Role of PANoptosis in cancer: Double-edged sword effects and targeted therapies

PANoptosis is a recently recognized inflammatory form of programmed cell death mediated by the cytoplasmic multiprotein complex termed the PANoptosome, which integrates pyroptosis, apoptosis, and necroptosis. In cancer, PANoptosis exhibits a marked double-edged sword nature. On the one hand, its chronic or dysregulated activation may promote tumor progression by sustaining inflammation, shaping an immunosuppressive microenvironment, and facilitating invasion and metastasis. On the other hand, robust induction of PANoptosis can suppress tumor growth by triggering immunogenic cell death, overcoming apoptotic resistance, and sensitizing tumors to chemotherapy, radiotherapy, and immunotherapy. Importantly, these opposing effects are not fixed properties of PANoptosis, but are jointly determined by signal strength, molecular activation patterns, tumor stage, and tumor heterogeneity. This review summarizes the molecular mechanisms of PANoptosis and its dual roles in cancer, with particular emphasis on therapeutic strategies targeting PANoptosis. Major translational challenges are also highlighted, including the predominance of preclinical evidence, the lack of robust biomarkers, and the risk of inflammation-related toxicity, all of which underscore the need for more precise and context-dependent regulation of PANoptosis in cancer therapy.