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.
范旗 et al. (Tue,) studied this question.