Pyroptosis Nyob rau hauv pem hauv ntej ntawm Anticancer Immunity
Nov 14, 2023
Abstract
Cov qog ua haujlwm rau apoptosis thiab kev tiv thaiv kab mob qog noj ntshav microenvironment yog ob qho tseem ceeb rau kev kho cov lus teb tsis zoo thaum muaj kev cuam tshuam txog kev mob qog noj ntshav. Pyroptosis, lytic thiab inflammatory programmed cell tuag txoj kev txawv ntawm apoptosis, tau ua rau muaj kev txaus siab ntawm cov kws tshawb fawb txog qog noj ntshav rau nws lub peev xwm los kho mob thiab daws cov teeb meem no. Cov pov thawj tsis ntev los no qhia tau hais tias pyroptosis induction nyob rau hauv cov qog nqaij hlav ua rau lub cev muaj zog teb thiab cim qog regression. Raws li nws cov nyhuv antitumor, pyroptosis yog kho los ntawm pore-forming gastrin proteins uas pab txhawb kev tiv thaiv kab mob ntawm tes thiab infiltration los ntawm lawv tso tawm ntawm pro-inflammatory cytokines thiab immunogenic khoom tom qab cell rupture. Xav txog nws qhov xwm txheej, txawm li cas los xij, aberrant pyroptosis kuj tseem cuam tshuam rau kev tsim cov qog-txhawb microenvironment, raws li pov thawj los ntawm upregulation ntawm gastrin proteins nyob rau hauv tej yam qog nqaij hlav. Hauv qhov kev tshuaj xyuas no, cov txheej txheem molecular uas ua rau pyroptosis tau qhia, ua raws li cov ntsiab lus ntawm cov kev sib txuas ntawm pyroptosis thiab mob qog noj ntshav. Peb piav qhia txog dab tsi paub txog qhov cuam tshuam ntawm pyroptosis ntawm kev tiv thaiv kab mob qog noj ntshav thiab muab kev nkag siab rau lub peev xwm ntawm kev siv pyroptosis ua ib qho cuab yeej thiab siv nws rau cov tswv yim tshiab lossis cov tswv yim tiv thaiv kab mob uas twb muaj lawm.
cistanche tubulosa- txhim kho lub cev tiv thaiv kab mob
Keywords: Pyroptosis, Antitumor immunity, Gasdermin, mob cancer, Kev tiv thaiv kab mob
Keeb kwm
Thaum lub sij hawm ntev evading nrhiav tau, lub hav zoov thiab physiological tseem ceeb ntawm programmed cell tuag (PCD) txoj kev txawv ntawm apoptosis tau garnered nce kev txaus siab nyob rau hauv xyoo tas los no, nyob rau hauv ib feem, vim muaj ntau heev ntawm apoptosis tsis kam nyob rau hauv cov qog [1]. Ntawm cov ntaub ntawv sib txawv no, pyroptosis, ib qho necrotic thiab lytic PCD, tau txawv nws tus kheej los ntawm lwm tus los ntawm nws lub peev xwm los ntxias cov lus teb muaj zog [2]. Zoo ib yam li necroptosis, ib qho programmed necrosis, pyroptosis ntseeg tau tias muaj nyob hauv qhov tseem ceeb ntawm kev tiv thaiv kab mob los ntawm kev ua rau cov tshuaj tiv thaiv kab mob los ntawm kev tso tawm cov tshuaj tiv thaiv kab mob hauv cellular, suav nrog kev puas tsuaj rau cov qauv molecular (DAMPs) thiab inflammatory cytokines [3]. Tsis zoo li necroptosis, uas yog kho los ntawm cov kab sib xyaw kinase domain-zoo li pseudokinase (MLKL) thiab caspase-independent [4], pyroptosis yog kho los ntawm gastrin (GSDM) tsev neeg cov proteins thiab, zoo li apoptosis, feem ntau caspase-dependent [5]. Lwm hom kev tswj hwm necrosis, xws li ferroptosis, kuj tau tshwm sim tsis ntev los no [6–10] thiab tau muab piv nrog rau necrosis thiab apoptosis hauv Table 1.
Txoj kev nrhiav kom kov yeej mob qog noj ntshav thiab nws qhov kev tshwm sim loj hauv ntiaj teb tau rov ua rau peb ntsib kev dag ntxias ntawm kev tuag thiab kev tshawb pom los ntawm cov qog nqaij hlav cancer. Txawm hais tias tseem muaj cov txheej txheem tsis zoo, pyroptosis sawv cev rau qhov muaj peev xwm siv tau thiab muaj peev xwm txhais tau tias tsis yog tsuas yog hla apoptosis tsis kam tab sis ua kom cov qog tshwj xeeb tiv thaiv kab mob thiab / lossis txhim kho cov txiaj ntsig ntawm cov kev kho mob uas twb muaj lawm. Ntawm no, peb tham txog cov kev paub tam sim no ntawm pyroptosis nyob rau hauv cov ntsiab lus ntawm kev tiv thaiv kab mob qog noj ntshav los muab kev pom rau nws lub peev xwm los tawm tsam mob qog noj ntshav.
Table 1 Kev sib piv ntawm cov ntawv xaiv cell tuag
Pyroptosis ntawm ib nrais muag
Pyroptosis tau piav qhia thawj zaug hauv xyoo 1990 hauv macrophages kis nrog S. enterica serovar Typhimurium (S. Typhimurium) [11] thiab S. flexneri [12]. Txawm hais tias Ameslikas xav tias yog tus txheej txheem ntawm apoptosis, kev tshawb fawb ntxiv tau qhia tias cov kab mob uas ua rau cov cell tuag no hnyav heev nyob ntawm caspase-1 [13], caspase uas tsis koom nrog kev tua apoptosis (ie, caspase{{6 }}). Tsis ntev tom qab ntawd hauv xyoo 2001, PCD no tau raug nplawm pyroptosis, lossis "ntoo poob", los piav qhia txog kev tso tawm cov cim qhia tawm los ntawm cov hlwb tuag. Pyroptotic hlwb qhia ntau yam nrog cov hlwb apoptotic, xws li chromatin condensation thiab DNA fragmentation, tab sis qhov txawv ntawm lawv cov nucleus tsis zoo, pore tsim, cell o, thiab osmotic lysis (Table 1) [14]. Feem ntau, pyroptotic cell rupture yog ua tiav los ntawm caspase-mediated activation ntawm pore-forming GSDM cov proteins tom qab kev khi ntawm DAMPs los yog cov kab mob sib txuas nrog cov qauv (PAMPs) [15]. Cov caspases tib yam no kuj tseem tuaj yeem ncaj qha lossis tsis ncaj qha rau kev loj hlob ntawm pro-inflammatory cytokines uas, nrog rau DAMPs, pib los yog perpetuate inflammatory teb thaum tso tawm. Txawm hais tias muaj lub luag haujlwm tiv thaiv tseem ceeb hauv kev daws teeb meem kab mob, pyroptosis tau cuam tshuam los ntawm ntau yam kab mob hauv tib neeg, xws li kab mob plawv [16], kab mob neurodegenerative [17], thiab HIV / AIDS [18]. Cov kab mob metabolic zoo li ntshav qab zib kuj tseem tuaj yeem txhawb nqa los ntawm pyroptosis los ntawm kev mob ntev thiab tsim cov tshuaj insulin-interfering cytokines [19]. Hauv kev mob qog noj ntshav, lub luag haujlwm ntawm pyroptosis zoo li ob-edged. Ntawm ib sab, pyroptosis tuaj yeem ua rau cov qog regression sai thiab, ntawm qhov tod tes, nws tuaj yeem pab txhawb kev loj hlob ntawm cov qog microenvironment. Yog li ntawd, cov qog nqaij hlav qog nqaij hlav tuaj yeem cuam tshuam lossis ua rau pyroptosis los txhawb lawv txoj kev loj hlob nyob ntawm cov ntsiab lus.
