The microbiota-lymphocyte protective axis (MLPA): a novel paradigm for overcoming radiation-induced lymphopenia (RIL) and potentiating the efficacy of tumor immuno-combination therapy.

Combination therapy involving radiotherapy and immune checkpoint inhibitors has become a cornerstone of modern oncology; however, its therapeutic efficacy is frequently compromised by radiation-induced lymphopenia, a phenomenon traditionally viewed as an unavoidable physical consequence of radiation exposure. Accumulating evidence suggests that RIL also reflects broader host-dependent biological dysregulation, extending beyond direct lymphocyte depletion. In this review, we introduce the microbiota-lymphocyte protective axis as a conceptual and integrative framework to recontextualize RIL as a biologically modulated state influenced by the gut microenvironment. We synthesize current mechanistic and clinical evidence indicating that microbial-derived signals may shape immune competence during radiotherapy by influencing hematopoietic lineage commitment within the bone marrow, cellular stress tolerance mechanisms such as DNA damage responses and mitochondrial quality control, as well as systemic neuroendocrine stress pathways. This framework supports a shift toward a dual-modulatory strategy that integrates lymphocyte-sparing radiotherapy approaches (e.g., stereotactic body radiotherapy) with microbiota-targeted interventions (e.g., postbiotics). While further validation is required, the MLPA model provides a biologically grounded perspective that may help refine personalized radio-immunotherapy strategies.