Cell death and immunity in cancer: From danger signals to mimicry of pathogen defense responses

Summary The immunogenicity of cancer cells is an emerging determinant of anti‐cancer immunotherapy. Beyond developing immunostimulatory regimens like dendritic cell‐based vaccines, immune‐checkpoint blockers, and adoptive T‐cell transfer, investigators are beginning to focus on the immunobiology of dying cancer cells and its relevance for the success of anticancer immunotherapies. It is currently accepted that cancer cells may die in response to anti‐cancer therapies through regulated cell death programs, which may either repress or increase their immunogenic potential. In particular, the induction of immunogenic cancer cell death ( ICD ), which is hallmarked by the emission of damage‐associated molecular patterns (DAMPs); molecules analogous to pathogen‐associated molecular patterns (PAMPs) acting as danger signals/alarmins, is of great relevance in cancer therapy. These ICD ‐associated danger signals favor immunomodulatory responses that lead to tumor‐associated antigens (TAAs)‐directed T‐cell immunity, which paves way for the removal of residual, treatment‐resistant cancer cells. It is also emerging that cancer cells succumbing to ICD can orchestrate “altered‐self mimicry” i.e. mimicry of pathogen defense responses, on the levels of nucleic acids and/or chemokines (resulting in type I interferon/ IFN responses or pathogen response‐like neutrophil activity). In this review, we exhaustively describe the main molecular, immunological, preclinical, and clinical aspects of immunosuppressive cell death or ICD (with respect to apoptosis, necrosis and necroptosis). We also provide an extensive historical background of these fields, with special attention to the self/non‐self and danger models, which have shaped the field of cell death immunology.