Programming regulated cell death to engineer whole-tumor-cell vaccines for cancer immunotherapy

Regulated cell death (RCD) encompasses a variety of genetically controlled cell death programs that are essential for maintaining tissue homeostasis and have emerged as promising therapeutic targets in oncology. When used to prepare whole-tumor-cell (WTC) vaccines, dying cancer cells provide broad tumor-antigen repertoires together with damage-associated molecular patterns (DAMPs) that can function as endogenous adjuvants. This review examines how distinct RCD pathways shape antitumor immunity and how they can be exploited to engineer next-generation WTC vaccines. We summarize the molecular and immunological features of major RCD modalities, including apoptosis, necroptosis, pyroptosis, ferroptosis, cuproptosis, and emerging forms of regulated death, emphasizing their divergent capacities to promote antigen uptake, dendritic-cell activation, cross-presentation, and T-cell priming. We also discuss key translational barriers, including tumor heterogeneity, immunosuppressive tumor microenvironments, variable sensitivity to RCD induction, empirical inactivation methods, and the lack of mechanism-informed potency assays. Particular attention is given to the safety challenge posed by highly inflammatory modalities such as necroptosis and pyroptosis, which require careful control to balance immunogenic potency with hyperinflammation or systemic toxicity. Future development should shift from procedure-defined tumor-cell killing toward precision RCD programming, quantitative validation of immunogenic "death fingerprints," rational combinations with immune-checkpoint blockade or microenvironment modulating therapies, and individualized optimization guided by dynamic immune monitoring. By clarifying the interplay between RCD and antitumor immunity, this review provides a framework for designing reproducible, mechanism-guided, and clinically translatable WTC vaccines.