noj ntshav tawm tsam ib feem ntawm cov txheej txheem tiv thaiv kab mob tuaj yeem cuam tshuam los ntawm kev thaiv lwm qhov ntawm cov txheej txheem tiv thaiv kab mob uas cuam tshuam los ntawm kev mob qog noj ntshav. Yog li ntawd, yuav tsum tau ceev faj kom paub meej txog kev nkag siab txog kev tiv thaiv kab mob cuam tshuam nrog kev txhim kho thiab kho mob qog noj ntshav.

2.1. Cancer - kev tiv thaiv kab mob

Kev tiv thaiv kab mob qog noj ntshav yog thawj zaug los ntawm Chen et al.20 hauv 2013. Nws piav qhia txog cov txheej txheem tiv thaiv kab mob ntawm tes tiv thaiv cov ntaub so ntswg. Nws suav nrog ob peb kauj ruam. Kauj Ruam 1, qog antigens raug tso tawm los ntawm cov qog nqaij hlav puas lawm thiab ntes los ntawm cov hlwb dendritic (DCs) rau kev ua haujlwm; Kauj Ruam 2, DCs nthuav tawm cov qog antigens rau MHCI thiab MHCII molecules ntawm T hlwb; Kauj Ruam 3, priming thiab ua kom cov nyhuv T cell teb; Kauj Ruam 4, effector T cells ncig mus rau cov qog; Kauj Ruam 5, effector T hlwb infiltrate rau hauv cov ntaub so ntswg; Kauj Ruam 6, effector T hlwb paub txog cov qog nqaij hlav cancer los ntawm TCR thiab MHC I complex; Kauj Ruam 7, effector T cells tua cov qog nqaij hlav cancer. Cov kauj ruam kawg ntawm kev tua kab mob qog noj ntshav pab txhawb rau kev tso tawm cov qog antigens los pib ib puag ncig tshiab ntawm kev tiv thaiv kab mob qog noj ntshav. Yog li ntawd, lub voj voog tiv thaiv kab mob qog noj ntshav tuaj yeem txhawb nqa tus kheej thaum pib. Lub voj voog tiv thaiv kab mob qog noj ntshav tseem ceeb qhia txog kev ua haujlwm tseem ceeb ntawm kev tiv thaiv kab mob ntawm tes hauv kev kho mob qog noj ntshav. Txawm li cas los xij, ntau cov pov thawj ua pov thawj tias kev tiv thaiv kev lom zem thiab kev tiv thaiv hauv lub cev ua lub luag haujlwm tseem ceeb hauv inhibiting mob qog noj ntshav43. Raws li tau piav qhia hauv daim duab 1, cov qog antigens los ntawm cov qog nqaij hlav cancer raug ntes los ntawm APCs. Raws li exogenous antigens, qog antigens yog endocytosed rau hauv endo nkaus xwb yog li qee lub tshuab feem ntau khi MHC II molecules uas nplua nuj nyob rau hauv endosome, uas ntxiv induce priming thiab ua kom cov CD4þ T hlwb. Txoj kev no yog classical humoral tiv thaiv kab mob, uas tua cov qog nqaij hlav cancer los ntawm antibody-antigen co-precipitation los yog antibody-dependent cell-mediated cytotoxicity (ADCC) kho los ntawm NK hlwb. Txawm li cas los xij, cov DCs tshwj xeeb, xws li CD8aþ DCs44, lossis cov xwm txheej tshwj xeeb, xws li endosome leakage ntawm qog antigens45, ua rau muaj kev nthuav tawm ntawm cov qog antigens. Nyob rau hauv qhov xwm txheej ntawm kev nthuav qhia, qog antigens uas muaj nyob rau hauv cytoplasm yog thauj los ntawm tus thauj khoom ntawm antigenic peptides (TAP) mus rau endoplasmic reticulum (ER), thiab muaj feem xyuam nrog cov tshiab MHC I molecules. Qhov kev nthuav qhia ntawm MHC I / antigen complex nws thiaj li ua rau ua kom CD8þ T hlwb. Yog li ntawd, peb tau hloov kho thiab nthuav dav cov ntsiab lus ntawm kev tiv thaiv kab mob qog noj ntshav hauv qhov kev tshuaj xyuas no (Daim duab 2). Peb tau piav qhia txog kev tiv thaiv kab mob qog noj ntshav raws li cov kauj ruam hauv qab no. (1) Tso cov qog antigens los ntawm cov hlwb puas lossis tuag; (2) uptake thiab nthuav qhia cov qog antigens los ntawm APCs; (3) priming thiab activation ntawm CD4þ thiab CD8þ T hlwb kom ua rau cov tshuaj tiv thaiv kab mob humoral thiab cellular tiv thaiv kab mob; (4) kev lag luam ntawm NK hlwb, qog cov tshuaj tiv thaiv kab mob tshwj xeeb, thiab CD8þ T hlwb; (5) infiltration thiab enrichment ntawm NK hlwb, qog antigen-specific antibodies, thiab CD8þ T hlwb rau hauv cov ntaub so ntswg cancer; (6) Kev lees paub thiab kev tshem tawm cov qog nqaij hlav cancer ntawm cytotoxicity ntawm CD8þ T hlwb thiab ADCC nyhuv kho los ntawm NK hlwb.

Daim duab 1 Adaptive immunity in cancer therapy. Kev tiv thaiv kab mob humoral: APCs nqa thiab nthuav tawm cov tshuaj tiv thaiv los ntawm MHC II molecules los qhib CD 4þ T hlwb; CD4þ T hlwb nthuav tawm antigens rau B hlwb, ua rau muaj kev tso tawm ntawm cov tshuaj tiv thaiv kab mob tshwj xeeb; antibodies koom nrog antigens thiab co-precipitate rau kev zom los ntawm macrophages los yog induce ADCC nyhuv kho los ntawm NK hlwb. Cellular immunity: Cov kab mob qog noj ntshav yog engulfed los ntawm APCs; APCs cross-tam sim no antigens rau naı¨ve CD8þ T hlwb los ntawm MHC I molecules, uas yog nrog los ntawm CTLA-4 qhia ntawm primed CD8þ T hlwb; primed CD8þ T hlwb paub cov qog nqaij hlav cancer ntawm MHC I / antigen complex thiab tua cov hlwb ntawm perforin, granzyme thiab Fas / FasL txoj hauv kev; Txawm li cas los xij, kev koom tes ntawm CTLA-4 lossis PD-1 nrog lawv cov ligands tuaj yeem ua rau muaj kev ua haujlwm tsis zoo ntawm primed CD8þ T hlwb.

2.2. Kev tiv thaiv kab mob thiab kev tiv thaiv kab mob hauv cov ntaub so ntswg

Kev sib raug zoo ntawm kev mob qog noj ntshav thiab kev tiv thaiv kab mob yog qhov nyuaj heev. Cov kev tshawb fawb tsis ntev los no tau qhia tias mob o tuaj yeem ua rau kev pib thiab kev loj hlob ntawm qog noj ntshav. Gene mutations los yog metabolite variations tshwm sim nyob rau hauv cov qog nqaij hlav cancer thaum lub sij hawm tumorigenesis. CD8þ T hlwb paub thiab rhuav tshem cov qog nqaij hlav cancer los ntawm kev saib xyuas cov kab mob txawv txav uas nthuav tawm los ntawm MHC I molecules ntawm cov qog nqaij hlav cancer, uas ua kom cov qog nqaij hlav tsawg tsawg uas xav tias kev hloov pauv tshwm sim hauv kwv yees li 107 e109 tib neeg lub hlwb txhua hnub. Feem ntau, cov txheej txheem tua CD8þ T hlwb ntawm cov qog nqaij hlav cancer tuaj yeem pib lub voj voog tiv thaiv kab mob qog noj ntshav thiab ua kom muaj txiaj ntsig zoo rau qhov tshwm sim ntawm qog noj ntshav. Txawm li cas los xij, CD8þ T hlwb qee zaum yog qhov muag tsis pom ntawm cov hlwb hloov pauv, uas yog hu ua lub cev tiv thaiv kab mob qog noj ntshav46. Tsis tas li ntawd, cov qog immunosuppressive macroenvironment tseem cuam tshuam kev ua haujlwm ntawm kev tiv thaiv kab mob qog noj ntshav. Cov laj thawj tseem ceeb ntawm kev tiv thaiv kev tiv thaiv kab mob thiab kev tiv thaiv kab mob tau sau tseg raws li hauv qab no (Daim duab 3).

(1) Kev xaiv lub cev tiv thaiv kab mob tso cai rau cov qog uas tsis muaj zog tiv thaiv kab mob kom dim ntawm kev tiv thaiv kab mob thiab xaiv cov kab mob proliferate47. Cov kab mob qog noj ntshav tshwm sim los ntawm cov kab mob oncogenic thiab cov tshuaj carcinogens yog cov tshuaj tiv thaiv kab mob thiab yooj yim tshem tawm los ntawm lub cev tiv thaiv kab mob, thaum cov qog nqaij hlav ntawm cov tsiaj dais tsis muaj zog immunogenicity thiab zoo li yuav khaws cia 48. (2) Antigen blockade lossis faus rau ntawm qhov chaw ntawm cov qog nqaij hlav cancer cuam tshuam rau kev lees paub thiab kev tawm tsam los ntawm lub cev tiv thaiv kab mob49. Qee cov qog nqaij hlav cancer overexpress mucopolysaccharides50, xws li sialic acid51 lossis glycoproteins52, tiv thaiv CD8þ T hlwb los ntawm kev lees paub cov tshuaj tiv thaiv los ntawm MHC I. Kev tshem tawm sialic acid tau pom los txhim kho cov tshuaj tiv thaiv kab mob qog noj ntshav53,54. (3) Kev txo qis ntawm MHC I molecules nyob rau saum npoo ntawm cov qog nqaij hlav cancer tuaj yeem txwv cov CD8þ T cell paub. Txawm li cas los xij, MHC I molecules kuj inhibit NK hlwb los ntawm kev khi cov neeg tua neeg-cell inhibitory receptors (KIR) ntawm NK hlwb. Qhov tsis muaj MHC I molecules activates NK hlwb los kho cov lysis lossis apoptosis ntawm cov qog nqaij hlav cancer57. Yog li ntawd, cov qog nqaij hlav cancer qhia cov tsis yog classical MHC I molecules (HLA-E thiab HLA-G) los koom nrog KIR thiab inhibit qhov kev ua ntawm NK cells58. (4) Disordered Fas qhia nyob rau saum npoo ntawm cov qog nqaij hlav qog nqaij hlav txwv lub peev xwm ntawm CD8þ T hlwb kom induce cancer cell apoptosis ntawm Fas/FasL pathway59. Tsis tas li ntawd, qee cov qog nqaij hlav overexpress thiab zais FasL los khi Fas molecules ntawm T hlwb thiab ua rau T cells60 tuag. (5) Cov kab mob qog noj ntshav secrete inhibitory yam tseem ceeb, xws li IL-10 thiab TGF-b txhawm rau txhawm rau tiv thaiv lub cev tiv thaiv kab mob61,62. Cov inhibitory molecules sib sau ua ke hauv cov ntaub so ntswg qog noj ntshav, ua kom muaj zog tiv thaiv kab mob microenvironment, uas ua rau tsis muaj zog thiab tua cov kab mob infiltrating 63. Tsis tas li ntawd, nyob rau hauv cov ntaub so ntswg cancer, stromal hlwb secrete indoleamine -2, 3- dioxygenase (IDO) los inhibit qhov kev loj hlob ntawm T cells64. IDO yog tus nqi-txheej enzyme rau tryptophan metabolism thiab tso tawm tryptophan nyob rau hauv microenvironment los inhibit effector T cell proliferation65. Cov cytokines uas muaj feem rau mob qog noj ntshav muaj nyob rau hauv Table 1 66e77. (6) Cov kab mob tiv thaiv kab mob muaj nyob hauv cov qog nqaij hlav, suav nrog mob qog noj ntshav nrog fibroblasts (CAFs), tswj T (Treg) hlwb, myeloid-derived suppressor cells (MDSCs), thiab M2-hom qog-associated macrophages (TAMs ). Mob qog noj ntshav, uas tuaj yeem suav hais tias yog qhov mob tsis zoo, tuaj yeem ua rau muaj kev raug mob zoo li cov lus teb, suav nrog kev ua kom txuas ntxiv ntawm fibroblasts. Thaum mob qog noj ntshav, cov qog nqaij hlav qog nqaij hlav qog nqaij hlav vascular endothelial loj hlob zoo (VEGF) thiab nrhiav cov fifi- fibroblasts, endothelial hlwb, thiab inflammatory cells.

