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This review integrates preclinical, translational, and clinical evidence on the immunological effects of HFRT when combined with immune checkpoint inhibitors (ICIs) and other immune-based therapies. Available evidence indicates that HFRT induces immunogenic cell death and activates the cGAS-STING pathway, enhancing dendritic cell priming and CD8+ T-cell trafficking. These processes are most likely to translate into systemic antitumour activity when checkpoint blockade is delivered with an appropriate peri-radiotherapy window. Under these conditions, HFRT may facilitate immune conversion of selected \u201ccold\u201d tumours, particularly in combination with PD-1\/PD-L1 blockade. Clinical outcomes remain heterogeneous across tumour types. Improved out-of-field responses and survival signals have been reported in non-small-cell lung cancer, head and neck squamous cell carcinoma, and triple-negative breast cancer, whereas tumours dominated by myeloid-driven or stromal suppression, such as pancreatic ductal adenocarcinoma, show limited benefit. From a clinical design perspective, effective HFRT-immunotherapy combinations require careful selection of fractionation, timing, and radiation geometry. Fractionation should preserve DNA sensing and dendritic-cell activation, checkpoint therapy should align with the peri-radiotherapy window, and radiation delivery should minimise immune suppression by sparing tumour-draining lymph nodes and limiting unnecessary low-dose exposure. HFRT can serve as a practical backbone for immune-based therapies when these variables are appropriately aligned.<\/jats:p>","DOI":"10.3389\/fonc.2026.1750519","type":"journal-article","created":{"date-parts":[[2026,2,5]],"date-time":"2026-02-05T05:22:51Z","timestamp":1770268971000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["From local control to immune modulation: hypofractionated radiotherapy as a backbone for cancer immunotherapy"],"prefix":"10.3389","volume":"16","author":[{"given":"Xiaoxuan","family":"Zhuang","sequence":"first","affiliation":[{"name":"Chongqing Medical University-University of Leicester Joint Institute, Chongqing Medical University","place":["Chongqing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yao","family":"Sun","sequence":"additional","affiliation":[{"name":"Shandong University Scientific Journal Press, Shandong University","place":["Jinan, 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