Programmed cell death in cancer: targeting necroptosis to kill tumor cell

Necroptosis is a precisely regulated form of programmed cell death (PCD) that exhibits necrotic morphology while being orchestrated receptor-interacting protein kinase 1 (RIPK1), receptor-interacting protein kinase 3 (RIPK3), and mixed lineage kinase domain-like pseudokinase (MLKL). In tumor biology, necroptosis plays a context-dependent dual role: it can suppress tumor progression by inducing immunogenic cell death (ICD) and activating anti-tumor immune responses; yet it may also promote tumor progression and immunosuppression by triggering inflammatory responses. Emerging evidence indicates that small molecule compounds, natural products, and nanomedicine technologies can effectively induce necroptosis in tumor cells, providing opportunities to overcome traditional chemotherapy resistance and enhance anti-tumor immunity. However, clinical translation faces numerous challenges, including frequent downregulation of key necroptotic proteins, the lack of robust predictive biomarkers, and potential tumor-promoting effects. This review offers an integrative perspective linking necroptosis molecular mechanisms, dual functional outcomes, and therapeutic strategies, highlighting both opportunities and risks. By providing mechanistic insights and a framework for rational design of necroptosis-based interventions, this work aims to guide future research toward effective and safe anticancer therapies. Schematic illustration of the mechanisms, dual roles in tumor therapy, and inducers of necroptosis.