Daim duab 2 Cancer-immunity cycle. (1) Tso cov qog antigens los ntawm cov hlwb puas lossis tuag; (2) uptake thiab nthuav qhia cov qog antigens los ntawm APCs; (3) priming thiab activation ntawm CD4þ thiab CD8þ T hlwb kom ua rau cov tshuaj tiv thaiv kab mob humoral thiab cellular tiv thaiv kab mob; (4) kev lag luam ntawm NK hlwb, qog cov tshuaj tiv thaiv kab mob tshwj xeeb, thiab CD8þ T hlwb; (5) infiltration thiab enrichment ntawm NK hlwb, qog antigen-specific antibodies, thiab CD8þ T hlwb rau hauv cov ntaub so ntswg cancer; (6) Kev lees paub thiab kev tshem tawm cov qog nqaij hlav qog noj ntshav los ntawm cytotoxicity ntawm CD8þ T hlwb thiab cov tshuaj tiv thaiv kab mob hauv cell-mediated cytotoxicity (ADCC) kho los ntawm NK hlwb. Tus tsim ntawm Fig. 2 tau tshwm sim los ntawm Fig. 1 ntawm Ref. 20 nrog kev tso cai txwv. Copyright ª 2013 Elsevier Inc. Fibroblasts thiab inflammatory cells yog cov khoom siv tseem ceeb ntawm tus tswv tsev-derived VEGF, uas tsim cov kab mob autocrine hauv cov ntaub so ntswg mob cancer78. Txawm li cas los xij, qhov txo qis ntawm fibroblast thiab hauv cov kab mob hauv lub cev ua haujlwm tau pom tom qab kho qhov txhab tsis tshwm sim hauv qog noj ntshav. (7) Cov chaw tiv thaiv kab mob

T-cell activation yuav tsum tau khi ntawm antigen-bound MHC I molecules rau TCRs thiab tswj los ntawm costimulatory los yog inhibitory signals, los yog kev tiv thaiv kab mob (Table 2). Immune checkpoint khub yog cov tswv yim tseem ceeb los ua kom nws tus kheej kam rau siab thiab tiv thaiv lub cev tiv thaiv kab mob los ntawm kev puas tsuaj rau cov ntaub so ntswg ib puag ncig thaum tiv thaiv kab mob. Cov tshuaj tiv thaiv kab mob kis tau "tus kheej" thiab "tsis txhob noj kuv" cov cim rau T hlwb. Cov kab mob qog noj ntshav khiav tawm ntawm lub cev tiv thaiv kab mob los ntawm kev txhim kho cov kab mob tiv thaiv kab mob. ICB cov tswv yim muab cov kev kho mob muaj zog los pab txhawb kev tiv thaiv kab mob qog noj ntshav. CTLA-4 tau nthuav tawm tseem ceeb hauv cov txheej txheem CD8þ T hlwb thiab sib koom B7 ligand nrog CD28. Kev koom tes ntawm B7 nrog CD28, nrog rau kev nthuav qhia antigen, activates naı¨ve T hlwb. Hloov pauv, kev khi ntawm B7 rau CTLA tiv thaiv T-cell ua kom. Kev tswj hwm ntawm CTLA-4 ntawm primed CD8þ T hlwb tiv thaiv kev tiv thaiv kab mob ntawm cov cellular overaction79. Txawm hais tias CTLA-4 feem ntau yog qhia rau ntawm CD8þ T cells, nws kuj tau pom ntawm Th thiab Treg cells80. Kev koom tes ntawm CTLA-4 ntawm Th cells txo Th kev ua haujlwm, thaum qhov kev qhia ntawm CTLA-4 ntawm Treg hlwb txhim kho lawv cov tshuaj tiv thaiv kab mob81. Lub luag haujlwm tseem ceeb ntawm PD-1 yog txhawm rau txwv T cell kev ua haujlwm hauv cov ntaub so ntswg peripheral hauv cov tshuaj tiv thaiv kab mob. Txawm li cas los xij, nws muaj kev tiv thaiv kab mob ua haujlwm thaum lub sijhawm mob qog noj ntshav. PD-1 tau qhia ntau yam qog-infiltrating lymphocytes (TILs), suav nrog CD8þ T, Treg, B, thiab NK cells82. Cov ligands ntawm PD-1 yog PD-L1 thiab PD-L2, uas feem ntau overex nias hauv cov qog nqaij hlav cancer83. Kev sib koom ua ke ntawm PD-1 thiab nws cov ligands tuaj yeem ua rau lub cev tsis ua haujlwm ntawm CD8þ T thiab NK hlwb. Txawm li cas los xij, PD-1 txhim kho kev loj hlob ntawm Treg hlwb nyob rau hauv muaj cov ligands 84. Hauv cov qog nqaij hlav, PD-L1 yog cov ligand loj ntawm PD-1. Txawm li cas los xij, theem ntawm PD-L1 qhia yog qhov sib txawv hauv cov qog nqaij hlav sib txawv, uas yuav yog qhov tseem ceeb thaum xav txog qhov ua tau ntawm cov tswv yim kho mob tiv thaiv PD-1 thiab PD-L1. Cov teebmeem tshuaj tiv thaiv kab mob ntawm CTLA-4 lossis PD-1 blockade tshwm sim los ntawm kev sib koom ua ke ntawm CD8þ T thiab NK cell activation thiab Treg cell inhibition.

Daim duab 3 Immunosuppression nyob rau hauv cov ntaub so ntswg cancer.

Table 1 Cancer-related cytokines.

2.3. Cancer immunotherapy restoring cancer tiv thaiv kab mob

Lub luag haujlwm ntawm lub cev tiv thaiv kab mob thaum pib mob qog noj ntshav, kev loj hlob, thiab metastasis tau txais kev saib xyuas ntxiv. Kev txheeb xyuas ntawm kev tiv thaiv kab mob qog noj ntshav koom nrog hauv kev mob qog noj ntshav tau txhawb nqa kev siv tshuaj tiv thaiv kab mob hauv cov neeg mob. Raws li kev tiv thaiv kab mob tiv thaiv kab mob tau ua ntau lub hom phiaj, cov txiaj ntsig kev kho mob ntawm cov neeg mob tau txais kev tiv thaiv kab mob qog noj ntshav tau maj mam txhim kho, lub sijhawm no, kev ruaj ntseg profile yog txhim kho. Feem ntau, cov tshuaj tiv thaiv kab mob qog noj ntshav uas ncaj qha rov pib dua lub voj voog tiv thaiv kab mob qog noj ntshav lossis txo cov tshuaj tiv thaiv kab mob hauv lub cev tiv thaiv kab mob qog noj ntshav, qhia tau tias muaj peev xwm tshem tau qog noj ntshav. Vim tias lub voj voog tiv thaiv kab mob qog noj ntshav tuaj yeem txhawb nqa tus kheej, txhua yam kev tiv thaiv kab mob uas txhawb nqa txhua kauj ruam ntawm kev tiv thaiv kab mob qog noj ntshav tuaj yeem ua tiav cov txiaj ntsig tiv thaiv tus kheej. Tam sim no siv cov tshuaj tiv thaiv kab mob qog noj ntshav los kho cov kab mob qog noj ntshav muaj xws li cov tshuaj tiv thaiv kab mob tsis muaj tshuaj tiv thaiv kab mob, tshuaj tiv thaiv kab mob monoclonal, kev kho ntawm tes (ACT), thiab tshuaj tiv thaiv qog noj ntshav.

2.3.1. Tsis yog tshwj xeeb immunotherapy (cytokines thiab immunostimulants)

Tsis yog cov tshuaj tiv thaiv kab mob tshwj xeeb, feem ntau suav nrog cytokines thiab immunostimulants, feem ntau ua rau lub cev tiv thaiv kab mob tiv thaiv kab mob qog noj ntshav. Cov tshuaj tiv thaiv kab mob tsis tshwj xeeb feem ntau muaj ntau yam txheej txheem los txhawb txoj kev tiv thaiv kab mob qog noj ntshav, suav nrog kev ua kom cov qog antigen uptake ntawm APCs, txhawb kev ua kom cov CD8þ T hlwb, thiab ua kom cov qog tiv thaiv kab mob los ntawm stimulating cytokines. Coley85 thawj zaug muab cov tshuaj tua kab mob (Coley's toxins) ua rau cov neeg mob qog noj ntshav thaum xaus ntawm lub xyoo pua puv 19. Coley cov co toxins hloov pauv cytokine qib thiab ua rau cov qog tshem tawm hauv qee cov neeg mob. Tom qab ntawd, ntau cov cytokines tau pom tias muaj cov tshuaj tiv thaiv kab mob, suav nrog IL-2, IFN-g, thiab GM-CSF86. IL-2 thiab IFN-g tau pom tias muaj peev xwm tiv thaiv qog noj ntshav. Txawm li cas los xij, kev siv tshuaj kho mob ntawm IL-2 thiab IFN-g yog cuam tshuam los ntawm kev mob toxicity tom qab kev tswj hwm kev tswj hwm 87. Fusing cytokines nrog cov hom phiaj cov protein tau pom tias yuav ua rau kom cov pob txha thiab txhim kho cov txiaj ntsig tom qab thaum txo cov kab mob toxicity88. Txawm li cas los xij, cov tswv yim fusion muaj qhov cuam tshuam rau cov cytokines sib txawv. Kev sib xyaw ntawm cov thev naus laus zis thev naus laus zis thiab cytokines muab cov tswv yim kho tshiab. Cov kab mob qog noj ntshav hloov nrog cytokine noob tau raug soj ntsuam raws li kev tiv thaiv kev tiv thaiv tom ntej nrog cov kab mob qog noj ntshav qus 89,90. Tsuas yog cov cytokines stimulatory, immunostain mutants, xws li agonists ntawm TLRs los yog STING protein, yog dav siv los ua kom muaj nuj nqi ntawm APCs91e93.

cistanche ntxiv cov txiaj ntsig

2.3.2. Monoclonal antibodies (mAbs)

Hauv kev tiv thaiv kab mob qog noj ntshav, cov tshuaj tiv thaiv kab mob monoclonal (mAbs) ua ib feem ntau ntawm US Food and Drug Administration (FDA)-pom zoo tshuaj. mAbs koom nrog cov hom phiaj ntawm kev sib raug zoo siab, uas ua kom qhov tseeb thiab ua haujlwm ntawm cov neeg ua haujlwm no. Tsis tas li ntawd, mAbs tuaj yeem kho ADCC ntawm NK hlwb, uas ntxiv txhawb kev tiv thaiv kab mob ntawm mAbs. Lub mAbs tsom rau kev tiv thaiv kab mob qog noj ntshav feem ntau yog muab faib ua ob pawg: cov tshuaj tiv thaiv kab mob tiv thaiv kab mob rau kev txo qis hauv kev tiv thaiv kab mob qog noj ntshav thiab tshuaj tiv thaiv kab mob sib txuas (ADCs) rau inducing tuag thiab antigen tso tawm ntawm cov qog nqaij hlav cancer. Lub hav zoov ntawm cov tshuaj tiv thaiv kab mob ntawm cov qog nqaij hlav qog nqaij hlav ua rau txo qis kev ua haujlwm ntawm kev tiv thaiv kab mob qog noj ntshav. Txhawm rau rov ua haujlwm ntawm primed CD8þ T hlwb, cov tshuaj tiv thaiv kab mob uas cuam tshuam kev koom nrog ntawm CTLA-4 lossis PD-1 nrog cov ligands tau kawm dav. Cov ntaub ntawv kho mob txhawb nqa kev sib raug zoo ntawm mAbs tawm tsam CTLA-4 (ipilimumab), PD- (nivolumab, pembrolizumab), thiab PD-L1 (ate zolizumab)94. Piv nrog CTLA-4 thiab PD-1 mAbs, PD-L1 mAbs tau pom tias muaj kev toxicity qis dua. Tsis ntev los no, ADCs tau nyiam, thiab peb hom ADCs tau ua lag luam txij li xyoo 2019. Cov tshuaj siv tshuaj niaj hnub tsis muaj kev xaiv thiab xav tau koob tshuaj ntau heev kom ua tiav cov txiaj ntsig kho. High-affinity antibodies tuaj yeem raug cuam tshuam nrog lawv lub hom phiaj. ADCs, tsim los ntawm cov tshuaj tiv thaiv kab mob "warhead", lub cleavable linker, thiab cov tshuaj cytotoxic, muab cov txiaj ntsig zoo ntawm cov tshuaj tiv thaiv kab mob thiab tshuaj lom neeg. Tam sim no pom zoo ADCs tsom biomarkers uas tau nthuav tawm ntau dhau ntawm cov qog nqaij hlav cancer, xws li HER-2, CD30, CD33, thiab CD2295. Txoj kev loj hlob ntawm ADC thev naus laus zis tau nthuav dav cov lus qhia rau cov kev kho mob no los ntawm leukemia mus rau cov kab mob malignancies. Enhertu, ADC tshiab, tau siv rau hauv cov neeg mob uas muaj HER{21}} lub mis zoo, plab, thiab cov qog nqaij hlav tsis me me, nrog lub hom phiaj teb (ORR) kwv yees li 60% 96. FDA pom zoo ADCs tau sau tseg hauv Table 3.

