Targeting E3 ubiquitin ligases: Mechanistic breakthroughs and novel clinical translation pathways for tumor radioimmunotherapy.

The combination of radiation therapy and immunotherapy has become a cornerstone of modern clinical cancer treatment. However, the inherent radiation resistance of tumors and complex immune evasion mechanisms remain major bottlenecks limiting their long-term effects and sustained efficacy. E3 ubiquitin ligases critically influence tumor sensitivity to radioimmunotherapy by controlling protein stability across DNA repair, immune signaling, and stress-response pathways. This review systematically dissects the multidimensional molecular network through which E3 ubiquitin ligases regulate radiosensitivity and immunoresponsiveness. At the intracellular level, we provide an in-depth analysis of how E3 ubiquitin ligases determine the fate of radiation-induced damage repair by precisely regulating the kinetics of the DNA damage response (DDR), cell cycle checkpoints, and apoptosis thresholds. At the extracellular level, this study focuses on the key roles of E3 ubiquitin ligases in reshaping the immune microenvironment, including the maintenance of spatiotemporal stability of immune checkpoints, the fidelity of antigen processing and presentation, and the epigenetic regulation of microenvironmental dynamic plasticity. Recent studies indicate that E3 ubiquitin ligases link radiation-induced DDR signaling to innate and adaptive immune activation, particularly through the induction of immunogenic cell death (ICD) and the calibration of innate immune sensing pathways like cGAS-STING. Finally, we provide a comprehensive synthesis of cutting-edge translational strategies targeting E3 ubiquitin ligases-ranging from canonical inhibitors to transformative proteolysis-targeting chimeras (PROTACs) and molecular glue degraders (MGDs)-offering novel paradigms for overcoming therapeutic resistance and refining personalized radioimmunotherapy.