Proton Therapy and Immune Preservation: Dosimetric Rationale, Clinical Evidence, and Implications for the Immunotherapy Era.

Abstract

Radiation-induced lymphopenia (RIL) is a clinically significant and potentially modifiable consequence of radiotherapy, independently associated with worse survival and attenuated immunotherapy efficacy across multiple disease sites. Its mechanistic basis lies in the exquisite radiosensitivity of circulating lymphocytes and the irradiation of hematopoietically active bone marrow and lymphatic structures within and adjacent to standard treatment fields. Proton therapy, through its fixed beam angles and lack of exit dose by virtue of the Bragg peak phenomenon, delivers substantially less integral dose to surrounding normal tissues, reducing cumulative radiation exposure to the circulating immune compartment. This dosimetric advantage translates into meaningfully lower rates of severe RIL in lung, esophageal, brain, and head and neck cancers. The effective dose to immune cells (EDIC) - a composite metric integrating mean heart dose, mean lung dose, and mean body dose to estimate cumulative lymphocyte irradiation over a treatment course - and the effective dose to immune cells, radiotherapy course-adjusted (EDRIC), have been validated as dosimetric predictors of RIL severity and as independent predictors of progression-free survival in stage III non-small cell lung cancer (NSCLC) patients receiving consolidative durvalumab. In an era defined by the widespread integration of immune checkpoint inhibitors (ICI) into radiotherapy-based regimens, preservation of immune competence during treatment has direct therapeutic implications. This review synthesizes mechanistic, dosimetric, and clinical evidence supporting the role of proton therapy in immune sparing, with emphasis on emerging randomized data and actionable treatment planning strategies.