2.3.3. ACT

ACT suav nrog kev ua kom muaj zog thiab nthuav dav ntawm autologous lub cev tiv thaiv kab mob hauv vitro, uas tom qab ntawd muab rov qab rau hauv tus neeg mob txhawm rau txhim kho lub peev xwm tiv thaiv kab mob ntawm lub cev. ACT ncaj qha nqa tawm kev txheeb xyuas thiab tua cov qog nqaij hlav qog noj ntshav thiab rov pib lub voj voog tiv thaiv kab mob qog noj ntshav los ntawm kev muab ntau cov qog antigens. Cov hlwb effector ntawm ACT yog cov lymphokine-activated killer (LAK) cells97, cytokine-induced killer (CIK) cells98 qog-infiltrating lymphocytes (TIL), DC, NK, TCR-T, thiab CAR-T99. Hauv kev kho tsis yog ACT tshwj xeeb, cov tshuaj tiv thaiv kab mob hauv lub cev, suav nrog LAK, CIK, DC, thiab NK, tsis paub txog cov qog nqaij hlav tshwj xeeb thiab tsis muaj MHC I txwv. Txawm hais tias tsis yog tshwj xeeb ACT txoj kev kho mob tau pom zoo ua haujlwm tiv thaiv kab mob qog noj ntshav uas tsis muaj MHC I molecules, qhov muaj peev xwm toxicity rau cov ntaub so ntswg tsis tuaj yeem tsis quav ntsej. Cov tshuaj tiv thaiv kab mob hauv cov tshuaj ACT tshwj xeeb, suav nrog TIL thiab TCR-T, tuaj yeem paub cov qog antigens. Kev lees paub thiab kev ua kom tuag tom qab hauv cov qog nqaij hlav cancer yog nyob ntawm MHC I molecules. Vim yog MHC I txwv, TIL- thiab TCR-T-raws li kev kho mob tshwj xeeb ACT tsis muaj txiaj ntsig tiv thaiv cov qog nqaij hlav cancer uas tsis muaj MHC I. Txawm li cas los xij, CAR-T siv cov qauv tshuaj tiv thaiv kab mob-antigen los hloov kev koom tes ntawm TCR-CD3 nrog MHC I. /antigen complex, uas zam qhov kev txwv MHC kuv. Txawm li cas los xij, CAR-T tsuas tuaj yeem tsom cov qog nqaij hlav qog noj ntshav nrog cov tshuaj tiv thaiv saum npoo, thiab tsis yog cov uas muaj cov tshuaj tiv thaiv sab hauv. CAR-T kev kho mob pom zoo los ntawm FDA, xws li Kymriah thiab Yescarta, feem ntau yog tsom rau cov qog ntshav qog ntshav. Daim ntawv thov CAR-T rau cov qog nqaij hlav tseem nyuaj. Kev txheeb xyuas cov kab mob kheesxaws zoo dua qub thiab kev tsim qauv tsim nyog ntawm CAR yog qhov tseem ceeb rau kev ua tiav ntawm CAR-T txoj kev kho. Ntxiv mus, cov thev naus laus zis zoo sib xws tau siv hauv CAR-NK hlwb, uas tau siv ntau yam kev tshawb fawb ua ntej. Cov neeg mob uas muaj kabmob kheesxaws feem ntau muaj lub cev tsis muaj zog, nrog rau cov kev txwv ntawm tus lej thiab kev ua haujlwm ntawm tus kheej-lymphocytes. Yog li ntawd, kev loj hlob ntawm lymphocytes los ntawm lwm qhov chaw yog suav hais tias yog ib qho kev tawg. Tsis ntev los no, induced pluripotent qia cell (iPSC) thev naus laus zis tau nthuav dav cov peev txheej thiab cov koob tshuaj ntawm cov lymphocytes thawj. Tej zaum vim yog lub cim xeeb ntawm epigenetic, piv rau cov hlwb somatic, iPSCs los ntawm cov ntshav qaum los yog cov ntshav lymphocytes peripheral nce qhov ua tau zoo ntawm CD4þ CD8þ lymphocyte ntau lawm101. CAR-T lossis CAR-NK cov kev kho mob raws li iPSCs tau pom muaj txiaj ntsig zoo rau cov neeg mob uas muaj B-cell malignancies thiab qog noj ntshav zes qe menyuam102. Tsis tas li ntawd, universal CAR-T kov yeej cov kev txwv uas cuam tshuam nrog lub xov tooj ntawm tes, muab ACT siv tau dav dav yam tsis muaj HLA-hloov. Yog li, MHC I, MHC II, thiab TCR cov molecules raug tshem tawm kom tsis txhob muaj kev hloov pauv lossis kev cuam tshuam ntawm kev cog qoob loo los ntawm kev kho cov noob laus. Tsis tas li ntawd, HLA-E lossis HLA-G kuv tau qhia kom tsis txhob muaj kev tiv thaiv kab mob los ntawm cov neeg mob NK cells103. Cov kev sim tshuaj ntsuam xyuas iPSC-derived ACT lossis universal CAR- kev kho mob tseem tab tom ua tam sim no.

2.3.4. Cov tshuaj tiv thaiv kab mob cancer

Cov qog pib thiab kev loj hlob feem ntau yog nrog los ntawm kev hloov pauv caj ces, uas tsim cov antigens tshwj xeeb uas txawv ntawm cov hauv ib txwm muaj autologous hlwb. Kev tso tawm ntawm cov qog antigens yuav tsum pib ua lub voj voog tiv thaiv kab mob qog noj ntshav. Txawm li cas los xij, qhov tsis muaj peev xwm ntawm APCs hauv cov qog microenvironment lossis qhov tsis muaj kev tiv thaiv kab mob ntawm cov qog antigens cuam tshuam rau kev ntes thiab nthuav tawm cov qog antigens. Cov tshuaj tiv thaiv kab mob qog noj ntshav, uas muaj cov qog antigens thiab adjuvants, lub hom phiaj kom kov yeej cov qog nqaij hlav hauv ib puag ncig, txhim kho lub cev tiv thaiv kab mob ntawm cov qog antigens, qhib autologous cellular thiab humoral kev tiv thaiv, thiab yog li tswj lossis tshem tawm cov qog nqaij hlav 104. Kev lig kev cai, cov tshuaj tiv thaiv kab mob qog noj ntshav tau suav nrog tag nrho cov cell (cov tshuaj tiv thaiv kab mob qog noj ntshav thiab cov tshuaj tiv thaiv DC), peptide, thiab tshuaj tiv thaiv nucleic acid. Nrog rau kev txhim kho tsis ntev los no hauv cov noob caj noob ces thiab bioinformatics, tus kheej qog neoantigens tuaj yeem txheeb xyuas tau sai- fified105. Cov txheeb ze rau qog-uas cuam tshuam cov antigens, neoantigens tau muab los ntawm cov qog nqaij hlav qog nqaij hlav thiab yog li ntawd, tag nrho cov antigens tshiab. Cov neoplastic neoantigens no feem ntau yog cov kab mob polypeptide uas muaj peev xwm khi nrog HLA; Txawm li cas los xij, lawv cov tshuaj tiv thaiv kab mob tsis paub meej thiab yuav tsum tau txiav txim siab hauv vivo kev sim. Cov tshuaj tiv thaiv Peptide thiab mRNA tshuaj tiv thaiv raws li neoantigens tuaj yeem ua rau muaj kev tiv thaiv kab mob qog noj ntshav thiab tiv thaiv kab mob ntawm tes14,106. Kev tshawb fawb tob txog kev tuag ntawm cov qog nqaij hlav cancer tau pom tias qee cov qog nqaij hlav cancer tuaj yeem ua rau lub cev tiv thaiv kab mob tom qab tuag, uas yog hu ua immunogenic cell death (ICD). Thaum cov qog nqaij hlav qog noj ntshav tuag ib txwm, lawv cov tshuaj tiv thaiv kab mob thiab cov tshuaj tiv thaiv immunostimulatory tau degraded los ntawm txoj kev apoptosis. Thaum lub sij hawm ICD, cov qog nqaij hlav cancer nthuav tawm lawv cov antigens thiab tso tawm cov qauv kev puas tsuaj nrog rau cov qauv molecular (DAMPs), suav nrog ATP, pab pawg neeg muaj zog protein ntau 1 (HMGB1), thiab calreticulin107. Cov DMAPs no ua rau muaj kev nce ntxiv thiab nthuav tawm cov qog antigens los ntawm APC hlwb, yog li ua rau muaj kev tiv thaiv kab mob. Hauv cov tshuaj tiv thaiv kab mob qog noj ntshav raws li txheej txheem ICD tau nthuav tawm cov txheej txheem tshuaj tiv thaiv kab mob tshiab ntawm cov tshuaj kws khomob, xws li doxorubicin (DOX)109. Tsis tas li ntawd, ntau txoj kev kho mob kheesxaws sab nraud, xws li kev kho mob photothermal, photodynamic therapy, thiab radiotherapy, tau pom tias yuav ua rau ICDs hauv cov qog nqaij hlav cancer. Txawm li cas los xij, cov txiaj ntsig ntawm cov tshuaj tiv thaiv hauv situ tsis tau lees paub, thiab nws nyob ncaj qha rau ntawm qhov immunogenicity ntawm qog antigens. Cov qog nqaij hlav uas muaj kev hloov pauv ntau dua muaj cov lus teb ntau dua rau cov tshuaj tiv thaiv hauv tsev. Tsis tas li ntawd, cov tshuaj tiv thaiv kab mob qog noj ntshav uas ua kom muaj zog tiv thaiv kab mob ntawm tes muaj txiaj ntsig zoo los tiv thaiv kab mob. Kev nthuav qhia ntawm APCs rau exogenous qog antigens yog qhov tseem ceeb rau kev ua kom lub cev tiv thaiv kab mob. Cov tshuaj tiv thaiv kab mob qog noj ntshav uas tuaj yeem tsom CD8aþ DCs hauv cov qog ntshav qog lossis tso cov qog qog ntshav los ntawm endo nkaus xwb yog li qee qhov system mus rau cytoplasm, provoke cross-presentation ntawm APCs thiab zoo dua anticancer cellular tiv thaiv.

Table 3 FDA pom zoo ADCs rau kev kho mob qog noj ntshav.

3. Nanomaterials provoking mob qog noj ntshav - kev tiv thaiv kab mob

Nanomaterials muaj ntau yam zoo, xws li qhov loj me, biocompatibility siab, thiab muaj peev xwm thauj khoom zoo heev. Raws li cov txheej txheem hauv qab ntawm kev tiv thaiv kab mob qog noj ntshav tau maj mam nthuav tawm, cov khoom siv nano yuav tsum muaj peev xwm los txhim kho ntau yam ntawm kev kho mob qog noj ntshav raws li kev tiv thaiv kab mob qog noj ntshav. Lub hom phiaj muaj peev xwm ntawm nanomaterials tuaj yeem ua kom ntseeg tau tias cov kauj ruam sib txawv ntawm kev tiv thaiv kab mob qog noj ntshav tau qhib nrog lub cev thiab qhov chaw, uas txo cov kev mob tshwm sim thaum ua kom muaj kev tiv thaiv kab mob tiv thaiv kab mob. Kev txheeb xyuas cov teebmeem EPR ua rau cov khoom siv nanomaterials (20e200 nm) yog ib tus khub tsim nyog rau kev xa tshuaj mob qog noj ntshav110. Kev siv cov khoom siv nanomaterials raws li cov neeg nqa khoom tuaj yeem txhawb kev tiv thaiv kab mob hauv cov ntaub so ntswg los txhim kho lub cev tiv thaiv kab mob thiab txo cov kab mob toxicity. Tsis tas li ntawd, nanomaterials nrog qhov loj me ntawm 25 nm feem ntau yuav tsom rau cov qog ntshav qab zib, uas ua rau muaj zog tiv thaiv kab mob ua rau raug mob los ntawm cov tshuaj tiv thaiv kab mob cancer111,112. Ntxiv nrog rau kev koom tes hauv kev tiv thaiv kab mob qog noj ntshav raws li cov neeg nqa tshuaj, cov khoom siv nano ntau ntxiv tau qhia los kho cov kev kho mob sab nraud, suav nrog kev kho mob photothermal thiab photodynamic, uas ua rau ICD hauv cov qog nqaij hlav qog noj ntshav los tsim cov tshuaj tiv thaiv kab mob hauv tsev thiab rov pib tiv thaiv kab mob qog noj ntshav. Tsis tas li ntawd, ib feem nanomaterials tau pom cov txiaj ntsig tshwj xeeb adjuvant, uas tuaj yeem txhawb lub cev kom tsim tau lub zog tiv thaiv kab mob thiab txo qis kev tiv thaiv kab mob qog noj ntshav. Cov hauv qab no yuav qhia meej txog yuav ua li cas nanomaterials li cov neeg nqa tshuaj, ICD inducers, thiab cov tshuaj tiv thaiv kab mob tiv thaiv kab mob tiv thaiv kab mob raws li kev tiv thaiv kab mob cancer. Ntau yam kev ua haujlwm ntawm nanomaterials nce qhov muaj peev xwm ntawm kev tsim kho mob qog noj ntshav combinatorial immunotherapy rau ib txhij tsom mus rau ob peb kauj ruam ntawm kev tiv thaiv kab mob qog noj ntshav kom ua tiav cov txiaj ntsig tiv thaiv kab mob ntau dua (Fig. 4).

cistanche ntxiv cov txiaj ntsig-yuav ua li cas ntxiv dag zog rau lub cev

3.1. Drug delivery platform

Hauv kev tiv thaiv kab mob qog noj ntshav, nanomaterials tau siv dav rau lub hom phiaj thiab txhawb kev tiv thaiv kab mob tiv thaiv kab mob lossis tshuaj tiv thaiv kab mob qog noj ntshav hauv cov ntaub so ntswg lossis cov ntaub so ntswg tiv thaiv kab mob (xws li cov qog ntshav qog). Cov tshuaj enriched txhim khu lub cev tiv thaiv kab mob ua kom lub cev tiv thaiv kab mob vim muaj kev nce siab ntxiv thiab tseem txwv kev puas tsuaj rau cov ntaub so ntswg los ntawm lub cev tiv thaiv kab mob. Nanomaterials uas tsom cov qog nqaij hlav cancer thiab cov qog nqaij hlav tuaj yeem muab faib ua cov neeg ua haujlwm nquag thiab nquag, raws li cov txheej txheem siv. Passive targeting vam khom ntawm cov khoom tshwj xeeb nanomaterials los ntawm cov ntaub so ntswg mob qog noj ntshav lossis cov qog nqaij hlav, thaum lub hom phiaj tseem ceeb feem ntau vam khom ntawm overexpression ntawm receptor molecules. Piv txwv li, av-integrins los yog folate receptors yog overexpressed nyob rau hauv ib co qog nqaij hlav cancer, thiab cov av-integrin ligand (iRGD) los yog folic acid tuaj yeem hloov kho ntawm cov khoom siv nanomaterials kom ua tiav lub hom phiaj nquag. Mannose receptors yog overexpressed nyob rau saum npoo ntawm APCs nyob rau hauv lymph nodes. Yog li ntawd, mannose tuaj yeem hloov kho ntawm nanomaterials rau lub hom phiaj APCs. Cancer tsom rau nanomaterials feem ntau yog ntim nrog cov tshuaj tiv thaiv kab mob uas tuaj yeem kov yeej lub cev tiv thaiv kab mob microenvironment, suav nrog cytokines, tshuaj tiv thaiv kab mob, thiab ICB cov tshuaj tiv thaiv. Nanomaterials uas tsom cov qog ntshav qab zib feem ntau yog thauj cov qog antigens los txhawb kev ua haujlwm thiab kev nthuav tawm ntawm antigens los ntawm DCs, thiab ua kom mob qog noj ntshav tshwj xeeb CD8þ T hlwb hauv cov qog ntshav. Kev txheeb xyuas thiab kev loj hlob ntawm ICD inducers tau coj mus rau kev siv nanomaterials los thauj cov neeg ua haujlwm rau cov ntaub so ntswg cancer. Tsis tas li ntawd, kev sib xyaw ua ke ntawm cov immunomodulators sib txawv hauv nanomaterials yuav ntxiv dag zog rau kev kho mob qog noj ntshav.

