Radiation-Induced Cell-Death States in Cancer: Toward Biomarker-Guided Radioimmunotherapy

Radiotherapy can convert local tumor injury into systemic antitumor immunity, but this effect depends less on the nominal mode of cell death than on the tissue state that follows irradiation. This narrative review reframes radiation-induced regulated cell death around four functional outputs: antigen preservation, productive innate sensing, effector-cell access, and suppressive remodeling. We distinguish early endoplasmic-reticulum-stress-associated damage-associated molecular pattern (DAMP) signaling from delayed micronucleus-driven cGAS-STING-type I interferon activation, emphasizing that apoptosis becomes immunogenic only in a permissive context. Ferroptosis offers a tractable but double-edged adjunct because lipid peroxidation can enhance tumor killing while impairing dendritic-cell cross-presentation. Necroptosis and pyroptosis are compartment- and genotype-dependent inflammatory amplifiers, whereas persistent senescence can promote fibrosis, immune suppression, and relapse. We further integrate tumor genotype, metabolic state, host lymphocyte reserve, spatial heterogeneity, radiation dose and field design, and checkpoint timing into four provisional states: primed immunogenic death, lytic but poorly sensed death, smoldering inflammatory suppression, and senescent-persistent residual disease. Serial tissue, blood, and imaging measurements may enable state assignment while preserving temporal and spatial context. These states are proposed for prospective testing rather than as established treatment categories.