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Review
. 2021 May 3;40(1):153.
doi: 10.1186/s13046-021-01959-x.

Pyroptosis: a new paradigm of cell death for fighting against cancer

Yixin Tan  1   2   3   4 , Quanzhu Chen  1   2   3 , Xiaoling Li  1   2   3 , Zhaoyang Zeng  1   2   3 , Wei Xiong  1   2   3 , Guiyuan Li  1   2   3 , Xiayu Li  3 , Jianbo Yang  5 , Bo Xiang  6   7   8 , Mei Yi  9   10   11
Affiliations
Review

Pyroptosis: a new paradigm of cell death for fighting against cancer

Yixin Tan et al. J Exp Clin Cancer Res. .

Erratum in

Abstract

Background: Unraveling the mystery of cell death is one of the most fundamental progresses of life sciences during the past decades. Regulated cell death (RCD) or programmed cell death (PCD) is not only essential in embryonic development, but also plays an important role in the occurrence and progression of diseases, especially cancers. Escaping of cell death is one of hallmarks of cancer.

Main body: Pyroptosis is an inflammatory cell death usually caused by microbial infection, accompanied by activation of inflammasomes and maturation of pro-inflammatory cytokines interleukin-1β (IL-1β) and interleukin-18 (IL-18). Gasdermin family proteins are the executors of pyroptosis. Cytotoxic N-terminal of gasdermins generated from caspases or granzymes proteases mediated cleavage of gasdermin proteins oligomerizes and forms pore across cell membrane, leading to release of IL-1β, IL-18. Pyroptosis exerts tumor suppression function and evokes anti-tumor immune responses. Therapeutic regimens, including chemotherapy, radiotherapy, targeted therapy and immune therapy, induce pyroptosis in cancer, which potentiate local and systemic anti-tumor immunity. On the other hand, pyroptosis of normal cells attributes to side effects of anti-cancer therapies.

Conclusion: In this review, we focus on the regulatory mechanisms of pyroptosis and the tumor suppressive function of pyroptosis. We discuss the attribution of pyroptosis in reprogramming tumor microenvironments and restoration of anti-tumor immunity and its potential application in cancer immune therapy.

Keywords: Adaptive immunity; Ferroptosis; Gasdermin; Immune checkpoint; Immunogenic cell death; Necroptosis; Tumor microenvironment.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
The canonical inflammasome and non-canonical inflammasome pathway in pyroptosis. The canonical inflammasome is assembled in response to exogenous pathogens and endogenous damage by intracellular sensor proteins, including NLRP1b, NLRC4, NLRP3, AIM2 and Pyrin. The canonical inflammasomes recruit pro-caspase 1 through inflammasome adaptor protein ASC, leading self-cleavage and activation of caspase 1. Active caspase 1 cleaves pro-inflammatory cytokines pro-IL-1β, pro-IL-18, leading to maturation of IL-1β, IL-18. Active caspase 1 cleaves GSDMD protein at the middle linker, liberating the cytotoxic N-terminus to form pore on plasma membrane, which allows the release of mature IL-1β, IL-18. In non-canonical pathway, LPS directly binds to murine pro-caspase 11 or its human homologs pro-caspase 4 and 5, leading activation of caspase 11/4/5. In non-canonical inflammasome pathway, cleavage of GSDMD is executed by active caspase 11 or caspase 4 and 5 upon direct binding of cytosolic LPS. Chemotherapy drugs could induce pyroptosis in epithelial cells through activating mitochondrial death machinery and caspase 3. In this case, GSDME is cleaved by active caspase 3. GSDME-N in turn activates NLRP3 inflammasome, leading to activation of caspase 1/GSDMD cascade, which promotes maturation of IL-1β, IL-18. Gasdermins could be cleaved by Lymphocyte-derived granzymes proteases, unleashing the pore-formation ability to trigger pyroptosis of cancer cells
Fig. 2
Fig. 2
Immunosuppressive tumor microenvironments. Tumor microenvironments are composed of cellular components, extracellular matrix and interstitial fluid. Chemokines secreted from cancer cells recruit a variety of immune cells infiltrating into tumor. The interactions between cancer cells and the infiltrated immune cells determine the progression of cancer and therapeutic efficacy. Immune suppressive cells, including Treg, MDSC and M2 type TAM, limit function of the cytotoxic T cells and make tumor microenvironments immunosuppressive. Furthermore, tumor derived cytokines, like TGF-β, IL-6, etc., also suppress immune responses
Fig. 3
Fig. 3
Induction of pyroptosis by therapeutic regimens evokes anti-tumor immune responses. Therapeutic modalities, including chemotherapy, targeted therapy, radiotherapy and CAR T cells, induce pyroptosis in cancer cells. Cancer cells undergoing pyroptotic cell death release pro-inflammatory factors (IL-1β, IL-18), alarmin (HMGB1, ATP, etc.), and causing intensive inflammation in the local environments. Pyroptosis in cancer generates abundant neoantigens, which are processed by antigen-presenting cells to promote the formation of antigen-specific cytotoxic T lymphocyte (CTL), thereby evoking anti-tumor immunity. Combination of pyroptosis-inducible therapeutic regimens with ICIs enhances anti-tumor immune responses and promotes tumor regression, achieving long-term control of cancer
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References

    1. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646–674. - PubMed
    1. Vanden Berghe T, Linkermann A, Jouan-Lanhouet S, Walczak H, Vandenabeele P. Regulated necrosis: the expanding network of non-apoptotic cell death pathways. Nat Rev Mol Cell Biol. 2014;15(2):135–147. - PubMed
    1. Kepp O, Senovilla L, Vitale I, Vacchelli E, Adjemian S, Agostinis P, Apetoh L, Aranda F, Barnaba V, Bloy N, Bracci L, Breckpot K, Brough D, Buqué A, Castro MG, Cirone M, Colombo MI, Cremer I, Demaria S, Dini L, Eliopoulos AG, Faggioni A, Formenti SC, Fučíková J, Gabriele L, Gaipl US, Galon J, Garg A, Ghiringhelli F, Giese NA, Guo ZS, Hemminki A, Herrmann M, Hodge JW, Holdenrieder S, Honeychurch J, Hu HM, Huang X, Illidge TM, Kono K, Korbelik M, Krysko DV, Loi S, Lowenstein PR, Lugli E, Ma Y, Madeo F, Manfredi AA, Martins I, Mavilio D, Menger L, Merendino N, Michaud M, Mignot G, Mossman KL, Multhoff G, Oehler R, Palombo F, Panaretakis T, Pol J, Proietti E, Ricci JE, Riganti C, Rovere-Querini P, Rubartelli A, Sistigu A, Smyth MJ, Sonnemann J, Spisek R, Stagg J, Sukkurwala AQ, Tartour E, Thorburn A, Thorne SH, Vandenabeele P, Velotti F, Workenhe ST, Yang H, Zong WX, Zitvogel L, Kroemer G, Galluzzi L. Consensus guidelines for the detection of immunogenic cell death. Oncoimmunology. 2014;3(9):e955691. - PMC - PubMed
    1. Yatim N, Cullen S, Albert ML. Dying cells actively regulate adaptive immune responses. Nat Rev Immunol. 2017;17(4):262–275. - PubMed
    1. Legrand AJ, Konstantinou M, Goode EF, Meier P. The diversification of cell death and immunity: memento Mori. Mol Cell. 2019;76(2):232–242. - PubMed