3.1.1. Cytokines thiab immunostimulants

Kev tswj hwm ntawm cov cytokines dawb thiab immunostimulants ua rau lub cev tsis muaj zog tiv thaiv kab mob. Cancer-targeted nanomaterials tuaj yeem txwv kev tiv thaiv kab mob tshwm sim hauv cov ntaub so ntswg. Tom qab kev sib sau ua ke ntawm cov tsis muaj molecular-yuag poly ethyleneimine (600 Da), kev sib txuas nrog b-cyclodextrin thiab IL-2 noob, thiab koom nrog folate, polymeric nanoparticles txog 100 nm inch, tau pom tias ua kom muaj kev ua haujlwm ntawm CD4þ T cells, CD 8þ T cells thiab NK cells, ua rau muaj kev rov qab los ntawm B16eF1 melanoma grafts113. Kev sib xyaw ua ke ntawm IL{11}} noob, IL{12}} noob, endosomally cleavable lipid, thiab endosomally cleavable RGD peptide generated nanoparticles kwv yees li 100 nm loj, uas ua rau muaj zog leukocyte infiltration thiab necrotic cancerous cheeb tsam114. Tsis tas li ntawd, loading IL-2-fused Fc proteins thiab agonistic CD137 antibody ntawm liposomes tuaj yeem khaws cov tshuaj tiv thaiv kab mob qog noj ntshav ntawm IL-2 thiab cov tshuaj tiv thaiv kab mob agonistic CD137, thaum txo cov kab mob toxicity tshwm sim los ntawm circulating leukocytes115 (Daim duab . 5). Tsuas yog cytokines, nanomaterials ua ke nrog immunostimulants xyuas kom lub zos ua kom cov qog-infiltrating leukocytes. Intravenous tswj ntawm cyclic-di GMP-loaded cationic lipids tau pom tias ua kom muaj txiaj ntsig ntawm kev tsim cov interferon (IFN) thiab ua kom cov NK hlwb, uas inhibited ntsws metastasis hauv B16-F10 xenograft nas model116. Tsis tas li ntawd, immunomodulator-loaded nanomaterials muaj peev xwm los tsom rau cov qog nqaij hlav qog noj ntshav. Piv txwv li, nanoparticles loaded nrog TLR7 / 8 agonist tshwj xeeb yog tsom rau DCs hauv cov ntaub so ntswg qog noj ntshav thiab tso cov qog ntshav los ntawm kev tsom mus rau qhov tsis zoo vim qhov cuam tshuam loj. PLGA-PEG polymeric nanomaterials txuam nrog anti-PD-1 antibody (aPD1) lossis CD8 antibody tau pom tias tshwj xeeb khi rau PD-1 zoo CD8þ T cells. Cov PLGA-PEG polymeric nanomaterials tau pom tias xa TGF-b inhibitors, thim rov qab cov nyhuv ntawm TGFb ntawm CD 8þ T cells118. Zoo sib xws nanoparticles dai kom zoo nkauj nrog aPD1 tau siv los xa cov NF-kB inhibitor rau PD-1 zoo TILs kom txo qis kev tsim tawm ntawm IL-10 thiab TGF-b, yog li txo qhov kev tiv thaiv kab mob119.

3.1.2. mAbs

ICB, txoj kev kho mAb ua tau zoo tshaj plaws siv hauv kev tiv thaiv kab mob qog noj ntshav, ua rau ob qho tib si TIL thiab cov hlab ntshav leukocytes, uas ua rau muaj kev tiv thaiv mob qog noj ntshav nrog rau kev mob autoimmune. Nanomaterials tuaj yeem thauj ICB cov tshuaj tiv thaiv mus rau cov ntaub so ntswg mob qog noj ntshav thiab ua kom muaj tshuaj lom. Tus kheej-degradable microneedles encapsulating aPD1 tau pom tias tso aPD1 rau cov ntaub so ntswg melanoma thiab cuam tshuam kev mob qog noj ntshav. Ntxiv nrog rau kev tso tawm kev tswj hwm, nanomaterials kuj tso cai rau ICB cov tshuaj tiv thaiv nrog ntau yam cuam tshuam, uas ntxiv dag zog rau kev sib cuam tshuam ntawm cov tshuaj tiv thaiv thiab lawv lub hom phiaj. Kev tsim kho ntawm multivalent anti-PD-L1 antibody (aPD-L1) los ntawm conjugating aPD-L1 nrog hyperbranched poly-(amidoamine) dendrimers, txhim khu kev khi avidity nrog PD-L1 rau-fold piv nrog dawb aPD-L1121. Ntxiv mus, fusion ntawm recombinant scFv ntawm aPD1 nrog lub cev tiv thaiv kab mob elastin-zoo li polypeptide (iTEP) ua rau nws tus kheej ua ke ntawm aPD1 nanoparticles, uas thaiv cov PD-1 lub cev tiv thaiv kab mob hauv vitro thiab hauv vivo122. Tsis tas li ntawd, nanoparticles co-loaded nrog mAbs sib txawv, xws li aPD1 thiab anti-OX40 antibody (aOX40) tau ua kom pom kev sib koom ua ke thiab txhim kho cov txiaj ntsig anticancer piv rau ob cov tshuaj tiv thaiv dawb dawb 123 (Fig. 6).

Daim duab 4 Nanomaterials tsom ntau theem ntawm kev tiv thaiv kab mob qog noj ntshav ib leeg lossis ib txhij. Tam sim no siv nanomaterials feem ntau induce ICD ntawm cov qog nqaij hlav cancer, txhawb cov antigen uptake thiab maturation ntawm APCs, txhim kho tus ntoo khaub lig-presentation ntawm APCs, thiab tswj lub immunosuppressive microenvironment ntawm cov ntaub so ntswg cancer.

3.1.3. Tshuaj tiv thaiv kab mob

Tumor antigens thiab adjuvants yuav tsum tau txhaj tshuaj tiv thaiv kabmob kheesxaws. Cov khoom xyaw, xws li immunostimulants, tuaj yeem txhim kho kev tiv thaiv kab mob qog noj ntshav ntxiv. Nanomaterials yog multifunctional platforms uas muab ntau yam zoo rau kev tsim cov tshuaj tiv thaiv kabmob kheesxaws, raws li hauv qab no124,125: (1) lub peev xwm rau ib txhij xa cov tshuaj tiv thaiv sib txawv rau tib APCs los txhawb kev tiv thaiv kab mob tshwj xeeb; (2) txhawb cov tshuaj tiv thaiv kabmob kheesxaws rau APCs hauv cov qog ntshav lossis cov qog nqaij hlav cancer los ntawm kev ua haujlwm tsis zoo lossis lub hom phiaj ua haujlwm; (3) kho qhov loj me thiab ntau qhov cuam tshuam ntawm cov tshuaj tiv thaiv kab mob qog noj ntshav kom ua rau muaj zog tiv thaiv kab mob; (4) kev tswj hwm thiab kev tso tawm ntawm cov qog antigens kom ntseeg tau tias lub sijhawm ntev ntawm kev tiv thaiv kab mob; (5) cytosolic xa cov qog antigens los txhawb kev nthuav tawm ntawm APCs kom ua tau zoo tshaj plaws naı¨ve CD8þ T hlwb. Tumor-associated antigens (TAAs) thiab cov qauv antigens tau siv dav rau kev txheeb xyuas thawj zaug thiab tsim cov tshuaj tiv thaiv kabmob kheesxaws txij li kev txheeb xyuas cov qog nqaij hlav tshwj xeeb yog qhov nyuaj. Raws li TAAs thiab qauv antigens (xws li ovalbumin, thiab OVA), ntau cov nanoparticles tau siv los tsim cov tshuaj tiv thaiv kab mob qog noj ntshav. Piv txwv li, biodegradable PLGA126, (LCP) nanoparticles127, glutathione-depletion mesoporous organosilica nanoparticles128, thiab protein nanoparticles129 tau ua tiav TAAs thiab qauv antigens, thiab tau pom los kho cov qog antigen-specific tiv thaiv. Tom qab qhov kev tshawb pom tias DCs ua lub luag haujlwm tseem ceeb hauv kev txhawb nqa thiab tuav cov tshuaj tiv thaiv kabmob kheesxaws, ntau cov tshuaj tiv thaiv kabmob kheesxaws tau tsim los rau lub hom phiaj DCs130. Piv txwv li, golden nanoparticles kwv yees li 14 nm hauv qhov loj me tau siv los thauj cov protein fluorescent liab (RFP) ua qauv antigen thiab CPG-ODN raws li adjuvants. Cov qauv tsim tau ua rau muaj kev nplua nuj ntawm nanoparticles hauv cov kua dej ntws tawm, lub siab titer ntawm cov tshuaj tiv thaiv RFP antibody, thiab cov regression ntawm RFP-expressing B16-F10 hlav131. Tsis tas li ntawd, DC-targeting molecules, xws li mannose lossis CD40 antibodies, feem ntau hloov kho ntawm nanoparticles xa cov tshuaj tiv thaiv kab mob qog noj ntshav rau DCs. Piv txwv li, PLGA-nanoparticles uas muaj Pam3CSK4, Poly (I: C), thiab OVA, tau cuam tshuam nrog cov tshuaj tiv thaiv CD40, uas ua rau muaj cov tshuaj tiv thaiv zoo rau DCs thiab ua kom muaj zog ntawm CD8þ T cells132. Raws li qhov xwm txheej ib txwm muaj, DCs nthuav tawm cov tshuaj tiv thaiv rau CD4þ T hlwb txhawm rau ua kom muaj kev tiv thaiv kab mob tom qab engulfing exogenous antigens. Txawm li cas los xij, kev tiv thaiv ntawm tes tau yooj yim los ntawm kev nthuav qhia ntawm DCs nrog kev pab ntawm MHC I molecules sawv cev rau kev tiv thaiv kab mob tiv thaiv kab mob ntau dua. Nanomaterials uas muaj peev xwm xa cov qog antigens rau hauv cytoplasm zoo heev txhim kho qhov tshwm sim thiab kev ua tau zoo ntawm kev nthuav qhia. Cov ntaub ntawv pov thawj zoo, xws li polyethyleneimine (PEI) thiab chitosan/calcium phosphate nanosheets, tau pom tias ua rau qhov kev khiav tawm ntawm cov khoom thauj ntawm cov khoom siv proton sponge effect45,133. Nanomaterials loaded nrog endosomal-kev cuam tshuam cov neeg ua haujlwm, xws li pore-forming peptides, tuaj yeem kho qhov kev khiav tawm ntawm cov khoom xa tuaj. Piv txwv li, Kong thiab Liu li al.134 tsim cov tshuaj tiv thaiv nano los ntawm kev thauj khoom PLGA nrog OVA thiab hydroxychloroquine (HCQ). HCQ induced membrane permeabilization ntawm endosome thiab txhawb kev tso tawm ntawm OVA. Piv rau PLGA/OVA nanoparticles, nano tshuaj tiv thaiv tau txhim kho qhov kev qhia ntawm MHC-I thiab cov costimulatory molecule CD86 ntawm BMDCs, nce qhov zaus ntawm IFN-gþ CD8þ T hlwb, IFN-gþ CD4þ T hlwb, thiab lub hauv paus nco. T hlwb, thiab txhawb nqa qhov tseem ceeb regression ntawm cov qog. Xyoo 2019, Xu et al.135 tau tsim dua lwm cov tshuaj tiv thaiv nano uas yooj yim rau kev nthuav tawm los ntawm kev thauj khoom OVA thiab CpG-ODN ntawm polyamide dopamine dendrimer hloov nrog guanidino benzoic acid (DGBA). Cov tshuaj tiv thaiv nano no tau ua rau muaj zog tiv thaiv kab mob tshwj xeeb ntawm tes thiab tiv thaiv qhov rov sib tw ntawm B16-OVA melanoma. Ntxiv mus, cov tshuaj tiv thaiv nano no tau pom tias muaj kev tiv thaiv kab mob tiv thaiv kab mob B16-OVA melanomas thaum ua ke nrog ICB lub tswv yim ntawm aPD-1. Tom qab kev loj hlob ntawm kev txheeb xyuas thev naus laus zis rau neoantigens, mob qog noj ntshav neoantigens tam sim no tau siv los tsim cov tshuaj tiv thaiv kab mob qog noj ntshav. Nanodiscs coated nrog neoantigens thiab CPG-ODN tau pom tias ua kom muaj cov kab mob qog nqaij hlav hauv nruab nrog cev thiab txhawb nqa mus txog 47-fold ntau neoantigen-specific CTLs dua li cov tshuaj tiv thaiv soluble136. Tsis tas li ntawd, kev siv T7 bacteriophages ua nanocarriers rau kev qhia ntawm neoantigens tuaj yeem tau txais cov tshuaj tiv thaiv nano uas muaj ntau hom neoantigens. Cov tshuaj tiv thaiv nano no tau tshaj tawm cov lus siab ntawm cov tshuaj tiv thaiv neoantigen thiab B cell teb.

