Low-dose radiotherapy as an immunomodulator in cancer: dose-specific mechanisms and hybrid high-dose/low-dose strategies

Low-dose radiotherapy (LDRT), conventionally defined as fractional doses of approximately 0.5–2 Gy, has attracted increasing interest as an immunomodulatory rather than a primarily cytoreductive use of ionizing radiation. Many of the immune mechanisms attributed to LDRT—immunogenic cell death (ICD), activation of the cyclic GMP-AMP synthase–stimulator of interferon genes (cGAS–STING) pathway, antigen release, and remodeling of the tumor immune microenvironment (TIME)—occur across a wide range of radiation doses and are therefore not exclusive to the low-dose setting. This review is organized around that distinction: For each mechanism, we separate effects shared with radiotherapy in general from those for which dose-specific evidence supports a preferential or qualitatively different response at low doses, including the avoidance of TREX1-mediated degradation of cytosolic DNA that follows single fractions above approximately 12–18 Gy; the relative sparing of tumor-infiltrating lymphocytes; and the reprogramming of vascular, stromal, and myeloid compartments that remain viable after irradiation. We then examine immune cell reprogramming, the current clinical evidence for combining LDRT with immune checkpoint inhibitors (ICIs), and “hybrid” high-dose/low-dose (HDRT–LDRT) regimens, in which ablative doses to selected lesions prime antigen release while low doses to the remaining disease sustain immune cell infiltration. Because most mechanistic data are derived from individual preclinical models, whereas clinical data remain confined to early-phase, largely single-arm studies, we indicate throughout whether a conclusion is established, emerging, or model-specific, and we outline the trials required to define the LDRT dose window, its sequencing with ICIs, and appropriate patient selection.