Cov txiaj ntsig ntawm cistanche tubulosa- ua kom muaj zog tiv thaiv kab mob
Molecular mechanisms ntawm pyroptosis
zoo li yuav nce ntxiv rau yav tom ntej, tam sim no muaj ob lub hauv paus tseem ceeb thiab ntau txoj hauv kev uas tau piav qhia txog hnub no (Daim duab 1). Nyob rau hauv txoj kev tseem ceeb, pyroptosis yog induced los ntawm GSDMD thiab muaj inflammatory caspase-1 (canonical pathway) los yog caspase-4/5 (los yog nas caspase-11) (non-canonical txoj kev). Ntawm lwm txoj hauv kev, qhov pom dav tshaj plaws yog GSDME-vim pyroptosis los ntawm caspase-3 [5], txawm hais tias txoj kev sib txawv uas cuam tshuam nrog lwm tus GSDM tsev neeg thiab caspases lossis granzymes kuj tau tshaj tawm. Raws li txoj cai, GSDMA, GSDMB, GSDMC, GSDM D, thiab GSDME yog tag nrho ntawm N-terminal pore-forming domain thiab C-terminal regulatory domain uas koom nrog thaj tsam txuas [20]. Raws li ib txwm muaj, thaj tsam txuas tso cai rau C-terminal domain los folds saum toj ntawm N-terminal domain thiab functionally inhibit nws cov kev ua rau tuag taus. Cleavage ntawm qhov chaw txuas los ntawm caspases lossis granzymes, txawm li cas los xij, tshem tawm qhov kev txwv tsis pub siv cov qauv no thiab ua rau kev hloov pauv ntawm N-terminal domain fragment rau hauv cov ntshav thiab mitochondrial membranes. Thaum khi, N-terminal domain oligomerizes thiab cov ntaub ntawv -barrel transmembrane pores uas pab txhawb kev tso tawm ntawm cov ntsiab lus pro-inflammatory, xws li interleukin (IL)- 1 thiab IL-18, thiab ua rau cell lysis los ntawm osmotic barrier kev puas tsuaj [21]. Hauv cov ntu tom ntej, cov ntsiab lus ntawm cov kauj ruam koom nrog hauv txhua txoj hauv kev uas ua rau pyroptosis tau muab.
Canonical inflammasome txoj kev
Nyob rau hauv txoj kev canonical inflammasome rau pyroptosis, kev paub txog DAMPs (xws li, fibrinogen, cov proteins kub poob siab, DNA) thiab / lossis PAMPs (piv txwv li, flagellin, glycans, lipopolysaccharides (LPSs)) los ntawm cov qauv lees paub receptors (PRRs) ua rau kev ua haujlwm ntawm ntsig txog cytosolic signaling complexes hu ua inflammasomes, uas feem ntau muaj xws li ib tug sensor protein, adaptor, thiab effector caspase [22]. Txawm hais tias muaj ntau yam PRRs, zoo li NOD-zoo li receptors (NLRs) thiab tus xov tooj zoo li receptors (TLRs), tau koom nrog hauv cov txheej txheem no, tsuas yog ib pawg ntawm cov no tau paub tias tuaj yeem ncaj qha sib sau ua ke inflammasomes thiab qhib cov cysteine protease caspase{ {3}} [23]. Tshwj xeeb, PRRs / inflammasome sensors nyob rau hauv no subset suav nrog NLR tsev neeg pyrin domain-muaj (NLRP)1, NLRP3, NLRP4, tsis tuaj nyob rau hauv melanoma 2 (AIM2), thiab Pyrin. Tom qab lawv ua kom tiav, feem ntau ntawm cov sensors cuam tshuam nrog adapter protein apoptosis-zoo li cov protein uas muaj CARD (ASC), uas ua rau caspase-1 los ntawm procaspase-1 recruitment thiab cleavage. Ntxiv nrog rau kev tso tawm thiab ua kom cov neeg tuag N-terminal domain ntawm GSDMD (GSDMD-N), caspase-1 kuj ua rau pro-IL-1 thiab pro-IL-18 rau hauv IL{{22 }} thiab IL-18, uas tau tso tawm los ntawm necrotic membrane pores tsim los ntawm GSDM DN [24].
Cov txiaj ntsig ntawm cistanche tubulosa-Antitumor
Tsis-canonical inflammasome txoj kev
Nyob rau hauv sib piv rau canonical inflammasome txoj kev, txoj kev uas tsis yog-canonical inflammasome txoj kev yog ywj siab ntawm caspase -1 thiab es tsis txhob cia siab rau caspase -4 thiab -5 nyob rau hauv tib neeg thiab caspase -11 nyob rau hauv nas. [25]. Kev ua kom cov caspases no tshwm sim los ntawm kev sib txuas ncaj qha ntawm LPS rau cov pro-caspases thiab hla qhov kev xav tau rau inflammasome sensors. Keeb kwm los ntawm cov kab mob gram-tsis zoo, cytoplasmic xa ntawm LPS tuaj yeem tshwm sim los ntawm kev kis kab mob lossis daim nyias nyias vesicles. Txawm hais tias cov caspases no tsis qhib IL-1 thiab IL-18 ncaj qha, lawv qhov tshwm sim ntawm pyroptosis los ntawm GSDMD cleavage ua rau muaj cov poov tshuaj ions uas ua rau NLRP3 inflammasome thiab upregulates qhov kev txiav txim ntawm caspase{11} } [26].