Daim duab 5 Liposomes anchoring IL-2-fused Fc thiab agonistic CD137 antibody ua rau muaj kev tiv thaiv kab mob qog noj ntshav yam tsis muaj kab mob toxicity. (A) Cryo-TEM duab ntawm IL-2-Fc-liposome (anti-CD137 liposomes zoo ib yam). (B) CD8þ T cell suav tau txiav txim tom qab kev kho mob polyclonal T hlwb los ntawm C57Bl/6 nas nrog soluble lossis liposomal IL-2-Fc (10 ng/mL ntawm cov protein). (C) secreted IFN-g tau soj ntsuam thiab tom qab ntawd qhib T hlwb raug tsim nrog soluble anti-CD137 lossis Lipo-aCD137 (qhov kawg ntawm aCD137 concentration: 10 mg / mL). (D) khov seem ntawm cov qog tom qab txhaj tshuaj ntawm Alexa-568-labeled aCD137 thiab IL-2-Fc thiab Lipo-aCD137 þ Lipo-IL2-Fc. (E) cov qog loj hauv C57Bl/6 nas tom qab kho nrog aCD137 þ IL-2-Fc, Lipo-aCD137 þ Lipo-IL-2-Fc, lossis Lipo-IgG. (F) Bioluminescence cov duab ntawm C57BL/6 nas nqa cov qog luciferase-expressing B16F10, tom qab kho nrog Lipo-aCD137 þ Lipo-IL-2-Fc lossis Lipo-IgG. Reprinted nrog kev tso cai los ntawm Ref. 115. Copyright ª 2019 Nature Publishing Group.

Daim duab 6 A dual immunotherapy nanoparticle targeting PD-1 thiab OX40 txhim kho kev tiv thaiv kab mob. (A) Schematic ntawm DINP-fais fab kev txhim kho ntawm kev sib xyaw ua ke immunotherapy. (B) dluab ntawm nanoparticles ua ntej thiab tom qab antibody conjugation (scale bar: 100 nm). (C) qog loj thiab ciaj sia nkhaus ntawm C57BL/6 nas nrog B16F10 cov qog tom qab kho nrog cov tshuaj sib txawv. (D) immunofluorescent duab ntawm cov qog tom qab kho nrog cov tshuaj sib txawv. Reprinted nrog kev tso cai los ntawm Ref. 123. Copyright ª 2018 WILEY-VCH Publishing Group.

3.2. Cov khoom siv ua haujlwm raws li ICD inducer

Hom thiab kev ua haujlwm ntawm nanomaterials muaj ntau haiv neeg. Lawv tuaj yeem siv los ua cov khoom siv tshuaj (xws li liposomes, mesoporous silicon, thiab polymers), thiab tseem muaj ntau yam haujlwm, xws li cov teebmeem photothermal, photodynamic teebmeem, tshuaj kinetic teebmeem, teebmeem magnetothermal, thiab cov teebmeem hluav taws xob. Ib feem ntawm nanomaterials nrog cov haujlwm no tau pom tias ua rau ICD hauv cov qog nqaij hlav cancer, yog li tso cov qog antigens thiab DMAPs151. Kev sib xyaw ua ke ntawm cov khoom siv nano nrog cov tshuaj tiv thaiv kab mob ib txwm muaj, xws li immunostimulants thiab tshuaj tiv thaiv kab mob tiv thaiv kab mob, muaj peev xwm ua tau zoo txhawb nqa ob peb kauj ruam ntawm kev tiv thaiv kab mob qog noj ntshav thiab thaum kawg ua tiav cov txiaj ntsig zoo tiv thaiv kab mob. Cov nram qab no ntawm qhov kev tshuaj xyuas no yuav qhia txog photothermal, photodynamic, radiotherapeutic, hemodynamic, thiab lwm yam kev ua haujlwm nanomaterials, thiab sib tham txog lawv cov kev siv hauv kev kho mob qog noj ntshav raws li kev tiv thaiv kab mob qog noj ntshav.

cistanche cov txiaj ntsig rau txiv neej-ua kom muaj zog tiv thaiv kab mob

3.2.1. Photothermal nano khoom

Photothermal agents (PTAs) hloov lub teeb lub zog rau hauv thermal zog. PTA nanomaterials feem ntau muab faib ua hlau-raws li inorganic agents, carbon-based inorganic agents, phosphorene-based agents, polymeric agents, thiab lwm yam tshiab PTAs152e154. Hlau-raws li inorganic PTAs suav nrog cov khoom siv hlau zoo tib yam (xws li Au, Ag, Pd, thiab Pt) thiab cov khoom siv semiconductor (muaj CuS, MoS2, thiab WS2). Hlau-raws li inorganic PTAs tau yooj yim synthesized nrog adjustable qhov ntau thiab tsawg thiab cov duab tab sis muaj qhov tsis zoo xws li qeeb metabolism npaum li cas thiab tsis paub meej txog lub sij hawm ntev toxicity profiles. Carbon-based inorganic PTAs yog tsim los ntawm graphene, carbon nanotubes, thiab fullerene. Thaum cov pa roj carbon-based inorganic PTAs muaj kev ua haujlwm siab photothermal hloov dua siab tshiab thiab ruaj khov, lawv muaj peev xwm ua rau mob ntsws thiab nyuaj rau tsim tawm ntawm qhov loj. Phosphorene-raws li PTAs, tshiab tsim nanomaterials, muaj ob-dimensional dub phosphorene thiab dub phosphorous quantum dots. Phosphorene-raws li PTAs muaj siab photothermal conversion efficiency thiab zoo heev biodegradation zog. Txawm li cas los xij, cov teeb meem nrog kev ruaj ntseg, kev tsim khoom loj, thiab kev cia muaj peev xwm tseem yuav daws tau. Ntxiv mus, qhov mob toxicity thiab tiv thaiv kab mob cuam tshuam nrog phosphorene-raws li PTAs tseem tsis meej. Polymeric PTAs, suav nrog polypyrrole (PPy) thiab polydopamine (PDA), tau yooj yim synthesized nrog adjustable molecular luj. Hais txog lwm yam tshiab PTAs, ob peb cov khoom siv ob sab tau tsim nrog kev ua haujlwm siab photothermal hloov dua siab tshiab, xws li C3N4 thiab MXenes nrog cov qauv dav dav Mnþ1Xn. Hauv Mnþ1Xn, M qhia txog kev hloov pauv hlau (Ti, V, Ta, Nb, Mo, thiab Zr) thiab X sawv cev rau C lossis N. Cov PTAs tsim nyog rau PTT hauv kev tiv thaiv kab mob qog noj ntshav yuav tsum ua raws li cov cai hauv qab no: (1) kev hloov pauv photothermal kuj siab. efficiency kom tsis txhob laser puas rau cov ntaub so ntswg ib txwm; (2) biocompatibility zoo heev thiab biodegradation kom tsis txhob muaj kab mob toxicity; thiab (3) lub teeb haum nyob rau hauv cheeb tsam NIR, uas yog qhov zoo tshaj plaws nyob rau hauv lub qhov rais thib ob NIR (NIR-II) (1000e1350 nm). Txog rau tam sim no, cov kev kho mob photothermal ua haujlwm raws li ob qho qauv: high-temperature PTT thiab low-temperature PTT. Rau qhov kub siab PTT, cov ntaub so ntswg qog nqaij hlav yog ablated ntawm qhov kub siab tshaj 50 C155. Kev kub siab thiab kev hloov hluav taws xob tuaj yeem ua rau cov ntaub so ntswg uas nyob ib sab 156. Feem ntau, cov kab mob mammalian teb rau cov cua sov los ntawm overexpressing heat shock proteins (HSPs), xws li HSP70 thiab HSP90. Yog li ntawd, kev tshawb fawb tau tsom mus rau rhiab cov qog nqaij hlav cancer rau qhov kub thiab txias PTT los ntawm inhibiting kev qhia thiab kev ua ntawm HSPs157. Cov kev tshawb fawb tsis ntev los no tau lees paub tias PTT tuaj yeem ua rau ICD hauv cov qog nqaij hlav cancer144. Qhov kub siab dua los ntawm irradiation ua rau muaj txiaj ntsig zoo ntawm tes tuag. Txawm li cas los xij, ICD biomarkers tsis tau nce nrog qhov kub thiab txias. ICD cov cim, xws li ATP tso tawm, HMGB1 tso tawm, thiab calreticulin qhia, tshwm sim ntau zaus ntawm 63.3e66.4 C dua li ntawm siab dua (83.0e83.5 C) thiab qis dua (50.7e52.7 C) kub. Ntxiv mus, kev txhaj tshuaj tiv thaiv tom qab nrog PTT-kho neuroblastomas sib txawv tau lees paub hauv vitro tshawb pom. Sib tw txhaj tshuaj tiv thaiv nas nrog neuroblast toma hlwb nyob rau hauv lub qhov rais kub zoo ua rau muaj kev vam meej nyob rau lub sij hawm ntev piv rau cov pab pawg siab dua lossis qis dua. Txawm li cas los xij, nws tsis yooj yim rau kev tshem tawm lub zog tiv thaiv kab mob tiv thaiv kab mob tsuas yog nyob ntawm antigen immunogenicity uas tshwm sim los ntawm PTT-induced ICD. Yog li ntawd, PTA nanomaterials feem ntau ua ke nrog lwm cov tshuaj tiv thaiv kab mob los txhim kho cov txiaj ntsig ntawm kev kho mob qog noj ntshav. Kev siv cov pa roj carbon nanotubes ua PTAs, ua ke nrog kev tswj hwm ntawm cov tshuaj tiv thaiv CTLA-4 cov tshuaj tiv thaiv zoo tiv thaiv kab mob qog noj ntshav nyob deb thiab mob qog noj ntshav hauv qab irradiation159. Hollow CuS nanoparticles coated nrog chitosan thiab CpG-ODN tau pom los ua kom NK hlwb thiab DCs nyob rau hauv cov ntaub so ntswg qog noj ntshav thiab ntws cov qog nqaij hlav, ua rau inhibition ntawm cov qog nqaij hlav hauv zos thiab nyob deb 160. Tsis ntev los no, cov kab mob mammalian tau siv rau hauv qhov tsim ntawm PTAs, Au nanoparticles (AuNPs). Kev kho ntawm B16F10 hlwb nrog HAuCl4 induced intracellular tiam ntawm AuNPs. Tom qab exocytosis, AuNPs tau encapsulated hauv B16F10 daim nyias nyias uas muaj ntau hom qog antigens. Tom qab ntawd, AuNP@B16F10 hlwb raug tsim nrog DC2.4 hlwb txhawm rau kho cov DC daim nyias nyias thiab daim ntawv AuNP@DCB16F10. Kev tswj hwm ntawm AuNP@DCB16F10 rau B16F10-cov kabmob nas ua rau muaj kev cuam tshuam loj heev rau kev txhim kho kabmob kheesxaws thiab qhib DCs thiab CD8þ T hlwb tom qab irradiation161 (Fig. 8). Txawm hais tias nanomaterial-mediated PTT tau siv dav hauv kev tshawb fawb hauv paus rau nws cov yam ntxwv tsis muaj kev cuam tshuam, tseem tsis muaj kev siv tshuaj kho mob tau zoo. Cov teeb meem ntawm nanomaterial-mediated PTT hauv kev kho mob hloov pauv tuaj yeem muab faib ua rau pawg. (1) Cov kev txwv tau muab los ntawm cov khoom nta ntawm cov nanomaterials feem ntau, suav nrog cov ntshav tsis muaj zog thiab tawg, tsis muaj peev xwm khiav mus ntev, ua rau lub siab ua kom muaj zog thiab mob, thiab cov txheej txheem pharmacokinetic tsis meej. (2) Cov kev txwv ntawm nanomaterial-based PTAs, suav nrog kev siv hluav taws xob tsis zoo thiab cov duab tsis zoo, tshwj xeeb tshaj yog rau PTAs kub. (3) Cov teeb meem muab tau los ntawm cov txheej txheem irradiation ntawm lub teeb, nrog rau lub teeb toxicity thiab superficial nkag mus rau cov ntaub so ntswg. (4) Dab tsi kub yog qhov zoo rau cov txheej txheem ICD? Puas muaj lub hauv paus ntsiab lus dav dav rau txhua tus nanomaterials-based PTAs (5) Qhov kev txwv ntawm kev paub txog cov txheej txheem ICD tshwm sim los ntawm nanomaterials-pab PTT, piv txwv li, txawm tias tag nrho cov nanomaterials-pab PTT ua rau ICD ntawm cov qog nqaij hlav cancer thiab yuav ntsuas thiab kwv yees li cas? Lub peev xwm ntawm nanomaterial-based PTAs los txhawb cov txheej txheem ICD. (6) Qhov kev siv ntawm cov txheej txheem ICD tshwm sim los ntawm cov khoom siv nanomaterials-pab PTT tsis txaus los ua kom muaj zog tiv thaiv kab mob qog noj ntshav, thiab kev sib xyaw ntawm nanomaterials-pab PTT nrog rau lwm yam kev kho mob qog noj ntshav yog qhov tsim nyog, uas ua rau muaj kev nyuaj ntawm kev kho mob.

Daim duab 7 Photothermal therapy nrog kev tiv thaiv kab mob-adjuvant nanoparticles induced anticancer tiv thaiv kab mob. (A) Schematic of immune-adjuvant nanoparticle tsim los ntawm PLGA loaded nrog ICG thiab R837 thiab nws cov nyhuv ntawm lub cev tiv thaiv kab mob. (B) cov qog ntim ntawm 4T1 thiab CT26 cov qog nyob deb tom qab kev kho mob ntawm cov qog thawj zaug. (C) CD4þ thiab CD8þ T cell suav ntawm cov qog nyob deb tom qab kev kho mob ntawm cov qog thawj zaug. Reprinted nrog kev tso cai los ntawm Ref. 145. Copyright ª 2016 Nature Publishing Group.

