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Low-dose radiotherapy (LDRT) has been suggested to modify the TME, potentially enhancing the effects of \u03b1PD-1.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We profiled murine HNSCC treated with LDRT (1\u00a0Gy) and\/or \u03b1PD-1 using single-cell RNA sequencing (scRNA-seq) and single-cell TCR sequencing (scTCR-seq), complemented by orthogonal functional assays and in situ validation (spatial transcriptomics and multiplex immunofluorescence).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      LDRT and \u03b1PD-1 synergistically suppressed tumor growth and remodeled the TME. Single-cell analyses showed malignant programs shifting from proliferative states toward stress- and interferon (IFN)-responsive states. Integrated scTCR-seq analysis revealed enhanced clonal expansion of tumor-reactive CD8\u207a T-cell subsets and reduced the frequency of CD4\u207a Treg-Ctla4 under combination therapy. TCR-based metrics (including STARTRAC) indicated higher migration potential and limited intratumoral clonal overlap for CD4\u207a Treg-Ctla4. An\n                      <jats:italic>Isg15<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic>high<\/jats:italic>\n                      <\/jats:sup>\n                      macrophage state (Macro-Isg15) was positively associated with CD4\u207a Treg-Ctla4 frequency and was more prominent under \u03b1PD-1 monotherapy. Ligand\u2013receptor inference highlighted a Macro-Isg15\u2013associated CXCL14\u2013CXCR4 chemokine axis enriched under \u03b1PD-1 monotherapy and attenuated in LDRT-containing regimens, suggesting reduced chemokine-driven support for CD4\u207a Treg-Ctla4 accumulation\/recruitment.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>These findings support an integrated framework in which LDRT augments \u03b1PD-1 efficacy by reprogramming malignant states and reshaping immune cell dynamics, including attenuation of immunosuppressive features within the TME. This preclinical evidence provides a rationale for translational evaluation of LDRT-based combination strategies in HNSCC.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s13046-026-03660-3","type":"journal-article","created":{"date-parts":[[2026,2,11]],"date-time":"2026-02-11T07:35:05Z","timestamp":1770795305000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["LDRT combined with anti-PD-1 promotes tumor regression in head and neck squamous cell carcinoma through tumor metaprogram evolution and immune cell reprogramming"],"prefix":"10.1186","volume":"45","author":[{"given":"Guanjun","family":"Li","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiangdi","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linxuan","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yannan","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liangfu","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhaoyuan","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junyan","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tingting","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yutong","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongqin","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yifei","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhigang","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,2,11]]},"reference":[{"issue":"6","key":"3660_CR1","doi-asserted-by":"publisher","first-page":"394","DOI":"10.3322\/caac.21492","volume":"68","author":"F Bray","year":"2018","unstructured":"Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. 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J Immunother Cancer. 2025;13(6):e011487.","DOI":"10.1136\/jitc-2025-011487"}],"container-title":["Journal of Experimental &amp; Clinical Cancer Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s13046-026-03660-3","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13046-026-03660-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13046-026-03660-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T18:04:44Z","timestamp":1781633084000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1186\/s13046-026-03660-3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,11]]},"references-count":45,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["3660"],"URL":"https:\/\/doi.org\/10.1186\/s13046-026-03660-3","relation":{},"ISSN":["1756-9966"],"issn-type":[{"value":"1756-9966","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2,11]]},"assertion":[{"value":"17 September 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"1 February 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"11 February 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The use of human tumor specimens in this study was approved by the Ethics Committee of Dongguan People\u2019s Hospital (The Tenth Affiliated Hospital of Southern Medical University) (Approval No. KYKT2022-045). Written informed consent was obtained from all participants.All experiments involving animals were conducted according to the ethical policies and procedures approved by the Animal Welfare and Ethics Committee of the Tenth Affiliated Hospital of Southern Medical University (Dongguan People\u2019s Hospital) (Approval No. IACUC-AWEC-202406501).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"68"}}