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.