Post-translational modification networks in tumor radiosensitivity: mechanistic insights and therapeutic opportunities

Radiotherapy is a central modality in cancer management, yet intrinsic and acquired radioresistance and dose-limiting normal tissue toxicities continue to constrain durable tumor control. Beyond genetic and transcriptional programs, post-translational modifications (PTMs) provide rapid and reversible regulation that can rewire radiation responses across tumor and stromal compartments. This review synthesizes recent advances defining how major PTM axes, including ADP-ribosylation, ubiquitination and deubiquitination, neddylation, SUMOylation, methylation, acetylation, and lactylation, shape tumor radiosensitivity and radiation-induced injury. We highlight mechanistic links to DNA damage recognition and repair pathway choice, chromatin remodeling, checkpoint control, and cell-fate decisions encompassing apoptosis and ferroptosis. We further discuss how PTM-driven metabolic and redox adaptation influences post-irradiation signaling, and how PTMs modulate anti-tumor immunity by affecting immunogenic cell death, antigen presentation, cytokine networks, and immune checkpoint regulation within the tumor microenvironment. In addition, we summarize emerging evidence for reciprocal crosstalk between PTM enzymes and non-coding RNAs, which can act as upstream regulators, scaffolds, or effectors to reinforce context-specific modification patterns and therapeutic vulnerabilities. Viewing radioresponse through a PTM-network lens reveals actionable nodes for radiosensitization and radioprotection. Targeting PTM writers, erasers, and readers, alone or in rational combinations with radiotherapy, DNA damage response inhibitors, epigenetic agents, and immunotherapy, may overcome resistance while improving the therapeutic window. Future efforts should prioritize context-specific biomarkers, on-target toxicity management, and mechanism-informed trial designs to translate PTM-guided strategies into clinically meaningful gains.