Expanding the Horizon of Targeted Radionuclide Therapy: Immunotherapy Combinations and FAP-Targeted Approaches.

Targeted radionuclide therapy (TRT) has emerged as a promising cancer treatment modality and is increasingly recognized as an immunomodulatory tool, similar to external beam radiotherapy (EBRT). Both forms of radiation can reshape the tumor immune microenvironment, providing a rationale for their combination with immune checkpoint inhibitors (ICIs) to harness synergistic effects while mitigating immunosuppressive mechanisms. Outcomes of such combinations depend on radiation dose/fractionation, treatment sequencing, target selection, and the choice of immunotherapeutic/radiopharmaceutical agents. Among novel TRT strategies, fibroblast activation protein-TRT (FAP-TRT) stands out for its targeting of cancer-associated fibroblasts (CAFs), key components of the tumor stroma involved in immune evasion and therapy resistance. Unlike conventional TRTs that directly target tumor cells, FAP-TRT acts on CAFs, potentially modulating the tumor microenvironment to enhance the immunomodulatory effects of radiation. This review examines the immunological effects of radiation-via EBRT or TRT-and the rationale for combining TRT with ICIs. We highlight preclinical and clinical studies demonstrating both the synergistic potential and context-specific limitations of TRT-ICI combinations. Emphasis is placed on the emerging role of FAP-TRT in remodeling the tumor microenvironment, converting "cold" tumors into "hot" phenotypes, and enhancing immune infiltration. Preclinical models show synergy between FAP-TRT and ICIs, but challenges remain, including clarifying FAP-TRT's effects on CAF subpopulations, optimizing radiopharmaceutical design, and addressing shared issues with TRT/EBRT-ICI combinations, such as dosing, sequencing, and target selection. The integration of TRT and immunotherapy-particularly FAP-TRT combinations-offers a compelling avenue for precision oncology and warrants further translational and clinical investigation.