Daim duab 1 Schematic ntawm pyroptosis signaling pathways. Txoj kev canonical inflammasome rau pyroptosis yog induced los ntawm ntau yam stimuli thiab ua rau caspase -1 ua kom, thaum txoj kev uas tsis yog-canonical yog induced los ntawm LPS thiab ua rau caspase -4/5 activation. Ob qho tib si qhib caspase-1 thiab caspase-4/5 cleave autoinhibited GSDMD ntawm nws thaj chaw txuas kom tso N-terminal domain ntawm GSDMD (GSDMD-N) los ntawm nws qhov kev tawm tsam C-terminal domain (GSDMD-C) . GSDMD-N tom qab ntawd hloov mus rau plasma membrane thiab ua rau oligomerization thiab pore tsim, uas ua rau muaj kev nce hauv osmotic siab thiab thaum kawg ntawm tes lysis. Pore tsim kuj pab txhawb kev tso tawm ntawm cov ntsiab lus intracellular thiab inflammatory cytokines IL-18 thiab IL{14}} tom qab lawv ua kom los ntawm caspase-1. Los ntawm lwm txoj hauv kev, GSDMD kuj tseem raug tshem tawm los ntawm caspase-8, zoo ib yam li GSDME, uas tuaj yeem raug tshem tawm los ntawm caspase-3 thiab granzyme B. Ib sab, GSDMD-N thiab GSDMB-N tuaj yeem ua raws NLRP3 los yog caspase -4. Hauv lwm txoj hauv kev, GSDMB yog cleaved los ntawm caspase -1 los yog granzyme A, thaum GSDMC yog cleaved los ntawm caspase-8 thiab transcriptionally upregulated nyob rau hauv hypoxia los ntawm pSTAT3 cuam tshuam nrog programmed tuag-ligand 1. Cov mechanisms ntawm GSDMA -mediated pyroptosis tseem tsis tau elucidated. AIM2, tsis tuaj hauv melanoma 2; DAMPs, kev phom sij cuam tshuam nrog cov qauv molecular; FADD, Fas-associated death domain protein; GSDMA/B/C/D/E, gastrin A/B/C/D/E; IL, interleukin; LPS, lipopolysaccharides; NLRP1/3/4, NLR tsev neeg pyrin domain-muaj 1/3/4; PAMPs, cov kab mob cuam tshuam nrog cov qauv molecular; RIPK1, receptor-interacting serine/threonine-protein kinase 1; pSTAT3, phospho-signal transducer thiab activator ntawm transcription 3; TAK1 (tseem hu ua MAP 3 K7), hloov pauv kev loj hlob ntawm beta-activated kinase 1
Lwm txoj kev
Nws tau tshaj tawm tias nyob rau hauv qee qhov xwm txheej, xws li kev kho tshuaj khomob lossis kev kho mob qog noj ntshav, txoj hauv kev los ntawm apoptosis mus rau pyroptosis tuaj yeem raug ntxias los ntawm caspase- 3 [5]. Txawm hais tias feem ntau cuam tshuam nrog kev tua apoptosis thiab kev hloov pauv morphological, caspases -3 tuaj yeem kho pyroptosis los ntawm kev tawg ntawm GSDME, uas zoo ib yam ua rau GSDME-N pore tsim thiab membrane permeabilization. Thaum GSDME qib siab, pyroptosis tau sai sai tom qab caspase-3 ua kom, tab sis thaum GSDME qib qis, apoptosis tau hais kom hloov [5]. Xav tias feem ntau ntawm cov proteases koom nrog hauv pyroptosis tuaj yeem kho apoptosis thaum lawv cov protein GSDM tsis tuaj [27, 28], nws yog qhov qhia tias qhov sib npaug ntawm pyroptosis thiab apoptosis feem ntau nyob ntawm GSDM protein ntau. Qhov kev xav no xav tau cov pov thawj ntxiv, txawm li cas los xij, vim nws tsis sib haum xeeb los ntawm kev tshawb fawb nyuaj rau lub luag haujlwm ntawm GSDME hauv pyroptosis [29, 30]. Ob peb lwm txoj hauv kev pyroptosis kuj tau tshaj tawm thiab, hauv luv luv, suav nrog GSDMD cleavage los ntawm caspase-8 [31], GSDME cleavage los ntawm caspase-8 [32] lossis granzyme B (GzmB) [33], GSDMB cleavage los ntawm caspase -1 [34] los yog granzyme A (GzmA) [35], GSDMC cleavage los ntawm caspase- 8 thiab transcriptional upregulation los ntawm hypoxia-activated programmed death-ligand 1 (PD-L1) thiab pSTAT3 [36], thiab GSDMA pore tsim los ntawm ib qho tsis paub mechanism [37].
Cov txiaj ntsig ntawm cistanche tubulosa-Antitumor
Pyroptosis thiab nws cov ntsiab lus hauv kev mob qog noj ntshav
Lub luag haujlwm tsis meej ntawm pyroptosis hauv kev mob qog noj ntshav zoo li yog cov ntsiab lus thiab nyob ntawm hom cell, noob caj noob ces, thiab lub sijhawm ntawm pyroptosis induction. Ua raws li kev qhia tsis meej thiab kev ua haujlwm ntev, GSDMs, inflammasomes, thiab / lossis pro-inflammatory cytokines tuaj yeem ua rau mob qog nqaij hlav los ntawm kev ua rau lub cev tiv thaiv kab mob, txhawb kev hloov pauv ntawm epithelial-rau-mesenchymal, thiab / lossis kho cov matrix metalloproteinases rau extracellular matrix remodeling. Tsis ntev los no, nws tau pom tias pyroptosis tuaj yeem ua rau mob qog nqaij hlav hauv cov qog nqaij hlav hauv plab (CRC) los ntawm kev nthuav tawm ntawm kev nthuav tawm ntawm cov cell nuclear antigen los ntawm highmobility pawg box protein 1 (HMGB1) tso tawm [39]. Hauv thaj chaw hypoxic ntawm MDA-MB-231 xenografts hauv cov nas liab qab, PD-L1- kho apoptosis rau pyroptosis hloov tau kuj tau tshaj tawm los pab txhawb cov qog nqaij hlav mob ntev [36], uas tuaj yeem txhawb cov qog loj hlob. thiab impede antitumor tiv thaiv [40]. Juxtaposing cov teebmeem no, txawm li cas los xij, pyroptosis tuaj yeem pib ua qog nqaij hlav thiab tua [5, 33, 41–43]. Hauv cov kab mob hepatocellular carcinoma (HCC), piv txwv li, pyroptosis induction los ntawm NLRP3 inflammasome activation ho impeded metastatic peev xwm nyob rau hauv vitro thiab qog loj hlob nyob rau hauv vivo nyob rau hauv tus nas xenograft qauv [44]. Lub tswv yim hais tias kev tiv thaiv pyroptosis muab qhov kev xaiv zoo dua hauv HCC hlwb ntxiv los ntawm kev soj ntsuam tias caspase -1 mRNA thiab cov protein ntau tau ua haujlwm tsis zoo hauv tib neeg HCC cov ntaub so ntswg thiab cov kab cell [45].
Muab ob lub luag haujlwm ntawm pyroptosis, nws cov molecular Cheebtsam yog, raws li ib tug yuav xav tau, txawv txav thiab sib txawv qhia thoob plaws cov qog nqaij hlav sib txawv (Table 2). GSDMs, piv txwv li, yog deregulated nyob rau hauv lub mis, plab hnyuv, ncauj tsev menyuam, thiab lub ntsws cancer, thiab lwm yam, thiab tau pom los tswj kev loj hlob, metastasis, kho tsis kam, thiab antitumor tiv thaiv thaum ua yeeb yam xws li oncogenes los yog qog suppressors [65, 66] . Hauv kev mob qog noj ntshav (GC), GSDMD kev nthuav qhia tau txo qis thiab ua rau muaj kev txhim kho qog nqaij hlav hauv vitro thiab hauv vivo, tejzaum nws los ntawm kev ua kom nrawm ntawm S / G2 cell hloov [57]. Hloov pauv, GSDMD cov protein ntau tau nce siab heev hauv cov qog nqaij hlav qog nqaij hlav tsis me me (NSCLC) piv rau cov kev tswj hwm uas nyob ib sab thiab tau cuam tshuam nrog cov qog loj dua, cov qog qog nqaij hlav qog metastasis ntau dua, thiab, hauv lub ntsws adenocarcinoma (LUAD), cov tsos mob tsis zoo [27 ]. Ntxiv mus, GSDMD knockdown nyob rau hauv NSCLC hlwb attenuated lawv proliferation los ntawm apoptosis induction thiab EGFR / Akt signaling inhibition. Zoo ib yam li GSDMD, GSDME kev qhia kuj tau txo qis hauv GC, nrog rau mob qog noj ntshav thiab CRC [47, 59, 67]. Hauv CRC tshwj xeeb, GSDME knockdown nce cellular invasiveness thiab colony tooj, whereas GSDME overexpression txo cell loj hlob thiab colony tsim [51]. Thaum kuaj cov qauv phais ntawm thawj GC, GSDMC qhia tau pom tsuas yog nyob rau hauv qee qhov xwm txheej, txawm hais tias qhov sib txawv ntawm kev tswj hwm hauv CRC, qhov uas nws txhawb nqa carcinogenesis thiab proliferation hauv vitro thiab qog loj hlob hauv vivo [50]. Cov qib siab ntawm GSDMB kuj tseem muaj feem cuam tshuam nrog ntau dua ntawm cov kab mob metastasis thiab qis dua cov neeg muaj sia nyob hauv cov neeg mob qog noj ntshav [46]. Ntawm lwm cov pyroptosis constituents, AIM2 qhia tau txo qis los yog tsis tuaj rau feem ntau ntawm CRC qog pom thiab khi rau cov neeg mob tsis zoo [52]. Tsawg AIM2 qib kuj cuam tshuam nrog kev mob qog nqaij hlav ntau dua hauv HCC, thaum AIM2 overexpression attenuated cell proliferation thiab ntxeem tau [61]. NLRP1 qib tau zoo sib xws hauv CRC cov ntaub so ntswg thiab txuas rau kev nce metastasis thiab kev ciaj sia tsis zoo [54]. Txawm li cas los xij, NLRP1 kuj tau cuam tshuam txog kev txhawb nqa qog. Nyob rau hauv melanoma, piv txwv li, NLRP1 tau pom los pab txhawb kom tau txais cov tshuaj tiv thaiv [62], thiab hauv kev mob qog noj ntshav ntawm lub mis, tau nthuav tawm ntau dhau hauv cov ntaub so ntswg thiab cuam tshuam nrog lymph node metastasis [49]. Hauv cov nas, NLRP1 kuj txhawb kev loj hlob ntawm qog nqaij hlav cancer mis, ntxeem tau, metastasis, thiab qog nqaij hlav [49]. Tsiv mus, caspase-1 qib mRNA tau txo qis hauv cov ntaub so ntswg qog noj ntshav ntawm cov neeg mob [48], thiab poob ntawm caspase-1 tau cuam tshuam nrog prostate [64] thiab CRC [53] tumorigenesis. Txawm hais tias nws lub luag haujlwm tseem ceeb hauv cov qog nqaij hlav hauv cov qog nqaij hlav no, caspase-1 qhia tau nce ntxiv hauv tib neeg cov ntaub so ntswg glioma thiab tau qhia tias ua lub luag haujlwm tseem ceeb hauv glioma cell proliferation thiab tsiv teb tsaws los ntawm nws txoj kev tswj ntawm pyroptosis thiab kev pab cuam tom qab rau cov qog hauv zos. microenvironment [60].
