Harnessing Immunogenic Cell Death to Boost the Impact of Radiation Therapy

Harnessing radiotherapy (RT) to effectively eliminate cancer cells has been a cornerstone of clinical oncology for decades. Beyond its well-established cytotoxic effects, RT triggers a diverse array of tumor cell death modalities, including apoptosis, necrosis, mitotic catastrophe, and, under specific conditions, immunogenic forms such as necroptosis and pyroptosis. Although apoptosis serves as a homeostatic and immunologically silent process that removes over 200 billion cells daily in our body, lytic forms of regulated cell death, such as necroptosis and pyroptosis, have evolved to detect and combat pathogens, thereby acting as potent danger signals that alert and mobilise immune responses. Here, we review emerging pathogen-mimicry approaches to rewire RT-induced cell death towards more immunogenic cell death modalities, aiming to transform RT from a primarily tumor-debulking modality into a driver of durable anti-tumor immunity.