The dual role of pyroptosis in prostate cancer: new perspectives from molecular mechanisms to clinical translation.

Pyroptosis, a gasdermin-mediated form of programmed inflammatory cell death, plays a complex and context-dependent dual role in the initiation, progression, and therapeutic response of prostate cancer. This review methodically elucidates canonical and non-canonical pyroptotic molecular pathways, emphasizing their dysregulation in prostate cancer. On one hand, the epigenetic silencing of key effector proteins, such as Gasdermin E (GSDME), weakens pyroptosis’s tumor-suppressive and immune-activating functions, thereby promoting therapeutic resistance. On the other hand, sustained pyroptosis-associated inflammatory signaling shapes an immunosuppressive microenvironment, driving tumor progression. The article further explores novel therapeutic strategies targeting pyroptosis pathways, including restoring GSDME expression, developing specific inducers, co-activation of pyroptosis and ferroptosis pathways, and combination applications with chemotherapy or immune checkpoint inhibitors, while highlighting the potential of nanodelivery systems for achieving tumor-selective activation. Notwithstanding the persistent difficulties in biomarker development, tumor selectivity, and clinical translation, the modulation of pyroptosis presents a remarkably promising new paradigm for surmounting therapeutic challenges in castration-resistant and neuroendocrine prostate cancers.