Needless hais, elucidating kev sib raug zoo ntawm pyroptosis thiab mob qog noj ntshav yuav tsum tau kev tshawb fawb ntau. Xav txog qhov tsis muaj kev pom zoo thoob plaws cov kev tshawb fawb, ib qho kev sib tw tseem ceeb yuav yog kom pom thiab sib koom ua ke ntawm cov qog nqaij hlav tshwj xeeb thiab kev tswj hwm ntawm txhua qhov pyroptotic molecular Cheebtsam. Nrog rau ntau txoj hauv kev ua rau pyroptosis thiab ntau cov khoom sib tshooj sib tshooj, nws yog qhov qhia tias ua rau txhua txoj hauv kev ntawm tag nrho cov qog nqaij hlav tshwj xeeb, tsis yog qhov cuam tshuam ntawm tus kheej ntawm txhua qhov, tej zaum yuav muaj txiaj ntsig zoo dua los nkag siab thiab / lossis cia siab tias yuav muaj qhov hloov pauv ntawm pyroptosis. Txawm li cas los xij, raws li txoj hauv kev tshiab pyroptosis tseem tab tom nrhiav pom, qhov sib txawv hauv peb txoj kev paub yuav tiv thaiv peb los ntawm kev nkag siab cov ntsiab lus loj dua kom txog rau thaum txhua txoj kev taw qhia tau elucidated thiab ua raws li cov txheej txheem tam sim no lossis ib qho tshiab.
Table 2 Kev nthuav qhia ntawm cov khoom siv pyroptotic hauv cov qog nqaij hlav thiab lawv cov txiaj ntsig cuam tshuam
Table 2 Kev nthuav qhia ntawm cov khoom siv pyroptotic hauv cov qog nqaij hlav thiab lawv cov txiaj ntsig cuam tshuam (Ntxiv)
Kev sib raug zoo ntawm pyroptosis thiab anticancer tiv thaiv kab mob
Lub peev xwm ntawm lub xov tooj ntawm tes tuag los ua kom lub cev tiv thaiv kab mob hloov pauv tau hu ua immunogenic cell death (ICD). Tshwj xeeb, lub peev xwm immunogenic ntawm cov kab mob qog noj ntshav tuag yog txhais los ntawm nws cov yam ntxwv antigenic thiab adjuvant, xws li muaj cov qog nqaij hlav nrog cov antigens thiab tso tawm ntawm endogenous DAMPs, raws li [68, 69]. Tsis zoo li apoptosis, uas yog ib qho tseem ceeb ntawm kev tiv thaiv kab mob, pyroptosis muaj cov tshuab molecular kom tshem tawm cov lus teb muaj zog thiab tau pom zoo tias yog ib hom ICD hauv qee kis [33]. Txawm hais tias kev sib txuas ntawm pyroptosis thiab kev tiv thaiv kab mob qog noj ntshav tseem tsis tau meej meej, ntau qhov kev tshawb fawb pom tau tias pyroptosis-mediated qog clearance tau ua tiav los ntawm kev ua kom lub cev tiv thaiv kab mob thiab ua haujlwm. Tsis tas li ntawd, ntxiv rau qhov tshwm sim tshwm sim los ntawm cov kev ntxhov siab sib txawv thiab kev hloov pauv ntawm apoptosis-rau-pyroptosis, qog cell pyroptosis tuaj yeem raug cuam tshuam ncaj qha los ntawm qee lub cev tiv thaiv kab mob, qhia tias pyroptosis tuaj yeem koom nrog kev tawm tswv yim zoo hauv kev tiv thaiv kab mob. Hauv cov ntu hauv qab no, cov kev tshawb fawb tsis ntev los no cuam tshuam txog pyroptosis hauv kev tiv thaiv kab mob qog noj ntshav tau qhia meej raws li GSDM protein koom nrog.
