{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T16:01:13Z","timestamp":1785427273371,"version":"3.56.0"},"reference-count":128,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T00:00:00Z","timestamp":1779062400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Science and Technology Council, NSTC, Taiwan","award":["114-2314-B-A49-067"],"award-info":[{"award-number":["114-2314-B-A49-067"]}]},{"award":["114-2314-B-A49-067"],"award-info":[{"award-number":["114-2314-B-A49-067"]}],"id":[{"id":"https:\/\/ror.org\/02kv4zf79","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Radiotherapy (RT) is a cornerstone of cancer treatment, traditionally recognized for its direct cytotoxic effects via DNA damage. However, emerging evidence highlights RT as a profound modulator of the tumor microenvironment (TME), acting as a \u201cdouble-edged sword\u201d that greatly influences the success of immune checkpoint inhibitors (ICIs). On the one hand, RT acts like an in situ vaccine, causing immunogenic cell death and activating the cGAS-STING pathway, which leads to dendritic cell maturation, T-cell infiltration, and reactive PD-L1 expression. This effect can turn \u201ccold\u201d tumors into \u201chot\u201d ones, making them more responsive to immune checkpoint blockade. On the other hand, RT can lead to resistance to ICIs by promoting an immunosuppressive environment, recruiting regulatory T cells, M2 macrophages, and myeloid-derived suppressor cells. This review analyzes the mechanisms behind this immunological duality and assesses how parameters such as dose, fractionation, and particle type (e.g., carbon ion versus photon therapy) can be optimized to enhance immune activation. Lastly, we discuss future strategies that focus on innate immunity and tumor metabolism, showing how targeting nutrient depletion and ferroptosis can break down immunosuppressive barriers and position RT as an essential component of precision immuno-oncology.<\/jats:p>","DOI":"10.3390\/ijms27104525","type":"journal-article","created":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T07:35:43Z","timestamp":1779176143000},"page":"4525","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["The Double-Edged Sword: How Radiotherapy Shapes the Tumor Immune Microenvironment to Modulate Responses to Checkpoint Inhibitors"],"prefix":"10.3390","volume":"27","author":[{"given":"Chen-Hsuan","family":"Chiang","sequence":"first","affiliation":[{"name":"Department of Biomedical Imaging and Radiological Sciences, National Yang Ming Chiao Tung University, Yangming Campus, No. 155, Sec. 2, Li-Nong St., Beitou, Taipei 112, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7820-7069","authenticated-orcid":false,"given":"Hui-Wen","family":"Chan","sequence":"additional","affiliation":[{"name":"Department of Biomedical Imaging and Radiological Sciences, National Yang Ming Chiao Tung University, Yangming Campus, No. 155, Sec. 2, Li-Nong St., Beitou, Taipei 112, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4016-6753","authenticated-orcid":false,"given":"Hui-Yen","family":"Chuang","sequence":"additional","affiliation":[{"name":"Department of Biomedical Imaging and Radiological Sciences, National Yang Ming Chiao Tung University, Yangming Campus, No. 155, Sec. 2, Li-Nong St., Beitou, Taipei 112, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Dertinger, H., and Jung, H. 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