Molecular mechanisms and functions of pyroptosis in inflammation and antitumor immunity

Junwei Hou; Jung-Mao Hsu; Mien-Chie Hung

doi:10.1016/j.molcel.2021.09.003

Molecular mechanisms and functions of pyroptosis in inflammation and antitumor immunity

Mol Cell. 2021 Nov 18;81(22):4579-4590. doi: 10.1016/j.molcel.2021.09.003. Epub 2021 Sep 24.

Authors

Junwei Hou¹, Jung-Mao Hsu², Mien-Chie Hung³

Affiliations

¹ Xiangya Cancer Center, Xiangya Hospital, Central South University, Xiangya Road 87, Changsha 410008, Hunan, China; Otolaryngology Major Disease Research Key Laboratory of Hunan Province, Xiangya Road 87, Changsha 410008, Hunan, China; Department of Otolaryngology Head and Neck Surgery, Xiangya Hospital, Central South University, Xiangya Road 87, Changsha 410008, Hunan, China; Department of Molecular and Cellular Oncology, the University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address: houjunwei210@163.com.
² Graduate Institute of Biomedical Sciences, Research Center for Cancer Biology and Center for Molecular Medicine, China Medical University, Taichung, Taiwan.
³ Graduate Institute of Biomedical Sciences, Research Center for Cancer Biology and Center for Molecular Medicine, China Medical University, Taichung, Taiwan; Department of Molecular and Cellular Oncology, the University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Biotechnology, Asia University, Taichung, Taiwan. Electronic address: mhung@cmu.edu.tw.

Abstract

Canonically, gasdermin D (GSDMD) cleavage by caspase-1 through inflammasome signaling triggers immune cell pyroptosis (ICP) as a host defense against pathogen infection. However, cancer cell pyroptosis (CCP) was recently discovered to be activated by distinct molecular mechanisms in which GSDMB, GSDMC, and GSDME, rather than GSDMD, are the executioners. Moreover, instead of inflammatory caspases, apoptotic caspases and granzymes are required for gasdermin protein cleavage to induce CCP. Sufficient accumulation of protease-cleaved gasdermin proteins is the prerequisite for CCP. Inflammation induced by ICP or CCP results in diametrically opposite effects on antitumor immunity because of the differential duration and released cellular contents, leading to contrary effects on therapeutic outcomes. Here, we focus on the distinct mechanisms of ICP and CCP and discuss the roles of ICP and CCP in inflammation and antitumor immunity, representing actionable targets.

Keywords: Antitumor immunity; Cancer cell pyroptosis; Gasdermin; Immune cell pyroptosis; Inflammation; Pyroptosis.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Review

MeSH terms

Animals
Antineoplastic Agents / pharmacology*
Apoptosis
Caspases / metabolism
Cell Line, Tumor
Disease Progression
Humans
Immune System
Inflammasomes
Inflammation*
Interleukin-18 / metabolism
Interleukin-1beta / metabolism
Intracellular Signaling Peptides and Proteins / metabolism*
Lipopolysaccharides / metabolism
Mice
Neoplasms / immunology*
Neoplasms / metabolism
Neoplasms / therapy*
Phosphate-Binding Proteins / metabolism*
Protein Binding
Proteolysis
Pyroptosis*
Signal Transduction

Substances

Antineoplastic Agents
GSDMD protein, human
IL1B protein, human
Inflammasomes
Interleukin-18
Interleukin-1beta
Intracellular Signaling Peptides and Proteins
Lipopolysaccharides
Phosphate-Binding Proteins
Caspases

Abstract

Publication types

MeSH terms

Substances

Grants and funding