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GSDMA
borate (Phe-BF3) ua ke nrog kub nanoparticle (NP) tus me nyuam, Wang li al. tau tshaj tawm ua tiav kev xa cov nas isoform ntawm GSDMA, Gsdma3, xaiv rau hauv tib neeg HeLa (cervical), nas EMT6 (mammary), thiab nas 4 T1 (mammary) cov qog nqaij hlav cancer, ua rau pyroptosis hauv 20-40% ntawm cov hlwb nyob ntawm lub cell. kab [70]. Thaum qhov kev xa khoom no tau siv rau BALB / c nas subcutaneously implanted nrog 4 T1 lossis EMT6 hlwb tom qab ob lub lis piam ntawm kev loj hlob, peb qhov kev kho mob nrog NP-Gsdma3 thiab Phe-BF3, los ntawm kev txhaj tshuaj intravenous lossis intratumoral, ua rau cov qog nqaij hlav. ; thiab tom qab 25 hnub, cov qog nqaij hlav tsis zoo. Hauv kev sib piv, tsis muaj qog nqaij hlav tau pom thaum NP-Gsdma3 lossis Phe-BF3 tau txhaj ib leeg, lossis thaum cov mutant uas tsis yog-pore-forming NP-Gsdma3 thiab Phe-BF3 tau txhaj ua ke, qhia tias Gsdma3 muaj nuj nqi yog tsim nyog rau cov nyhuv antitumor. . Interestingly, hauv NP-Gsdma3 thiab Phe-BF3 kho BALB / c nas, nws tau pom tias pyroptosis tsawg dua 15% ntawm 4 T1 qog hlwb txaus los tshem tawm tag nrho cov qog mammary graft. Cov qog regression no tsis muaj nyob rau hauv Nu/Nu nas uas tsis paub tab T hlwb, txawm li cas los xij, qhia tau hais tias cov qog tshem tawm cov nyhuv ntawm Gsdma3-kuaj pyroptosis yog, tsawg kawg yog ib feem, nyob ntawm lub cev tiv thaiv kab mob. Yog li ntawd, kev nce hauv CD3+ T cell infiltration, nrog rau kev txo qis hauv CD4+ FOXP3+ T regulatory cells hauv BALB/c nas, tsuas yog pom hauv 4 T1 qog. kho nrog NP-Gsdma3 thiab Phe-BF3. Tsis tas li ntawd, kev txo qis ntawm CD4+ thiab CD{41}} cov neeg nyob hauv cov qauv kev kho mob no tiv thaiv cov qog regression, txhais tau hais tias ob qho tib si CTLs thiab CD4+ T pab hlwb ua lub luag haujlwm tseem ceeb hauv lub sijhawm pyroptosis-induced qog clearance. Thaum piv nrog PBS tswj 4 T1 cov qog, kev tshuaj xyuas ntxiv kuj tau qhia tias thaum CD4+, CD8+, natural killer (NK), thiab M1 macrophage cell pejxeem tau nce hauv NP- Gsdma3 thiab Phe-BF3 kho. Cov qog nqaij hlav, cov pejxeem ntawm monocytes, neutrophils, myeloid-derived suppressor hlwb, thiab M2 macrophages poob. Ntxiv rau qhov nce IL-1 , IL-18, thiab HMGB1 cov ntshav thiab qog qog, ntau yam tshuaj tiv thaiv kab mob thiab tshuaj tiv thaiv kab mob (xws li, Cd69, Gzma, Gzmb) tau pom tias muaj kev tswj hwm thiab ntau yam kev tiv thaiv kab mob thiab cov kab mob protumor. noob (xws li, Csf1, Vegfa, Cd274) downregulated nyob rau hauv 4 T1 qog kho nrog NP-Gsdma3 thiab Phe-BF3 nyob rau hauv BALB/c nas [70].
GSDMD
Tsom ntsoov rau lawv cov kev saib xyuas ntawm cytotoxic T lymphocytes (CTLs), Xi thiab cov npoj yaig tau tshuaj xyuas CTLs cov lus qhia ntawm GSDM noob nyob rau hauv kev sib raug zoo nrog CD8+ T cell markers hauv LUAD, ntsws squamous cell carcinoma (LUSC), thiab melanoma qog cov qauv siv cov ntaub ntawv The Cancer Genome Atlas (TCGA) [71]. Ntawm tsib GSDM noob tswv cuab, tsuas yog GSDMD qhia tau pom muaj kev sib raug zoo nrog CD8+ T cell marker noob (piv txwv li, CD8A, CD8B, PRF1, GZMA, GZMB, thiab IFNG) hauv CTLs thoob plaws peb lub qog qog. Ib qho kev sib raug zoo ntawm GSDMD thiab CD8A, GZMB, thiab IFNG qhia hauv CTLs kuj tau pom nyob rau hauv ntau lwm hom qog thiab hauv 30 thawj qog qog los ntawm cov neeg mob NSCLC, ntxiv kev lees paub cov koom haum pom los ntawm TCGA. Kev tshawb fawb ntxiv tau nthuav tawm tias qhov kev qhia ntawm GSDMD hauv kev qhib CTLs los ntawm OT-1 nas tau nce ntau dua piv nrog cov tsis muaj T lymphocytes. Ib yam li ntawd, tib neeg CD8+ T hlwb tau tswj hwm GSDMD tom qab lawv ua haujlwm, thiab hauv LUAD thiab LUSC cov ntaub so ntswg kuaj, qib siab ntawm GSDMD protein tau pom hauv qog-infiltrating lymphocytes (TILs). Hauv ob qho tib si OT-1 thiab tib neeg-tsim CD8+ T hlwb, kev ua kom lub cev ntawm caspase-11 lossis caspase{15}} tau txhim kho, thiab tsom lawv nrog cov plaub hau luv luv RNA attenuated GSDMD kev tawg. Thaum qhib OT-1 T hlwb tau koom ua ke nrog ovalbumin-expressing Lewis ntsws carcinoma (3LL-OVA) hlwb, kev sib koom ua ke ntawm GSDMD thiab GzmB tau pom nyob rau hauv CTLs nyob ze lawv lub cev tiv thaiv kab mob; Ntxiv mus, CTL cytotoxicity ntawm 3LL-OVA hlwb tau poob qis tom qab GSDMD knockdown. Cov txiaj ntsig zoo sib xws tau sau tseg siv tib neeg CTLs thiab H1299 NSCLC cell kab [71]. Xav tias ib txoj hauv kev tseem ceeb uas CTLs tua cov qog hlwb yog los ntawm kev tso tawm ntawm cytotoxic molecules rau hauv lub cev tiv thaiv kab mob uas lawv tsim, nws tau xav tias kev xa ntawm GSDMD thiab GzmB mus rau hauv cov qog nqaij hlav cancer yuav yog lub hauv paus ntawm CTL cytotoxicity pom hauv. txoj kev tshawb no [71].
GSDMB
Tsis ntev tom qab Xi thiab cov npoj yaig cov ntawv tshaj tawm, lub tshuab ntawm NK- thiab CTL-induced qog cell pyroptosis los ntawm granzyme tso tawm tau ntxiv dag zog los ntawm ntau qhov kev tshawb fawb [33, 35, 72]. Nyob rau hauv sib piv rau Xi li al., Txawm li cas los xij, Zhou et al., piv txwv li, cuam tshuam kev koom tes ntawm GzmA thiab GSDMB, es tsis yog GzmB thiab GSDMD, hauv cov kab ntawm tes lawv tau tshuaj xyuas, txhawb kev xav tias lub xov tooj ntawm tes teb rau granzymes thiab GSDMs. yog contextual thiab nyob ntawm lub cell hom [35, 71]. Tshwj xeeb, nws tau pom tias yuam kev ntawm GSDMB tab sis tsis muaj lwm tus GSDM cov tswv cuab hauv tib neeg lub raum embryonic (HEK)- 293 T hlwb tsis muaj cov lus qhia endogenous ntawm GSDMs tau muab cov pyroptotic tua ntawm 293 T hlwb los ntawm kev sib koom ua ke ntawm tib neeg NK{{10 }}MI cells [35]. Interestingly, GSDMB-mediated tua los ntawm NK hlwb zoo li caspase-ywj siab, raws li kev kho mob nrog pan-caspase inhibitor tsis muaj txiaj ntsig. Qhov inhibition ntawm granzymes lossis NK cell degranulation thiab perforin, txawm li cas los xij, tsis tsuas yog thaiv NK cell-induced pyroptosis tab sis kuj GSDMB cleavage hauv 293 T hlwb. Ntawm tsib tus tib neeg granzymes hauv HEK-293F hlwb, nws tau pom tias tsuas yog GzmA sai cleaved GSDMB hauv tus qauv zoo ib yam li pom hauv NK cell-tua tshuaj ntsuam xyuas. Thaum GzmA tau electroporated rau hauv GSDMB-reconstituted 293 T hlwb, dav GSDMB cleavage thiab pyroptotic tua tshwm sim; tab sis thaum ib qho tsis muaj protease-deficient GzmA S212A mutant yog electropo rated los yog tsis-cleavable GSDMB K244A mutant los yog K229A / K244A ob chav mutant tau nthuav tawm, pyroptosis induction tau txo qis. Ib yam li ntawd, GzmA-mediated cleavage ntawm GSDMB yog xav tau nyob rau hauv physiological tej yam kev mob rau NK cell pyroptotic tua ntawm 293 T hlwb, thiab muaj kev cuam tshuam rau lub cleavage, xws li GSDMB mutant qhia, taw tes 293 T hlwb ntawm pyroptosis kuj. Hauv tib neeg cov kab mob qog noj ntshav endogenously nthuav qhia GSDMB, tshwj xeeb tshaj yog OE19 (esophageal carcinoma), SW837 (CRC), thiab SKCO1 (CRC), nws tau qhia ntxiv tias GzmA xa los ntawm electroporation lossis perforin txaus los ntxias GSDMB-mediated pyroptosis [35].
