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Ionizing radiation (IR) can convert \u2018cold\u2019 tumors into \u2018hot\u2019 lesions but rarely elicits durable immunity alone.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>This study investigated the synergistic antitumor effects of hypofractionated ionizing radiation (IR) combined with anti-PD-L1 therapy in CRC. Transcriptomic analysis of paired CRC biopsies (GSE179351) was performed to identify gene expression changes following combination therapy. In vivo efficacy was assessed in syngeneic BALB\/c mice bearing CT26.WT tumors treated with 18 Gy IR (in 3 fractions) and anti-PD-L1 (10\u2005mg\/kg). Immunohistochemistry, flow cytometry, cytokine quantification, and Western blotting were used to evaluate immune cell infiltration, IFN-\u03b3 expression, and activation of JAK1\/STAT1 signaling and apoptosis. To directly test the requirement of STAT1 signaling, CT26.WT cells were treated with the JAK1 inhibitor Itacitinib.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Combination therapy induced 701 differentially expressed genes enriched in JAK\u2013STAT signaling and apoptosis pathways. In vivo, IR\u2009+\u2009anti-PD-L1 significantly delayed tumor growth versus monotherapy without added systemic toxicity. Enhanced CD8\n                      <jats:sup>+<\/jats:sup>\n                      T-cell infiltration and increased IFN-\u03b3 levels were observed in both tumor and spleen. Mechanistically, IR alone did not activate STAT1 signaling, while exogenous IFN-\u03b3 or IR\u2009+\u2009IFN-\u03b3 induced JAK1\/STAT1 phosphorylation and caspase-3 cleavage in CRC cells, promoting STAT1-dependent apoptosis. These findings highlight IR's role in priming an IFN-\u03b3\u2013rich tumor microenvironment that enhances the efficacy of PD-L1 blockade.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>The study supports radio-immunotherapy as a promising approach for patients with pMMR\/MSS CRC and provides a mechanistic rationale for clinical trials optimizing fractionation or targeting the IFN-\u03b3\/JAK-STAT pathway.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1177\/15330338251406931","type":"journal-article","created":{"date-parts":[[2025,12,17]],"date-time":"2025-12-17T18:22:12Z","timestamp":1765995732000},"update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":2,"title":["Combining Radiation and anti-PD-L1 Enhances the Antitumor Activity in Colorectal Cancer via IFN-\u03b3-Dependent Activation of STAT1"],"prefix":"10.1177","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3244-1076","authenticated-orcid":false,"given":"Xiao","family":"Yang","sequence":"first","affiliation":[{"name":"Nankai University"},{"name":"Department two of Gastroenterology, Tianjin Union Medical Center, The First Affiliated Hospital of Nankai University, Tianjin, 300121, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dan-Dan","family":"Gao","sequence":"additional","affiliation":[{"name":"Jinan Maternity and Child Care Hospital"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heng","family":"Zhang","sequence":"additional","affiliation":[{"name":"Tianjin Union Medical Center, The First Affiliated Hospital of Nankai University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wan-Jun","family":"Sun","sequence":"additional","affiliation":[{"name":"Tianjin Union Medical Center, The First Affiliated Hospital of Nankai 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