Targeting pyroptosis for cancer immunotherapy: mechanistic insights and clinical perspectives

Abstract

Pyroptosis is a distinct form of programmed cell death characterized by the rupture of the cell membrane and robust inflammatory responses. Increasing evidence suggests that pyroptosis significantly affects the tumor microenvironment and antitumor immunity by releasing damage-associated molecular patterns (DAMPs) and pro-inflammatory mediators, thereby establishing it as a pivotal target in cancer immunotherapy. This review thoroughly explores the molecular mechanisms underlying pyroptosis, with a particular focus on inflammasome activation and the gasdermin family of proteins (GSDMs). It examines the role of pyroptotic cell death in reshaping the tumor immune microenvironment (TIME) involving both tumor and immune cells, and discusses recent advancements in targeting pyroptotic pathways through therapeutic strategies such as small molecule modulators, engineered nanocarriers, and combinatory treatments with immune checkpoint inhibitors. We also review recent advances and future directions in targeting pyroptosis to enhance tumor immunotherapy with immune checkpoint inhibitors, adoptive cell therapy, and tumor vaccines. This study suggested that targeting pyroptosis offers a promising avenue to amplify antitumor immune responses and surmount resistance to existing immunotherapies, potentially leading to more efficacious cancer treatments.