Synergistic Mechanisms and Clinical Progress of Radionuclide Therapy Combined with Immune Checkpoint Inhibitors in Colorectal Cancer.

Background: Radionuclide therapy (RNT) and immune checkpoint inhibitors (ICIs) show mechanistic synergy in colorectal cancer (CRC), but clinical evidence remains limited.Objective: To summarize biological rationale, translational mechanisms, and current clinical evidence supporting RNT-ICI combinations in CRC.Methods: Narrative translational review integrating preclinical studies, radionuclide therapy literature, and CRC radiotherapy-ICI clinical trials.Results: ICIs are effective mainly in MSI-H/dMMR CRC, whereas MSS/pMMR tumors remain resistant. RNT-particularly Y-90 radioembolization-may induce immunogenic cell death, cGAS-STING activation, type I interferon signaling, and stromal remodeling. A pilot clinical study of Y-90 plus dual ICIs demonstrated feasibility and safety but limited efficacy. Evidence from EBRT-ICI CRC studies supports radiation-induced immune priming but is not directly transferable to RNT.Conclusion: RNT-ICI combinations are biologically plausible but not yet clinically validated. Future progress requires biomarker-driven, dosimetry-informed, and liver-dominant trial designs.