3.2.2. Photodynamic nano khoom

Hauv PDT, photosensitizers (PSs) tuaj yeem nqus cov photons thiab hloov lawv los ntawm lub xeev hauv av mus rau lub xeev zoo siab. Nyob rau hauv lub xeev zoo siab, PS feem ntau tsis ruaj khov thiab yooj yim hloov hluav taws xob hluav taws xob mus rau lwm cov substrates. Hauv hom I cov tshuaj tiv thaiv, PS nyob rau hauv lub xeev zoo siab, reacts nrog cell membrane los yog lwm yam biomolecules los tsim radicals, uas ntxiv reacts nrog O2 los tsim cov khoom oxygenated. Hauv hom II cov tshuaj tiv thaiv, PS hauv lub xeev zoo siab ncaj qha cuam tshuam nrog O2 los tsim cov pa oxygen, uas yog lub zog ROS162 (Daim duab 9). Yog li, PDT cov zis muaj feem cuam tshuam nrog O2 concentration. Nyob rau hauv ib puag ncig hypoxic qog, nws yog ib qho nyuaj rau kev ua tau zoo nrog PDT. Txawm hais tias PDT tau tshwm sim nyob rau xyoo 1970s thiab tau siv los kho cov qog nqaij hlav sab nraud, PDT-mediated immune activation tau lees paub nyob rau xyoo 20th century, thiab cov kev kho mob tseem nyob hauv kev txhim kho163e165. Hauv kev tshawb fawb tsis ntev los no, PDT tau pom tias yog ib txoj hauv kev zoo ntawm kev ua rau ICD hauv cov qog nqaij hlav cancer166,167. Qhov tseem ceeb, nws zoo nkaus li tias ROS yuav tsum muaj rau ICD vim tias qhov kev tiv thaiv kab mob ntawm cov txheej txheem yog inhibited loj heev nyob rau hauv muaj cov antioxidants. PS ntawm PDT suav nrog cov organic dyes thiab nanomaterials. Organic dyes muaj ob peb qhov tsis zoo, suav nrog hydrophobicity, qhov tob tob tob, thiab tsis tshua muaj kev mob qog noj ntshav. Kev siv nanomaterials raws li cov neeg nqa khoom rau cov organic PSs tuaj yeem kov yeej lawv ob peb qhov tsis txaus, thiab cov ntsiab lus cuam tshuam tau qhia hauv Tshooj 3.1.3. Nyob rau hauv no, peb yuav qhia nanomaterials uas muaj ib tug intrinsic muaj peev xwm mus elicit photodynamic txheej txheem thiab lawv daim ntawv thov nyob rau hauv cancer immunotherapy. Feem ntau PDT nanomaterials suav nrog cov hlau zoo nkauj nanomaterials, carbon-based nanomaterials, phosphorene dub, thiab nanoscale hlau-organic moj khaum (MOFs) 168. Luv luv, noble metallic nanomaterials yog sawv cev los ntawm kub thiab nyiaj nanoparticles. Kub nanorods, piv txwv li, tau tshaj tawm los tsim singlet oxygen nyob rau hauv NIR lub teeb ntawm 915 nm, uas rhuav tshem B16F0 melanoma hlav hauv tus qauv nas. Tsis tas li ntawd, cov nanorods kub no ua rau muaj qhov kub thiab txias nyob ib puag ncig cov ntaub so ntswg tom qab irradiation nrog NIR lub teeb ntawm 780 nm169. Kev hloov hauv lub teeb pom kev tuaj yeem hloov kho tus qauv ntawm PTT thiab PDT. Carbon-based PS nanomaterials muaj carbon nanotubes, fullerenes, thiab graphene quantum dots. Native carbon-based PS tsim cov pa oxygen singlet nyob rau hauv NIR irradiation. Txawm li cas los xij, doping thiab kev hloov kho saum npoo tuaj yeem ua rau cov pa roj carbon-based PS nrog kev ua haujlwm zoo quantum hloov dua siab tshiab raws li NIR irradiation170e172. Dub phosphorene nrog ib tug tunable band sib txawv, zoo heev biocompatibility, thiab biodegradation yog thawj zaug siv raws li PS nyob rau hauv 2015. Dub phosphorene pom ib tug kwv yees li 0.91 quantum yield ntawm singlet oxygen raws li 660 nm irradiation thiab ua rau tseem ceeb cell tuag thiab qog suppression173. MOFs sib sau ua ke nrog cov organic PSs li ligands, thiab hlau ions (Hf, Fe, Zn, thiab Zr ions) ua cov chaw hlau, tau pom tias ua haujlwm raws li PS nanomaterial174,175. Piv txwv li, ib qho tshiab porphyrin derivative, 5, 15- di (p-benzoato) porphyrin (H2DBP) tau tshwm sim nrog HfCl4 los ntawm cov tshuaj tiv thaiv solvothermal los tsim cov qauv DBP-UiO MOF. DBP-UiO-O MOF tau qhia txog kev txhim kho PDT kev ua tau zoo thiab tshem tawm cov qog nqaij hlav hauv kwv yees li ib nrab ntawm cov nas tom qab kev tswj hwm ib zaug, thiab ib zaug raug rau 640 nm irradiation176. Cov kev tshawb fawb tom qab tsim cov tshuaj chlorin-based MOF los ntawm kev hloov H2DBP nrog 5,15-di (p-benzoate)-chlorin (H2DBC) kom tau DBCUiO, uas muaj redshift excitation thiab ib qho 11-fold ntau dua extinction coefficient piv rau PAB-UiO177. Piv rau PTAs, hom thiab daim ntawv thov muaj peev xwm ntawm PS nanomaterials tam sim no raug txwv. Feem ntau PS nanomaterials zoo siab nyob rau hauv lub teeb pom kev lossis thaj tsam NIR-I, uas txwv qhov tob ntawm cov ntaub so ntswg nkag. Ob-photon excitation PDT nanomaterials muab kev daws teeb meem rau NIR-II irradiation178. Cov pa ib-photon excitation ntawm PSs absorbs ib photon los ua PSs. Txawm li cas los xij, ob-photon excitation PSs muaj peev xwm nqus tau ob lub zog photons ib txhij kom ua tiav lub zog sib txawv ntawm PSs los ntawm qhov sib npaug ntawm ob lub zog photon. Ob-photon excitation tso cai rau cov ntaub so ntswg sib sib zog nqus thiab txo photobleaching ntawm PSs. Piv txwv li, CdSe QDs tau siv los ua ob-photon excitation nanomaterials uas tuaj yeem zoo siab nyob rau hauv 1100 nm laser thiab emit photons nrog lub wavelength ntawm 635 nm. Lub silicon phthalocyanine 4 (Pc 4) conjugated ntawm CdSe QDs tau nqus tau 635 nm photons thiab ua haujlwm raws li PS ntawm FL fluorescence resonance zog hloov pauv (FRET) txheej txheem ntawm QD thiab Pc 4179. Txawm hais tias tam sim no PS nanomaterials tuaj yeem cuam tshuam cov qog nqaij hlav hauv zos. , kev tiv thaiv kab mob qog noj ntshav nyob deb thiab metastatic yog nyob ntawm kev sib xyaw nrog lwm cov tshuaj tiv thaiv kab mob qog noj ntshav. Piv txwv li, Fe-TBP MOF tau tsim los ntawm [Fe3O(OAc)6(H2O)3] OAc thiab 5,10,15,20-tetra (p-benzoate) porphyrin (TBP) ligand. Fe3þ tuaj yeem cuam tshuam nrog H2O2, uas muaj ntau nyob rau hauv cov ntaub so ntswg qog noj ntshav, tsim O2 thiab yooj yim hypoxia hauv cov ntaub so ntswg, ua rau kev txhim kho PDT efficiency. Fe-TBP ua ke nrog aPD- 1 inhibited ob qho tib si cov qog nqaij hlav hauv zos thiab cov qog nqaij hlav nyob deb ntawm abscopal teebmeem180. Tsis ntev los no, poly (g-glutamic acid) @glucose oxidase @carbon dot nanoparticles tau tsim thiab ua ke nrog aPD-1. Cov nanomaterial no generated O2 los ntawm H2O2 nyob rau hauv Mn2þ catalysis thiab mediated carbon dot-based PDT, uas ntxiv induced anticancer lub cev tiv thaiv kab mob tiv thaiv cov kho thiab tsis kho cov qog nyob deb 181. Piv rau cov pa organic PSs, kev ua haujlwm nanomaterial-mediated PDT yog qhov tsawg. Kev txhim kho ntawm NIR-II-elicited PDT nanomaterials nrog biocompatibility zoo heev thiab biodegradation yuav muab sijhawm tshiab rau PDT. Tsuas yog cov kev txwv dav dav ntawm nanomaterials, nanomaterials-pab PDTowns nws cov teeb meem tshwj xeeb. Ua ntej, nws muaj phototoxicity thiab tsis zoo cov ntaub so ntswg nkag qhov tob, uas yog ib qho teeb meem tshwm sim hauv kev kho photoirradiation. Qhov thib ob, zoo dua intracellular uptake ntawm PDT nanomaterials yog tsim nyog, rau lub ROS uas ua nyob rau hauv PDT yog active thiab tsuas zoo nyob rau hauv lub nanometer ntau yam. Thib peb, nws yuav tsum ua kom tiav qhov sib npaug ntawm PTT thiab PDT cov txheej txheem cuam tshuam los ntawm nanomaterials, rau ntau nanomaterials muaj peev xwm hloov photons mus rau hauv tshav kub thiab muaj zog dawb radicals tib lub sijhawm. Thib plaub, O2 yog qhov tsim nyog rau PDT thiab hypoxia hauv cov ntaub so ntswg qog nqaij hlav impedes efficiency ntawm PDT. Txawm li cas los xij, kev xa tawm ntawm O2 nrog nanomaterial-based PS ua rau nyuaj rau kev siv tshuaj thiab tsis ruaj khov.

3.2.3. Xov tooj cua nanomaterial

Radiotherapy yog ib txoj kev kho mob uas paub tab. Qee cov nanomaterials ntseeg tau tias yuav txhim kho cov nyhuv ntawm radiotherapy. Ua ke nrog nws txoj kev muaj peev xwm ua rau mob qog noj ntshav, nanomaterial-based radiotherapy tuaj yeem txo qhov kev puas tsuaj rau ib puag ncig cov ntaub so ntswg182. Radiotherapy-enhanced nanomaterials feem ntau yog tsim los ntawm high-Z ntsiab. Cov xov tooj cua nrov tshaj plaws yog kub-raws li nanoparticles184. Lwm cov kev tshawb fawb radiosensitizers suav nrog lanthanide-based NPs185,186, Bi2Se3 nanoparticles187 thiab Hf-based MOF nanomaterials188,189. Cov radiosensitizing nanoparticles tau pom los txhim kho kev ua haujlwm ntawm kev kho hluav taws xob los ntawm kev txhim kho cov duab hluav taws xob thiab Compton, uas ua rau muaj kev nce ntxiv ntawm cov hluav taws xob theem nrab thiab kev tsim cov ROS. Thaum lub sij hawm siv hluav taws xob, DNA radicals yuav tsum tau hnov ​​​​mob nrog O2 los txhawb DNA ob txoj hlua tawg. Yog li ntawd, qhov chaw hypoxic ntawm cov ntaub so ntswg qog nqaij hlav tsis muaj zog tiv thaiv kab mob los ntawm kev siv xov tooj cua. Txhawm rau tiv thaiv qhov tsis txaus ntseeg microenvironment, radiosensitizers feem ntau yog nrog O2 xa khoom molecules, xws li MnO2 nanoparticles lossis per-flfluorocarbons. Piv txwv li, core-plhaub Au@MnO2-PEG tau tsim los ua ke cov xov tooj cua sensitizer high-Z atoms thiab O2 generators. Lub Au core, lub npe nrov radiosensitizer, tuaj yeem txhim kho kev tsim cov DNA radicals. MnO2 muaj peev xwm decompose H2O2 rau O2 kom kov yeej hypoxia-mediated resistance rau radiotherapy190. Tsis tas li ntawd, perfluorocarbon-coated hollow Bi2Se3 nanoparticles tau pom los txhim kho kev siv hluav taws xob ntawm kev siv hluav taws xob los ntawm peb lub tshuab: perfluorocarbon, raws li tus neeg nqa khoom O2, txo cov mob hypoxic hauv cov qog nqaij hlav; Bi2Se3 nanoparticles, raws li radiosensitizers nrog siab Z atom Bi, zoo txhim kho cov nyhuv photoelectric ntawm RT; Bi2Se3 absorbed NIR lub teeb thiab tsim cov nyhuv photothermal los ua kom cov ntshav intertumoral, yog li txhim kho cov concentration ntawm O2 hauv cov qog nqaij hlav 191. Cov nyhuv abscopal, thawj zaug tau tshaj tawm hauv xyoo 1953, qhia txog kev hloov pauv ntawm lub cev tiv thaiv kab mob hauv xov tooj cua 192. Cov kev tshawb fawb tom qab pom tau hais tias kev kho mob hluav taws xob tuaj yeem txhim kho qhov kev qhia ntawm MHC I molecules thiab TAAs, yog li ua rau cov tshuaj tiv thaiv antigen ntawm DCs thiab kev ua kom thiab kev lag luam ntawm CD8þ T cells193. Cov kev tshawb fawb ntxiv tau pom tias kev kho mob hluav taws xob tau txhim kho lub cev tiv thaiv kab mob ntawm ICD194. Kev sib txuas xov tooj cua nrog rau lwm cov tswv yim tiv thaiv kab mob ua kom muaj zog tiv thaiv kab mob thiab ua rau muaj kev sib koom ua ke tiv thaiv kab mob. Piv txwv li, Hf-based nMOFs nrog cov teebmeem radiosensitizing induced muaj zog CRT raug thiab ua kom lub cev tiv thaiv kab mob hlwb (xws li DC, CD4þ T, CD8þ T, thiab NK hlwb), uas ntxiv inhibited kev loj hlob ntawm thawj thiab nyob deb cov qog. Ntxiv mus, kev sib txuas Hfbased nMOFs nrog aPD-L1 kom meej meej txhim kho lub cev tiv thaiv kab mob thiab yuav luag tshem tawm cov qog nqaij hlav hauv plab thiab abscopal 188. Radiotherapy ua tiav cov ntaub so ntswg tob dua li kev yees duab irradiation. Kev tiv thaiv kab mob elicitation mediated los ntawm radiotherapy yog cov ntaub ntawv zoo piv nrog cov duab irradiation. Txawm li cas los xij, cov qog nqaij hlav hypoxic microenvironment yog ib qho teeb meem rau kev kho hluav taws xob los tsim ROS txaus. Tsis tas li ntawd, kev siv hluav taws xob tiv thaiv kab mob hauv cov qog nqaij hlav cancer, zoo li kev tswj hwm DNA kho enzymes, txo cov txiaj ntsig ntawm kev kho mob qog noj ntshav. Tsis tas li ntawd, nws yog ib qho tsim nyog yuav tsum ua tib zoo soj ntsuam cov txiaj ntsig los tiv thaiv qog noj ntshav los ntawm kev txhim kho lub cev tiv thaiv kab mob thiab tus nqi ntawm nanomaterial. Ntxiv mus, cov kev txwv dav dav ntawm nanomaterials tsis tuaj yeem tsis quav ntsej hauv kev kho hluav taws xob.

