Cancer cell death: Cell-autonomous and immunogenic dimensions

Regulated cell death (RCD) shapes neoplastic transformation, tumor progression, and response to treatment. While apoptosis was long viewed as the only RCD variant, additional modalities, including necroptosis, pyroptosis, and ferroptosis, have been characterized. These interconnected pathways operate in a context-dependent manner to influence the dynamic interplay between malignant and non-malignant cells that governs disease progression or regression, both naturally and during therapy. Major advances stemmed from recognizing immunogenic cell death (ICD) as an RCD type defined by the emission of immunomodulatory damage-associated molecular patterns (DAMPs) from dying cancer cells. The balance between immunostimulatory and immunosuppressive DAMPs dictates whether neoplastic cells undergoing RCD effectively activate adaptive immunity. Thus, ICD provides mechanistic grounds for the durable efficacy of certain cancer therapeutics, and underpins their synergy with immune checkpoint inhibitors. Understanding the molecular determinants of RCD and ICD is reshaping oncology, allowing for an increasingly refined integration between cytotoxicity and durable anticancer immune responses.