Qhov tseem ceeb, lwm cov kab mob qog noj ntshav nrog cov qib tsis txaus ntseeg GSDMB, xws li OE33 (esophageal carcinoma cells) thiab HCC1954 (cov qog nqaij hlav cancer mis), tuaj yeem raug cuam tshuam los ua kom GSDMB nthuav tawm los ntawm kev raug rau cytokines feem ntau tso tawm los ntawm activated cytotoxic lymphocytes, zoo li interferon-gamma. (IFN-) thiab qog necrosis factor-alpha (TNF-) [35]. Nyob rau hauv lem, IFN- priming ho txhim kho pyroptotic cell tuag nyob rau hauv ib tug xov tooj ntawm cov cell kab, tab sis qhov no tshwm sim nyob rau hauv lub kawg ntawm GzmA. Zoo ib yam li lawv cov incubation nrog NK-92MI hlwb, 293 T hlwb qhia CD19 thiab GSDMB tau pom tias muaj GSDMB cleavage thiab pyroptosis teb rau incubation nrog tib neeg anti-CD19 chimeric antigen receptor (CAR) -T hlwb. Qhov no cleavage thiab pyroptosis induction, txawm li cas los xij, tsis tau tshwm sim thaum tsis muaj kev sib tw ntawm GSDMB tau qhia hauv 293 T hlwb lossis thaum GZMA raug tsoo hauv CAR-T hlwb. Tsiv mus tom ntej, pab pawg tau pom tias, txawm hais tias GSDMB muaj tsis muaj orthologs hauv nas, CTLs tsim los ntawm OT-1 cov nas hloov pauv tuaj yeem siv nas GzmA (mGzmA) txhawm rau txhawm rau tib neeg GSDMB thiab ua rau muaj pyroptosis hauv nas MC38 CRC hlwb qhia tib neeg GSDMB. Siv cov kev paub no rau hauv tus qauv vivo, pab pawg pom tsis muaj qhov sib txawv ntawm qhov kev loj hlob ntawm cov nas CT26 CRC cov hlwb hauv BALB / c nas seb tib neeg GSDMB tau rov tsim dua hauv cov hlwb lossis tsis, txawm li cas los xij. Tom qab ntawd nws tau tshaj tawm tias qhov kev lees paub ntawm CT26 qog hlwb los ntawm CTLs hauv cov qauv yuav raug cuam tshuam los ntawm programmed cell death protein 1 (PD-1)- programmed-death ligand 1 (PD-L1) kev sib cuam tshuam, yog li, tiv thaiv CTL xa ntawm mGzmA rau hauv lub hom phiaj CT26 hlwb thiab induction ntawm CT26 cell pyroptosis. Zoo kawg nkaus, los ntawm kev thaiv PD-1-PD-L1 khi rau hauv cov qauv los ntawm PD-1 tshuaj tiv thaiv kab mob, pab pawg tau tuaj yeem txo qis kev loj hlob ntawm kev tswj CT26 qog thiab yuav luag tag nrho kev loj hlob ntawm tib neeg GSDMB- qhia txog CT26 qog. Ib feem inhibition ntawm qog loj hlob kuj tau pom nyob rau hauv CT26 qog qhia txog GzmA-resistant ob chav mutant daim ntawv ntawm GSDMB nyob rau hauv lub PD-1 antibody mob, tab sis tsuas yog rau ib tug npaum li cas ze ntawm cov qog nqaij hlav. Cov pab pawg kuj tau tshaj tawm cov kev tshawb pom zoo sib xws uas siv qhov hnyav dua B16-F10 melanoma qog qauv hauv C57BL/6 nas [35]. Ua ke, cov kev tshawb pom no tsis tsuas yog pom tau tias GSDMB-mediated pyroptosis ua qis qis ntawm GzmA tab sis cov cytotoxic lymphocytes tuaj yeem xa GzmA mus rau GSDMB-qhia cov qog nqaij hlav los pab txhawb kev tiv thaiv kab mob.
GSDME
Zhang et al. kuj tau tshaj tawm no tib lub tswv yim ntawm pyroptosis induction los ntawm cytotoxic lymphocytes tab sis taw qhia rau GSDME thiab GzmB txoj kev koom tes [33]. Ua rau cov kev tshawb pom no, nws tau pom tias ectopically qhia nas GSDME (mGSDME) nyob rau hauv murine 4T1E cov qog nqaij hlav cancer mis engrafted rau hauv immunocompetent BALB/c nas ho inhibit 4T1E qog loj hlob thiab ua rau muaj kev nce rau hauv infiltration ntawm NK hlwb thiab cov qog-mob macrophages. (TAM) [33]. Tsis tas li ntawd, NK cell thiab CD8+ TIL qhia ntawm GzmB thiab perforin hauv cov qog no nce, nrog rau CD8+ TIL tsim tawm ntawm IFN- thiab TNF thaum txhawb nqa los ntawm phorbol 12- myristate { {11}}acetate thiab ionomycin. Conversely, kev qhia ntawm cov tsis ua hauj lwm los yog tsis-cleavable versions ntawm mGSDME nyob rau hauv 4T1E hlwb txo cov teebmeem no, thaum mGSDME knockout nyob rau hauv EMT6 cov qog muaj qhov cuam tshuam. Thaum 4T1E cov qog hlwb uas qhia txog kev txhim kho ntsuab fluorescent protein (eGFP) tau cog rau hauv cov nas no, cov naj npawb ntawm eGFP-zoo CD8+ TILs tau pom tias muaj ntau dua thaum 4T1E hlwb kuj overexpressed mGSDME. eGFP-zoo TILs hauv mGSDME overexpressing qog kuj muaj ntau dua perforin qhia thiab cytokine ntau lawm thib ob rau GFP staining; thiab ob npaug ntawm eGFP-zoo TAMs nyob rau hauv cov qog no piv rau kev tswj tau qhia tau hais tias ntau dua qog cell phagocytosis, uas tej zaum yuav pab txhawb kev tiv thaiv kab mob tiv thaiv kab mob. Txhawm rau soj ntsuam kev sib txuas ntawm GSDME-mediated qog suppression thiab tiv thaiv kab mob, NSG cov nas uas tsis muaj cov lymphocytes paub tab thiab perforin-deficient BALB / c nas tau cais ua haujlwm los ntawm pab pawg los qhia tias cov tshuaj tiv thaiv qog ntawm GSDME yog ob leeg lymphocyte- thiab perforin- nyob thiab cuam tshuam txog kev koom tes ntawm NK thiab CD8+ T hlwb. Los ntawm kev tshawb nrhiav ntxiv, nws tau pom tias tib neeg NK cell kab YT tuaj yeem qhib pyroptosis hauv GSDME-qhia HeLa hlwb thiab kwv yees los ntawm kev sim siv tib neeg cov kab mob neuroblastoma SH-SY5Y cell kab tias qhov induction tau ua tiav los ntawm GzmB, uas tsis tsuas yog cleaves GSDME ntawm tib lub vev xaib xws li caspase-3 tab sis tsis ncaj qha qhib caspase-3. Kev sim tshuaj tiv thaiv / kev sib tw kuj tseem qhia tau hais tias pyroptosis yog ib hom ICD, uas zoo ib yam nrog kev nkag mus rau hauv lub cev thiab txhim kho lub cev tiv thaiv kab mob ua haujlwm tau pom nyob rau hauv kev sim ua ntej nrog mGSDME-overexpressing hlwb [33].