Daim duab 8 Kub nanoparticles nyob rau hauv situ generated nyob rau hauv B16F10 thiab DCs rau kev sib xyaw ntawm PPT thiab immunotherapy. (A) Schematic ntawm kev tsim kho thiab kev tiv thaiv kab mob ntawm AUNP@DCB16F10. (B) TEM images of AUNP@DCB16F10. (C) kub hloov (DT) ntawm AuNP, AuNP@DCL929, thiab AuNP@DCB16F10. (D) cov duab nthuav tawm cov hlwb nyob / tuag tom qab kho nrog AuNP@DCB16F10 lossis / thiab laser. (E) thawj lub qog ntim tom qab kev kho mob qhia. (F) qhov hnyav ntawm qog nqaij hlav nyob deb tom qab kev kho mob qhia. (G) DC maturation tom qab kev kho mob qhia. (H) CD4þ T cell suav tom qab kev kho mob qhia. Reprinted nrog kev tso cai los ntawm Ref. 161. Copyright ª 2019 ACS Publishing Group.

Daim duab 9 ROS tiam nyob rau hauv kev kho mob photodynamic.

3.2.4. Lwm cov khoom siv nanomaterials

Ntxiv nrog rau kev txhim kho kev ua haujlwm ntawm PTT, PDT, thiab kev kho hluav taws xob, nanomaterials kuj nthuav tawm lwm yam kev ua haujlwm, nrog rau cov nyhuv chemodynamic, inducing ferroptosis thiab magnetic hyperthermia (MHT) cov teebmeem. Cov nyhuv chemodynamic feem ntau yog muab los ntawm Fenton cov tshuaj tiv thaiv, uas feem ntau piav qhia txog cov tshuaj tiv thaiv ntawm Fe2þ nrog H2O2 los tsim Fe3þ thiab hydroxyl radicals ($OH) uas muaj peev xwm oxidizing siab. Cov ntsiab lus siab ntawm $ OH ua rau tuag taus rau cov qog nqaij hlav cancer. Tsuas yog ferrous ions, lwm yam cations, xws li Cu2þ, Mn2þ, V2þ, thiab Cr4þ, muaj peev xwm catalyzing Fentonlike reactions195. Piv rau ruaj khov Fe3O4 nanoparticles uas tsuas yog siv surficial Fe2þ rau catalyze Fenton cov tshuaj tiv thaiv, amorphous Fe nanoparticles (AFeNPs), uas yuav ua tau zoo dua ionized nyob rau hauv ib tug acidic qog microenvironment thiab tso tawm active Fe2þ, txhim kho cov inhibition ntawm cancer kev loj hlob19. Txawm hais tias H2O2 tam sim no muaj ntau dua hauv cov qog nqaij hlav qog noj ntshav piv nrog cov hlwb ib txwm muaj, endogenous H2O2 zoo li tsis txaus los kho cov tshuaj tua kab mob rau cov qog nqaij hlav hauv vitro. Rau ntau txoj kev kho CDT, kev muab H2O2 ntxiv yog tsim nyog los ua kom mob qog noj ntshav tuag thiab qog regression197. Yog li, CDT feem ntau yog ua ke nrog lwm yam kev kho mob qog noj ntshav. Piv txwv li, peb pab pawg tau tsim Z-scheme heterojunction nrog FeS2 core thiab Fe2O3 plhaub. Cov tshiab 2D thermally oxidized pyrite nanosheets (TOPY NSs) tuaj yeem tua cov qog nqaij hlav cancer los ntawm kev noj glutathione, Fenton cov tshuaj tiv thaiv, heterojunction-mediated PDT, thiab PTT. Ntxiv mus, TOPY NSs yuav luag tshem tawm HepG2 xenograft qog nyob rau hauv irradiation ntawm 650 thiab 808 nm. Raws li CDT tsim ROS li PDT ua, nws tuaj yeem ua rau ICD hauv cov qog nqaij hlav cancer thiab. Txawm li cas los xij, kev sib cuam tshuam ntawm CDT thiab lub cev tiv thaiv kab mob yuav tsum tau kawm ntxiv. Ferroptosis yog ib hom tshiab ntawm kev tsim cell tuag. Nyob rau hauv qhov kev txiav txim ntawm divalent hlau los yog ester oxygenase, nws catalyzes lub siab qhia ntawm unsaturated fatty acids ntawm lub cell membrane ua lipid peroxidation, yog li inducing cell tuag. ROS ntau lawm hauv ferroptosis thiab qhov tsis yog-apoptotic xwm ntawm ferroptosis qhia nws lub peev xwm los hloov kho lub cev tiv thaiv kab mob. Ferroptocide, ib yam khoom tshiab tau txheeb xyuas ntuj, tau ua pov thawj los ua rau ferroptosis ntawm covalent conjugation ntawm thioredoxin, ib qho tseem ceeb ntawm cov kab mob antioxidant. Lub ferroptosis induced 40% qog retardation nyob rau hauv 4T1- bearing BALB/c nas tab sis muaj tsawg inhibition nyob rau hauv 4T1- bearing liab qab nas, uas qhia txog kev koom tes ntawm T thiab B hlwb nyob rau hauv ferroptosis meditated nyob rau hauv vivo qog inhibition198 . Cov nanomaterials inducing chemodynamic teebmeem tuaj yeem pib cov txheej txheem ferroptosis vim Fenton cov tshuaj tiv thaiv tuaj yeem pib liposome peroxidation199. Txawm li cas los xij, ob peb nanomaterials uas tsis muaj cov hlau divalent qhia lub peev xwm ua rau ferroptosis. PEGylated ultrasmall silica nanoparticles (kwv yees li 6 nm) tau pom tias ua rau ferroptosis nyob rau hauv cov zaub mov tsis muaj cov qog nqaij hlav cancer. Lub cell tuag vim yog silica nanoparticles yog inhibited los ntawm kev kho mob ntawm scavengers ntawm lipid ROS (liproxstatin-1) los yog glutathione repletion los ntawm kev ntxiv ntawm glutathione los yog N-acetylcysteine ​​(NAC). Tsis tas li ntawd, kev txhaj tshuaj ntawm cov tshuaj silica (12 nmol ib koob) cuam tshuam kev loj hlob ntawm 786-O thiab HT-1080 xenograft qog hauv cov nas liab qab. Thiab cov koob tshuaj intraperitoneal ntawm liproxstatin-1 txo qis qhov cuam tshuam ntawm qog nqaij hlav inhibition200. Tsis ntev los no, arginine-nplua nuj manganese silicate nanobubbles (AMSNs) tau raug pov thawj los ua rau ferroptosis los ntawm kev ua haujlwm zoo ntawm glutathione (GSH) yog li inducing inactivation ntawm glutathione-dependent peroxidases 4 (GPX4). Manganese nyob rau hauv AMSNs kho qhov depletion ntawm GSH, thiab arginine hloov kho muab qog lub peev xwm. AMSNs induced qog inhibition los ntawm ferroptosis mechanism hauv vitro thiab hauv vivo201. Tsis ntev los no, hybrid core-plhaub vesicles (HCSVs) tau tsim los ntawm kev siv ascorbic acid (AA) ua cov tub ntxhais thiab PLGA ua lub plhaub dai kom zoo nkauj nrog hlau oxide nanocubes (IONCs). HCSVs induced raug calreticulin los ntawm Fenton cov tshuaj tiv thaiv thiab ferroptosis zoo li cell tuag tom qab kev kho magnetic teb. Ntxiv mus, kev txhaj tshuaj intratumoral ntawm HCSVs tau txhawb nqa kev loj hlob ntawm splenocytes, DC ua rau hauv inguinal LNs, thiab T cell ua kom cov qog thiab LN202. MHT feem ntau yog nyob ntawm cov ntaub ntawv superparamagnetic, uas tuaj yeem ua tiav lub hom phiaj sib nqus thiab hloov hluav taws xob rau hluav taws xob thermal nyob rau hauv ib qho chaw sib nqus sib nqus. Piv rau PDT thiab PTT, MHT muaj peev xwm nkag mus tob dua thiab cuam tshuam nrog qis toxicity rau cov ntaub so ntswg 203. Fe3O4 nanoparticles yog cov khoom siv superparamagnetic nanomaterials, uas tuaj yeem ua kom cov qog kub siab tshaj 43 C thiab ua rau kom muaj zog thiab loj hlob ntawm CD4þ thiab CD8þ T hlwb. Qhov inhibition ntawm cov qog nqaij hlav thiab theem nrab los ntawm Fe3O4 nanoparticles qhia txog kev koom tes ntawm lub cev tiv thaiv kab mob. Siv Fe nanoparticles (FeNPs) raws li MHT cov neeg sawv cev, kev tswj hwm hauv zos ntawm PLGA-R837 thiab kev tswj hwm kev tswj hwm ntawm aCTLA-4 kuaj xyuas qhov thaiv tau pom tias muaj txiaj ntsig tiv thaiv kab mob qog noj ntshav205. Hauv kev xaus, kev ua haujlwm nanomaterials uas induce photothermal, photodynamic, radiosensitizing, chemodynamic, ferroptotic, thiab sib nqus hyperthermia teebmeem, qhia tau hais tias muaj peev xwm ua rau cov txheej txheem ICD ntawm cov qog nqaij hlav cancer uas tuag cov qog nqaij hlav tuaj yeem tso cov qog antigens thiab tam sim no immunostimulatory signals los qhib APCs. . Lub peev xwm ICD nano-inducers tau sau tseg hauv Table 4. Rau ntau cov khoom siv nano, txawm tias lawv induce ICD ntawm cov qog nqaij hlav qog noj ntshav thiab seb ICD lub zog puas txaus los rov pib kho mob qog noj ntshav tseem yuav tau kawm. Tsis tas li ntawd, ib qho me me ntawm cov ntaub ntawv qhia txog kev ua haujlwm nanomaterials inducing ICD yog qhov nyuaj los piav qhia thiab txhua yam khoom siv nanomaterials ntawm tib hom tuaj yeem ua rau ICD. Txawm li cas los xij, qhov tsis muaj tus qauv tsim qauv thiab kev tshawb fawb ntawm cov txheej txheem ICD kho los ntawm nanomaterials impedes lub rational optimization ntawm ICD nano-inducers.

