Immune-sparing radiotherapy in solid tumors: radiation-induced lymphopenia, circulating immune-cell dose, and biomarker-guided optimization of radioimmunotherapy

Radiotherapy is a central component of solid tumor management and can enhance antitumor immunity through antigen release, immunogenic cell death, innate immune activation, and tumor microenvironment remodeling. However, radiotherapy can also induce systemic immune injury by depleting circulating lymphocytes and irradiating lymphoid organs. This review aims to examine radiation-induced lymphopenia (RIL) as a clinically relevant manifestation of systemic immune injury and its potential implications for radioimmunotherapy. This narrative review discusses the biological basis of RIL, including lymphocyte radiosensitivity, circulating blood exposure, lymphoid-organ irradiation, treatment volume, fractionation, systemic therapy, and patient immune reserve. It also summarizes clinical evidence regarding the association of severe or persistent RIL with outcomes across solid tumors and examines emerging dosimetric and biological biomarkers relevant to immune-sparing radiotherapy. Severe or persistent RIL has been associated with inferior outcomes across multiple solid tumors and may be particularly relevant in patients receiving immune checkpoint inhibitors. Emerging dosimetric biomarkers include effective dose to immune cells, estimated dose of radiation to immune cells, circulating blood dose, blood dose-volume histograms, immune dose-volume histograms, marrow dose, spleen dose, and low-dose bath metrics. Potential biological biomarkers include baseline absolute lymphocyte count, treatment-related lymphocyte decline, immune recovery kinetics, inflammatory indices, immune-cell subsets, circulating tumor DNA (ctDNA) dynamics, and plan-derived immune exposure. Together, these parameters may support a biomarker-guided framework for immune-sparing radiotherapy. RIL should not be regarded merely as a laboratory abnormality, but as a clinically relevant systemic immune injury that may reflect reduced systemic immune competence and influence radioimmunotherapy efficacy. Immune-sparing radiotherapy should not compromise target coverage or tumor control, but may provide a clinically meaningful direction for optimizing radioimmunotherapy in solid tumors.