Cov kev tshawb pom no yog ua raws li cov los ntawm Liu li al., uas tau hais tias CAR-T hlwb tuaj yeem ua rau GSDME-mediated qog cell pyroptosis hauv B leukemic thiab cov qog nqaij hlav los ntawm perforin thiab GzmB tso tawm [72]. GzmB kuj tau pom zoo kom nrawm nrawm GSDMB thiab qhib caspase-3 hauv Luc-Raji thiab NALM- 6 hlwb, txawm hais tias nws tso tawm thiab muaj peev xwm ua rau nas B16 melanoma cell pyroptosis tau pom tias nyob ntawm CAR-T cell qog antigen affinity thiab co-signaling domains los yog nws kom muaj nuj nqis thaum tso tawm, feem. Kev kho cov macrophages los ntawm tib neeg nrog supernatants los ntawm co-cultured CD19-CAR-T hlwb thiab qog nqaij hlav cancer (NALM-6, Raji, los yog thawj B leukemic cells) ua rau macrophage activation ntawm caspase{14} }, cleavage ntawm GSDMD, thiab tso tawm ntawm IL-6 thiab IL-1 . Cov kev soj ntsuam no, txawm li cas los xij, tsis tau pom yog tias cov qog nqaij hlav qog noj ntshav tsis txaus hauv GSDME lossis macrophages hauv caspase-1, GSDMD, lossis NLRP3. Nws kuj tau tshaj tawm tias ATP thiab HMGB1 nyob rau hauv kev sib koom ua ke pyroptotic supernatants feem ntau txaus los txhawb cov macrophage IL-1 secretion thiab IL-6 upregulation. Hauv qhov loj, cov kev tshawb pom no ua rau pom cov neeg pom nyob rau hauv cov kab mob leukemia CAR-T cell-induced cytokine release syndrome (CRS) nas qauv (siv Raji lossis NALM-6 hlwb hauv cov nas uas muaj kev tiv thaiv kab mob loj heev), uas qhia tias CAR-T Kev kho cell elicited CRS los ntawm GSDME-facilitated pyroptosis. Qhov kev xav no tau txhawb ntxiv thaum thawj B leukemic hlwb los ntawm cov neeg mob ua ntej CD19-Kev kho mob CAR T cell raug tshuaj xyuas thiab pom tias GSDME nce qib yuav cuam tshuam nrog CRS hnyav dua [72].
Ib cag, nws tsim nyog hais tias nyob rau hauv ib qho kev tshawb fawb cais, kev kho mob-induced pyroptosis hauv melanoma hlwb ntawm GSDME thiab caspase-3 raws li txhawb HMGB1 tso tawm thiab tau ncaj qha mus khi rau infiltration ntawm ob lub qog-txuas nrog T hlwb thiab activated dendritic hlwb. [73]. Nws yog, yog li ntawd, pom zoo los ntawm pab pawg neeg tias DAMPs, zoo li HMGB1, tuaj yeem qhib cov hlwb dendritic uas, dhau los, ua rau T cell proliferation thiab maturation thiab pab txhawb rau kev tiv thaiv kab mob tiv thaiv kab mob [73].
cistanche tubulosa- txhim kho lub cev tiv thaiv kab mob
Kev cia siab rau pyroptosis hauv kev kho mob qog noj ntshav
Nyob rau hauv xyoo tas los no, ntau qhov kev tshawb fawb tau qhia txog qhov ua tau thiab kho qhov muaj peev xwm ntawm kev siv cov pyroptosis los koom nrog kev tiv thaiv kab mob los ntawm ntau hom phiaj thiab kev xa khoom (Fig. 2). Siv cov qog-cell-derived microparticles (TMP), piv txwv li, Gao li al. tau xa cov methotrexate mus rau hauv cholangiocarcinoma (CCA) cov hlwb los ntxias GSDME mediated pyroptosis, ua rau kev ua kom cov neeg mob tau txais cov macrophages thiab nrhiav cov neutrophils rau cov qog nqaij hlav rau cov tshuaj tiv thaiv qog noj ntshav [74]. Tsis tas li ntawd, thaum qhov kev xa tawm ntawm methotrexate-TMP no tau nkag mus rau hauv cov kua tsib lumen ntawm extrahepatic CCA cov neeg mob, kev ua kom neutrophil thiab kev daws teeb meem ntawm biliary obstruction tau pom nyob rau hauv 25% ntawm cov neeg mob [74]. GSDME-mediated pyroptosis kuj tau pom tias tau tshwm sim hauv melanoma los ntawm kev sib xyaw ntawm BRAF thiab MEK inhibitors, ua rau lub cev tiv thaiv kab mob hauv lub cev / ua kom muaj zog thiab melanoma regression [73]. Hauv lwm lub tswv yim, metformin, cov tshuaj feem ntau siv los kho mob ntshav qab zib hom 2, tau siv los tiv thaiv qog noj ntshav cell proliferation los ntawm kev ua kom tsis muaj zog pyroptosis los ntawm caspase-3 [75]. Tshwj xeeb, metformin tau pab txhawb rau mitochondrial tsis ua haujlwm thiab ua rau txoj hauv kev AMPK/SIRT1/NF-κB, txhawb nqa Bax tsub zuj zuj thiab cytochrome c tso tawm, uas, dhau los, ua rau caspase-3 ua kom thiab GSDME cleavage [75]. Ntau yam ntawm cov tshuaj me me-molecule inhibitors tsom KRAS-, EGFR-, lossis ALK-mutant ntsws qog noj ntshav kuj tau tshawb pom los ua kom cov pyroptotic tuag los ntawm caspase-3- kev sib haum xeeb ntawm GSDME tom qab ua kom muaj txoj hauv kev mitochondrial intrinsic apoptosis [43]. Cov pab pawg nrhiav pom tau hais tias ob txoj hauv kev PCD no tswj hwm ib leeg thiab cov pyroptosis tuaj yeem siv los ua kom muaj txiaj ntsig ntawm kev kho mob qog noj ntshav, txawm hais tias cov nyhuv no tau txo qis thaum qhov kev ua haujlwm apoptotic tsis zoo [43]. Hauv cov qog nqaij hlav cancer ntawm lub mis, kev kho mob nrog RIG- 1 agonist tau ua rau txoj hauv kev ntawm apoptosis extrinsic thiab pyroptosis, ua kom STAT1 thiab NF-κB thiab txhim kho lymphocyte-recruiting chemokines [76]. Yog li ntawd, kev txo qis hauv qog nqaij hlav cancer mis thiab qog loj hlob tau nrog kev nce hauv qog lymphocytes tom qab RIG-1 ua kom cov nas [76]. Txawm hais tias kev hloov pauv ntawm apoptosis mus rau pyroptosis tseem tsis tau paub meej, tsis ntev los no tau tsim cov NF-κB inhibitor, 13d, tau pom los ntes cov qog nqaij hlav cancer hauv theem G2 / M thiab txhawb qhov kev hloov no [77]. Kev kho mob nrog 13d kuj ua rau muaj cov nyhuv antitumor muaj zog hauv vivo thaum pom cov tshuaj toxicity tsawg [77], zoo ib yam li L61H10, lwm qhov sib xyaw tau tshaj tawm los ua kom muaj kev hloov pauv apoptosis-rau-pyroptosis, kuj zoo li los ntawm NF-κB inhibition [78].
