Pyroptotic cell death: an emerging therapeutic opportunity for radiotherapy

Abstract

Pyroptotic cell death, an inflammatory form of programmed cell death (PCD), is emerging as a potential therapeutic opportunity for radiotherapy (RT). RT is commonly used for cancer treatment, but its effectiveness can be limited by tumor resistance and adverse effects on healthy tissues. Pyroptosis, characterized by cell swelling, membrane rupture, and release of pro-inflammatory cytokines, has been shown to enhance the immune response against cancer cells. By inducing pyroptotic cell death in tumor cells, RT has the potential to enhance treatment outcomes by stimulating anti-tumor immune responses and improving the overall efficacy of RT. Furthermore, the release of danger signals from pyroptotic cells can promote the recruitment and activation of immune cells, leading to a systemic immune response that may target distant metastases. Although further research is needed to fully understand the mechanisms and optimize the use of pyroptotic cell death in RT, it holds promise as a novel therapeutic strategy for improving cancer treatment outcomes. This review aims to synthesize recent research on the regulatory mechanisms underlying radiation-induced pyroptosis and to elucidate the potential significance of this process in RT. The insights gained from this analysis may inform strategies to enhance the efficacy of RT for tumors.

Pore formation at the lytic synapse triggers the canonical pyroptotic cell death pathway

“…In the context of oncology, multiple chemotherapeutics 19,110,111 , small molecule inhibitors 112 , radiation [113][114][115] , and tumor immunotherapy 25,27 as well as nanoparticle-based approaches for therapeutic delivery of gasdermins 41,116 have been shown to drive tumor cell pyroptosis, which strongly favours anti-tumor immunity and tumor clearance, particularly in the context of turning "cold" tumors "hot" (reviewed in 24,98 ). Mass spectrometry-based human proteomics studies have revealed that GSDMD-mediated pyroptosis releases several hundred different proteins, through a combination of conventional secretion, unconventional secretion, vesicle/lysosome release, and passive cell lysis (e.g.…”