Combining Radiation Therapy and Tumor-Infiltrating Lymphocyte Therapy: Biological Rationale, Clinical Synergies, and Future Directions.

Tumor-infiltrating lymphocyte (TIL) therapy is the first adoptive cellular therapy approved to treat solid tumors and has demonstrated durable responses in advanced melanoma. However, its clinical implementation is limited by the need for tumor harvesting, manufacturing delays, and lymphodepleting conditioning. These logistic challenges are also opportunities for physicians and scientists to consider combining TIL therapy with radiation therapy (RT), a modality with well-established roles in cancer care. RT exerts both immunostimulatory and immunosuppressive effects, influencing antigen presentation and T-cell trafficking while also contributing to lymphocyte depletion in a dose- and context-dependent manner. These properties provide a strong biologic rationale for integration with TIL therapy but also introduce important uncertainties. Preclinical studies suggest RT can enhance TIL expansion and function, while early clinical experience supports the feasibility of RT delivery before and after TIL therapy in selected scenarios. However, prospective clinical data remain limited, and key questions regarding optimal timing, dose, and target selection are unresolved. In this review, we propose a workflow-based framework for combining RT with TIL therapy across pre-harvest, bridging, peri-infusion, and post-infusion settings. RT is a promising partner to TIL therapy, but prospective studies will ultimately be needed to define how best to integrate RT in order to translate biologic synergy into consistent clinical benefit.