The double-edged sword of pyroptosis targeting in cancer therapy.

Pyroptosis, a lytic and pro-inflammatory form of programmed cell death executed by gasdermin (GSDM) family proteins through plasma membrane pore formation, represents a double-edged sword in cancer therapy. Initially distinguished from apoptosis and necrosis by its dependence on inflammatory caspases and inflammasome activation, pyroptosis is now understood to be fundamentally driven by the N-terminal fragments of cleaved GSDMs, which oligomerize to form cytotoxic pores. In cancer, pyroptosis induction exerts potent anti-tumor effects by directly eliminating malignant cells and stimulating immunogenic cell death (ICD), releasing damage-associated molecular patterns (DAMPs) that recruit and activate immune cells, thereby synergizing with immune checkpoint blockade. Key strategies to induce tumor pyroptosis include chemotherapy, targeted agents, engineered bispecific antibodies, innovative nanoplatforms delivering bioactive N-terminal domains of GSDMs or pyroptosis inducers, and specific natural compounds. However, this therapeutic potential is counterbalanced by significant challenges: constitutive GSDM expression in normal tissues underlies severe chemotherapy toxicity; chronic pyroptosis in hypoxic tumor cores promotes immunosuppressive necrosis and metastasis; and non-lytic functions of GSDM can suppress anti-tumor immunity. Furthermore, cancer cells evade pyroptosis through epigenetic silencing, alternative splicing generating dominant-negative isoforms, and ubiquitin-mediated degradation of GSDMs. Harnessing the anti-tumor potential of pyroptosis while circumventing its detrimental roles requires precise targeting strategies, leveraging biomarkers for patient stratification, and understanding context-dependent outcomes.