Lymphocytes are pivotal effectors in anticancer immunity, yet their profound radiosensitivity makes them vulnerable to collateral damage during radiotherapy (RT).This radiation-induced lymphopenia (RIL) undermines the efficacy of radioimmunotherapy and correlates with poor prognosis.Our work underscores that even low-dose splenic irradiation (e.g., a mean dose of 5 Gy) significantly increases severe RIL risk.This review synthesizes mechanistic insights into RIL, linking splenic irradiation and disruption of lymphoid homing to systemic immunosuppression.We critically evaluate transformative strategies to reconcile this paradox: FLASH-RT and spatially fractionated RT minimize lymphocyte exposure, while synergistic integration of low-dose and ablative RT reshapes the tumor microenvironment.Precision-guided immunotherapy sequencing-CTLA-4 blockade pre-RT and PD-1 inhibition post-RT-further exploits temporal windows of immune activation.By harnessing lymphocyte migration dynamics and radiomics, we chart a roadmap for lymphocyte-sparing radioimmunotherapy.We ultimately advocate for a 'Protect and Amplify' paradigm, prioritizing immune preservation to unlock durable antitumor responses, particularly in advanced cancer.
Zhou et al. (2026) studied this question.