Ib qho teeb meem tseem ceeb hauv kev txhim kho pyroptosis-raws li kev tiv thaiv kab mob qog noj ntshav yog qhov tseeb tias ntau cov qog noj ntshav txo qis lawv txoj kev qhia ntawm GSDM cov proteins lossis nthuav tawm cov ntawv hloov pauv, tsis ua haujlwm ntawm lawv [33]. Hmoov zoo, qhov teeb meem no tau ua rau muaj kev txaus siab ntawm ntau tus kws tshawb fawb uas tau pib tsim cov kev daws teeb meem ntse, xws li Fan et al., uas tau mus txog qhov teeb meem los ntawm epigenetic targeting [79]. Los ntawm kev siv decitabine rau demethylate GSDME ua ke nrog nanolipo qee qhov nqa cov tshuaj khomob uas ua rau caspase-3, pab pawg tau thim rov qab GSDME ua kom ntsiag to hauv cov qog hlwb thiab ua rau pyroptosis. Ntxiv nrog rau kev txo cov qog loj hlob, metastasis, thiab rov ua dua, cov txheej txheem no kuj txhawb kev tiv thaiv kab mob los ntawm pyroptosis-induced cytokine tso [79]. Xav txog tias 91% ntawm cov neeg mob qog noj ntshav cuam tshuam txog GSDME kev hloov pauv tau soj ntsuam los ntawm Zhang li al. tau pom tias ua rau poob ntawm kev ua haujlwm [33], txawm li cas los xij, nws yog qhov qhia tias kev tsom xam ntawm epigenetic tej zaum yuav tsis yog ib txoj hauv kev zoo los ntxias pyroptosis hauv qee cov neeg mob. Lub hom phiaj xa khoom ntawm GSDM cov proteins uas ua haujlwm ncaj qha rau cov qog nqaij hlav cancer ntawm nanotechnology [70], yuav muab txoj hauv kev txhim khu kev qha thiab muaj txiaj ntsig los hla qhov teeb meem no. Lwm qhov teeb meem tseem ceeb uas ntsib ze li ntawm txhua txoj kev tiv thaiv kab mob tiv thaiv kab mob tiv thaiv kab mob yog cov kab mob dysregulation tshwm sim los ntawm kev tiv thaiv kab mob microenvironment, xws li los ntawm inhibitory receptors zoo li PD-1. Hais txog qhov no, Lu et al. engineered NK92 hlwb uas muaj ib tug chimeric costimulatory converting receptor (CAR) uas converts lub inhibitory PD-1 teeb liab mus rau ib tug activating teeb liab, zoo txhawb lub hlwb 'anttumor kev ua si tiv thaiv H1299 mob ntsws cancer hlwb [80]. Nyob rau hauv vitro, CR NK92 hlwb sai tua H1299 hlwb los ntawm GSDME-mediated pyroptosis thiab, nyob rau hauv vivo, ho inhibited qog loj hlob [80]. Ua ke nrog Liu thiab cov npoj yaig cov kev soj ntsuam ntawm CAR-T cell-induced pyroptosis [72], nws zoo nkaus li tias yav tom ntej kev tshawb nrhiav rau hauv CAR-raws li kev kho mob, txawm tias nyuaj, yuav muaj txiaj ntsig tshwj xeeb. Ntxiv mus, qhov txaus siab thiab loj hlob ntawm cov ntaub ntawv qhia tias pyroptosis induction synergizes nrog PD-1 inhibitors kom tig 'txias' qog 'kub' qhia tias peb tsuas yog pib nkag siab txog qhov sib xyaw ua ke ntawm pyroptosis (Fig. 2) [35 , 70] ib.
Daim duab 2 Pyroptosis heats anticancer tiv thaiv kab mob. 'Cov qog mob khaub thuas': cov qog hlwb tsim cov kab mob tiv thaiv kab mob microenvironment thiab zam kev tiv thaiv kab mob thiab tua los ntawm kev nrhiav cov tshuaj tiv thaiv kab mob, ua kom cov kab mob tiv thaiv kab mob, tiv thaiv kev nthuav tawm antigen, thiab tso tawm cov tshuaj tiv thaiv kab mob. 'Cov qog ua kom sov': ntau lub tswv yim yog siv los ua kom cov qog cell pyroptosis thiab "tshav kub" qog los ntawm lub cev tsis muaj zog. 'Sov qog': pyroptotic qog hlwb tso tawm pro-inflammatory cytokines thiab cov khoom siv tshuaj tiv thaiv kab mob uas ua rau lub cev tiv thaiv kab mob thiab kev nrhiav neeg ua haujlwm. 'Cov qog kub': cov tshuaj tiv thaiv kab mob infiltrated paub thiab tua cov qog hlwb, thiab qhov kev tua no tuaj yeem koom nrog hauv cov lus qhia zoo uas txhim kho cov qog nqaij hlav. Kev tshem tawm cov qog tuaj yeem nce ntxiv los ntawm cov tswv yim kho mob combinatorial. CAR-T, chimeric antigen receptor T cell; CR-NK, chimeric costimulatory converting receptor natural killer cell; DC, dendritic cell; GSDMs, gastrin proteins; HMGB1, high-mobility pawg lub thawv protein 1; IFN-, interferon-gamma; IL, interleukin; MDSCs, myeloid-derived suppressor hlwb; MHC, loj histocompatibility complex; NK, ntuj killer cell; NP, nanoparticle; PD-L1, programmed tuag-ligand 1; PD-1, programmed cell death protein 1; TNF-, qog necrosis factor-alpha; Tregs, tswj T cells
Cov lus xaus thiab cov kev xav yav tom ntej
Raws li kev mob hlwb tuag hom, pyroptosis plays lub luag haujlwm tseem ceeb hauv kev tiv thaiv qog nqaij hlav los ntawm galvanizing tiv thaiv qog lub cev tiv thaiv kab mob ua haujlwm. Qee qhov xwm txheej, nws tau qhia tias pyroptosis induction ib leeg tuaj yeem txaus los cuam tshuam cov qog loj hlob, txawm hais tias muaj kev hloov pauv hauv nws cov txiaj ntsig thiab cuam tshuam tsis zoo (xws li, CRS hauv CAR-T cell therapy) qhia tias nws txoj haujlwm kho mob yuav zoo tshaj plaws thaum siv ua ke nrog lwm cov tshuaj tiv thaiv kab mob thiab kho kom haum rau cov neeg mob thiab cov qog nqaij hlav. Ib qho ntawm cov teeb meem loj tshaj plaws uas ntsib txoj haujlwm kho mob ntawm pyroptosis zoo li yog qhov tsis sib xws hauv kev qhia thiab kev ua haujlwm ntawm pyroptosis-hais txog Cheebtsam, tsis tsuas yog hla cov qog nqaij hlav sib txawv tab sis kuj nyob hauv lawv. Txawm li cas los xij, kev nce qib hauv molecular, genetic, thiab epigenetic lub hom phiaj / kev xa khoom, nrog rau cov tshuaj muaj tseeb thiab tus kheej, muab kev cia siab tias tsis ntev peb yuav muaj cov cuab yeej thiab kev paub xav tau los siv cov cuab yeej muaj zog no ua riam phom tiv thaiv kab mob.
Cov ntaub ntawv
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