Table 4 Muaj peev xwm ICD nano-inducers

3.3. Immunomodulatory adjuvants

Adjuvants yog cov khoom tseem ceeb ntawm cov tshuaj tiv thaiv niaj hnub no, uas ntxiv dag zog thiab / lossis ua kom lub cev tiv thaiv kab mob tiv thaiv kab mob lossis kab mob malignancies. Hauv kev txhaj tshuaj tiv thaiv kab mob qog noj ntshav, nws yog ib qho tseem ceeb los ua kom muaj zog tiv thaiv kab mob ntawm cov qog nqaij hlav qog. Nanomaterials nrog ntau qhov ntau thiab tsawg, cov duab, thiab cov kev hloov kho saum npoo tuaj yeem ua haujlwm raws li cov khoom siv hauv qab no 206: kev xa khoom thiab kev tso tawm zoo ib yam ntawm antigens, tsom rau APCs hauv txoj kev ua haujlwm lossis kev ua haujlwm, kev xa tawm cytosolic ntawm antigens los txhim kho qhov cross-presentation ntawm APCs, thiab modulate lub cev tiv thaiv kab mob. Kev siv cov khoom siv nanomaterials raws li kev xa khoom los thauj cov qog antigens mus rau lub cev tiv thaiv kab mob thiab cytoplasm ntawm DCs tau piav qhia hauv Tshooj 3.1.3. Ntawm no, peb yuav tham txog cov teebmeem immunomodulatory ntawm nanomaterials thiab lawv daim ntawv thov hauv kev kho mob qog noj ntshav. Cov teebmeem immunomodulatory ntawm nanomaterials feem ntau muaj xws li inflammasome activation, ntxiv rau kev ua kom lub cev, thiab kev nrhiav neeg ntawm lub cev tiv thaiv kab mob 207. Alum adjuvants, uas tau siv dav hauv kev kho mob, tau pom tias yuav ua rau NLPR3 inflammasome activation. Thaum raug kev phom sij, xws li cov kab mob, DAMPs lossis PAMPs, NLPR3, thiab lwm yam proteins uas muaj feem xyuam rau tus kheej yuav cuam tshuam rau tus kheej los tsim cov khoom hnyav molecular hnyav uas ua rau cov autocleavage ntawm caspase-1. Qhov no ntxiv tswj kev zais cia ntawm IL-b thiab IL-18208. Ntxiv rau alum, ntau cov ntaub ntawv nanomaterials tau pom tias yuav ua rau NLRP3 inflammasome activation, suav nrog carbon dub nanoparticles209, SiO2 210,211, thiab TiO2 nanoparticles212. Inflammasomes tau qhib rau hauv cov lus teb rau cov teeb liab txaus ntshai muab los ntawm nanoparticles, xws li lysosomal destabilization thiab ROS ntau lawm. Ntxiv cov proteins muaj nyob rau hauv cov ntshav thiab cov ntaub so ntswg hauv tib neeg thiab vertebrates. Cov tshuaj ntxiv tuaj yeem qhib los ntawm antigen-antibody complexes lossis kab mob, ua rau cov lysis lossis phagocytosis ntawm cov kab mob pathogenic. Cov kev tshawb fawb tsis ntev los no tau pom tias opsonin, ib hom kev ntxiv, tuaj yeem nqus mus rau nanoparticles los kho qhov kev lees paub thiab endocytosis ntawm cov khoom los ntawm phagocytic hlwb. Tom qab noj los ntawm phagocytes, nanomaterials tej zaum yuav induce phagocytes synthesize thiab secrete proinflammatory cytokines thiab chemokines kom nrhiav tau lub cev tiv thaiv kab mob, xws li macrophages, DCs, thiab T hlwb. Piv txwv li, hauv xyoo 2010, Yang et al.213 tau tshaj tawm ib qho [Gd@C82(OH)22]n nanoparticles, uas induced cytokine ntau lawm (xws li IL-12p70), co-stimulatory molecule qhia, thiab MHC molecule qhia. hauv DCs. Tsis tas li ntawd, cov nas txhaj tshuaj tiv thaiv OVA thiab [Gd@C82(OH)22]n nthuav tawm Th1 lub cev tiv thaiv kab mob. Nyob rau hauv 2017, Luo et al.214 tau tsim tshiab polymeric PC7A nanoparticles, uas yog ultra-pH rhiab heev thiab muaj txoj kab uas hla ntawm 20e50 nm rau cov qog nqaij hlav qog. Siv PC7A ua tus nqa khoom yam tsis muaj lwm yam tshuaj tiv thaiv kab mob kom xa cov qog antigens mus rau cov qog nqaij hlav muaj zog inhibited kev loj hlob ntawm melanoma thiab mob qog noj ntshav. Cov PC7A nanoparticles tau pom los tswj lub cev tiv thaiv kab mob, suav nrog kev txhawb nqa DC kev loj hlob los ntawm txoj kev STING. Lub immunoregulatory muaj nuj nqi ntawm nanomaterials feem ntau tsis quav ntsej nyob rau hauv daim ntawv thov ntawm nanomaterials rau kev xa tshuaj. Tsis ntev los no, kev pom zoo tias ntau ntawm nanomaterials cuam tshuam rau lub cev tiv thaiv kab mob tau mus txog. Kev cuam tshuam ntawm kev tiv thaiv kab mob ntawm nanomaterials yog ntau haiv neeg. Txawm hais tias peb tsuas yog qhia txog cov nyhuv immunostimulatory ntawm nanomaterials, lwm yam nanomaterials uas provoked o los yog immunosuppression tau tshaj tawm. Ib tug loj npaum li cas ntawm kev tiv thaiv kev ntsuam xyuas ntawm nanomaterials yuav tsum tau sau. Cov kev sib raug zoo ntawm cov qauv ntawm nanomaterials thiab immunoregulatory muaj nuj nqi tseem yuav uncovered.

Daim duab 10 NIR ua rau PDT combinatorial therapy nrog kev tiv thaiv kab mob tiv thaiv kab mob. (A) Schematic uas qhia txog kev ua haujlwm tiv thaiv kab mob ntawm UCNP-Ce6-R837. (B) qog ntim ntawm thawj thiab nyob deb CT26 qog tom qab kev kho mob qhia; qib CD8þ CTL cells (C), Treg cells (D), thiab CD8þ CTL/Treg ratio (E) hauv cov qog nyob deb, thiab IFN-g cytokine qib hauv sera (F) los ntawm cov nas tom qab kev kho mob qhia. Reprinted nrog kev tso cai los ntawm Ref. 215. Copyright ª 2017 ACS Publishing Group.

3.4. Combinatorial cancer immunotherapy enabled los ntawm nanomaterials

Kev siv tshuaj tiv thaiv kab mob sib xyaw ua ke uas ua ib txhij ntawm cov khoom sib txawv tau piav qhia saum toj no, lossis ntawm cov kauj ruam sib txawv ntawm kev tiv thaiv kab mob qog noj ntshav, muaj peev xwm ua kom muaj zog tiv thaiv kab mob antigen tshwj xeeb ntawm tes. Nanomaterials, uas ua raws li cov neeg nqa khoom, ICD inducers, thiab immunomodulatory cov neeg ua haujlwm, muaj peev xwm los koom ua ke sib txawv tshuaj tiv thaiv kab mob ua haujlwm rau hauv ib lub platform thiab kom ua tiav cov txiaj ntsig zoo tiv thaiv kab mob. Thaum pib, nanomaterials tau siv los ua ke xa cov qog antigens thiab immunostimulatory cov neeg ua haujlwm rau kev tsim cov tshuaj tiv thaiv kab mob qog noj ntshav uas muaj zog ua ke nrog cov tshuaj tiv thaiv kab mob. Piv txwv li, Xu et al.127 hauv 2013 tsim lipid-calcium-phosphate (LCP) nanoparticles hloov nrog mannose rau lub hom phiaj DCs, uas tau co-loaded nrog tyrosinase-related protein 2 (Trp 2) peptide li melanoma antigens thiab CPG ODN li. ib adjuvant. Tsis ntev los no, nanomaterials nruab nrog inducers ntawm ICD thiab immunostimulatory agents tau siv ua ke nrog ICB kev kho mob. Piv txwv li, xyoo 2017, Chen et al.145 tau npaj ib lub nanosystem uas muaj PLGA loaded nrog ICG thiab R837. ICG tsim cov nyhuv photothermal muaj zog, uas kho qhov tso tawm ntawm cov qog antigens. R837, lub zog TLR-7 agonist, muaj peev xwm qhib DCs. Kev siv PLGA rau kev sib koom ua ke ntawm ICG thiab R837 tau pom tias yuav ua rau muaj zog tshaj plaws ntawm DC maturation thiab TNF-kev tsim tawm hauv qab 808 nm irradiation. Tom qab kev kho mob ua ke nrog aCTLA-4, PLGA-ICG-R837 nrog laser irradiation yuav luag tshem tawm 4T1 thiab CT26 cov qog nyob deb ntawm xenograft, thiab ua tau zoo inhibited metastasis thiab rov tshwm sim ntawm cov qog. Qhov inhibition ntawm kev loj hlob ntawm qog noj ntshav, metastasis, thiab rov ua dua tau txhim kho los ntawm kev ua kom thiab loj hlob ntawm CD4þ thiab CD8þ T hlwb, thiab txo qis ntawm Treg hlwb. Tom qab ntawd, Xu et al.215 tau tsim ib lub tshuab ua haujlwm ntau lub nano uas sib txuas cov nanoparticles upconversion (UCNPs), Ce6, R837, thiab aCTLA-4. UCNPs tau hloov kho nrog amphiphilic polymers thauj khoom Ce6 thiab R837. UCNPs tau tuaj yeem nqus lub teeb ntawm 980 nm thiab tawm lub teeb ntawm 550 nm kom qhib Ce6 thiab tsim ROS. UCNP-Ce6-R837 tau pom tias muaj peev xwm ua rau DC maturation thiab pro-inflammatory cytokine secretion nyob rau hauv 908 nm irradiation. Tsis tas li ntawd, UCNP-Ce6-R837 ua ke nrog kev tswj hwm ntawm aCTLA-4 robustly inhibited kev loj hlob ntawm thawj, nyob deb, thiab metastatic qog (Fig. 10).

Daim duab 11 Hauv qhov chaw txhaj tshuaj tiv thaiv los ntawm kev sib xyaw RT þ BNP. Reprinted nrog kev tso cai los ntawm Ref. 217. Copyright ª 2019 John Wiley and Sons Group.

Daim duab 12 Lub tswv yim ntawm OSPS mediated combinatory cancer therapy. Reprinted nrog kev tso cai los ntawm Ref. 218. Copyright ª 2019 John Wiley and Sons Group.

Daim duab 13 Anticancer tiv thaiv kab mob tshwm sim los ntawm OSPS. (A) OSPS-mediated qog inhibition thiab ntsws metastasis. (B) Kev loj hlob nkhaus ntawm thawj cov qog nyob rau hauv 4T1 cov qog nqaij hlav nas. (C) Kev loj hlob nkhaus ntawm cov qog nyob deb ntawm 4T1 cov nas uas muaj kabmob. (D) H&E staining ntawm ntsws metastasis nyob rau hauv 4T1 cov qog nqaij hlav nas. (E) Tus naj npawb ntawm cov metastatic nodules nyob rau hauv 4T1 qog-cov kabmob nas (F) Kyn / Trp piv hauv thawj qog hauv 4T1 qog-cov kabmob nas. (G) Cov pej xeem ntawm CD3þCD8þ T cells hauv cov qog nyob deb. (H) IFN-g-tsim T-cells hauv cov qog nyob deb. (I) Treg hlwb hauv cov qog nyob deb. *P < 0.05, **P < 0.01, ***P < 0.001, n Z 5. CSPN, nanoparticles tsis NLG919. Reprinted nrog kev tso cai los ntawm Ref. 218. Copyright ª 2019 John Wiley and Sons Group.

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4. Cov lus xaus

Kev sib cuam tshuam ntawm mob qog noj ntshav nrog lub cev tiv thaiv kab mob yog qhov nyuaj. Kev tsim qog nqaij hlav feem ntau yuav tsum tau kuaj lub cev tiv thaiv kab mob mus ntev thiab kev tiv thaiv kab mob microenvironment. Yog li ntawd, tus neeg lub cev tiv thaiv kab mob yuav tsis txaus los ntawm nws tus kheej kom tshem tawm cov qog nqaij hlav cancer. Kev siv cov neeg ua hauj lwm sab nraud uas rov pib lub voj voog tiv thaiv kab mob qog noj ntshav ntawm ib lossis ntau kauj ruam yog lub hauv paus ntawm kev kho mob qog noj ntshav. Txhim kho lub voj voog tiv thaiv kab mob qog noj ntshav muaj xws li cov kauj ruam tseem ceeb hauv qab no: ua cov qog antigens muaj rau APCs, ua rau kev loj hlob ntawm APCs, txhawb kev nthuav tawm ntawm APCs, thiab ua kom lub cev tiv thaiv kab mob microenvironment. Targeting ntau lub ntsiab lus tseem ceeb ib txhij yog ib txoj hauv kev zoo los kov yeej cov txheej txheem them nyiaj thiab txhawb kev tiv thaiv kab mob qog noj ntshav muaj zog. Nanomaterials yog siv dav hauv kev kuaj mob thiab kev xa tshuaj vim tias lawv qhov loj me, cov duab, thiab cov khoom siv tau zoo. Kev loj hlob thiab kev tshawb fawb tob ntawm nanomaterials qhia tau hais tias nanomaterials tsis tuaj yeem siv rau kev xa tshuaj xwb, tab sis kuj muaj ntau yam khoom, xws li lawv cov nyhuv photothermal, photodynamic effect, muaj peev xwm txhim kho hluav taws xob, sib nqus hyperthermia effect, thiab immunomodulatory nyhuv. Cov khoom no tso cai rau cov khoom siv nanomaterials siv los ua ib lub platform rau kev sib koom ua ke ntawm ntau hom tshuaj los yog cov tswv yim tsom mus rau cov kauj ruam sib txawv ntawm cov kab mob qog noj ntshav, uas txhawb nqa ntxiv, lossis txawm tias muaj txiaj ntsig zoo los tiv thaiv qog noj ntshav. Raws li lub platform xa tshuaj zoo heev, nanomaterials muaj lub peev xwm los thauj khoom thiab tso tawm ntau lub immunomodulators ib txhij rau cov ntaub so ntswg mob qog noj ntshav lossis cov qog nqaij hlav kom muaj zog ua kom muaj zog sib txawv ntawm cov kab mob qog noj ntshav, xws li cov khoom noj qog nqaij hlav, ua kom APCs, thiab inhibition. ntawm lub cev tiv thaiv kab mob los yog kev tiv thaiv kab mob tiv thaiv kab mob. Raws li kev ua haujlwm nanomaterials, nanomaterials muaj peev xwm ua rau cov txheej txheem ICD ntawm cov qog nqaij hlav cancer, yog li inducing uptake ntawm immunogenic qog antigens los ntawm APCs thiab ua kom cov APCs. Raws li rau immunomodulators, nanomaterials yuav ua hauj lwm raws li adjuvant thiab ncaj qha induce lub activation ntawm inflammasome thiab zus tau tej cov stimulatory cytokines rau ua kom lub cev tiv thaiv kab mob thiab yooj yim ntawm immunosuppression. Peb lub ntsej muag ntawm nanomaterials ua rau lawv yog ib tus neeg sib tw zoo tshaj plaws rau kev tswj xyuas cov kab mob qog noj ntshav. Ntxiv mus, nanomaterials tuaj yeem muaj ntau lub luag haujlwm tib lub sijhawm, piv txwv li, cov khoom siv nanomaterials muaj peev xwm xa cov khoom me me molecular immunomodulators.