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However, cGAS\/STING deficiency in colorectal cancer (CRC) may suppress the RT-induced antitumor immunity. Therefore, we aimed to evaluate the importance of the dsRNA-mediated antitumor immune response induced by RT in patients with CRC.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>Cytosolic dsRNA level and its sensors were evaluated via cell-based assays (co-culture assay, confocal microscopy, pharmacological inhibition and immunofluorescent staining) and in vivo experiments. Biopsies and surgical tissues from patients with CRC who received preoperative chemoradiotherapy (neoCRT) were collected for multiplex cytokine assays, immunohistochemical analysis and SNP genotyping. We also generated a cancer-specific adenovirus-associated virus (AAV)-IFN\u03b21 construct to evaluate its therapeutic efficacy in combination with RT, and the immune profiles were analyzed by flow cytometry and RNA-seq.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Our studies revealed that RT stimulates the autonomous release of dsRNA from cancer cells to activate TLR3-mediated IFN-I signatures to facilitate antitumor immune responses. Patients harboring a dysfunctional TLR3 variant had reduced serum levels of IFN-I-related cytokines and intratumoral CD8<jats:sup>+<\/jats:sup> immune cells and shorter disease-free survival following neoCRT treatment. The engineered cancer-targeted construct AAV-IFN\u03b21 significantly improved the response to RT, leading to systematic eradication of distant tumors and prolonged survival in defective TLR3 preclinical models.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>Our results support that increasing cancer-intrinsic IFN\u03b21 expression is an immunotherapeutic strategy that enhances the RT-induced antitumor immune response in locally patients with advanced CRC with dysfunctional TLR3.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1136\/jitc-2023-008515","type":"journal-article","created":{"date-parts":[[2024,5,15]],"date-time":"2024-05-15T07:07:50Z","timestamp":1715756870000},"page":"e008515","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":20,"title":["Colorectal cancer-specific IFN\u03b2 delivery overcomes dysfunctional dsRNA-mediated type I interferon signaling to increase the abscopal effect of radiotherapy"],"prefix":"10.1136","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0266-3233","authenticated-orcid":false,"given":"Kevin Chih-Yang","family":"Huang","sequence":"first","affiliation":[{"name":"Department of Biomedical Imaging and Radiological Science, China Medical University, Taichung, Taiwan"},{"name":"Translation Research Core, China Medical University Hospital, Taichung, Taiwan"},{"name":"Cancer Biology and Precision Therapeutics Center, China Medical University, Taichung, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shu-Fen","family":"Chiang","sequence":"additional","affiliation":[{"name":"Lab of Precision Medicine, Feng-Yuan Hospital Ministry of Health and Welfare, Taichung, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hsin-Yu","family":"Chang","sequence":"additional","affiliation":[{"name":"Translation Research Core, 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