{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T20:59:48Z","timestamp":1792789188621,"version":"4.5.0"},"reference-count":33,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T00:00:00Z","timestamp":1759968000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004663","name":"Ministry of Science and Technology of the People\u2019s Republic of China","doi-asserted-by":"publisher","award":["2021YFC2302500"],"award-info":[{"award-number":["2021YFC2302500"]}],"id":[{"id":"10.13039\/501100004663","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004663","name":"Ministry of Science and Technology of the People\u2019s Republic of China","doi-asserted-by":"publisher","award":["2021YFC2302501"],"award-info":[{"award-number":["2021YFC2302501"]}],"id":[{"id":"10.13039\/501100004663","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Shanghai Municipal Science and Technology Major Project","award":["ZD2021CY001-ZXS006R1-2"],"award-info":[{"award-number":["ZD2021CY001-ZXS006R1-2"]}]},{"name":"Fudan-Advaccine Join-Laboratory Innovation Grant"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background: Most immunologically \u201ccold\u201d tumors do not respond durably to checkpoint blockade because tumor antigen (TA) release and presentation are insufficient to prime effective T-cell immunity. While prior work demonstrated synergy between cisplatin and a TLR7\/8\/9 agonist (CR108) in 4T1 tumors, the underlying mechanism\u2014particularly whether chemotherapy functions as a broad antigen-releasing agent enabling TLR-driven immune amplification\u2014remained undefined. Methods: Using murine models of breast (4T1), melanoma (B16-F10), and colorectal cancer (CT26), we tested multiple chemotherapeutic classes combined with CR108. We quantified intratumoral and systemic soluble TAs, antigen presentation and cross-priming by antigen-presenting cells, tumor-infiltrating lymphocytes, and cytokine production by flow cytometry\/ICS. T-cell receptor \u03b2 (TCR\u03b2) repertoire dynamics in tumor-draining lymph nodes were profiled to assess amplitude and breadth. Tumor microenvironment remodeling was analyzed, and public datasets (e.g., TCGA basal-like breast cancer) were interrogated for expression of genes linked to TA generation\/processing and peptide loading. Results: Using cisplatin + CR108 in 4T1 as a benchmark, we demonstrate that diverse chemotherapies\u2014especially platinum agents\u2014broadly increase the repertoire of soluble tumor antigens available for immune recognition. Across regimens, chemotherapy combined with CR108 increased T-cell recognition of candidate TAs and enhanced IFN-\u03b3+ CD8+ responses, with platinum agents producing the largest expansions in soluble TAs. TCR\u03b2 sequencing revealed increased clonal amplitude without loss of repertoire breadth, indicating focused yet diverse antitumor T-cell expansion. Notably, therapeutic efficacy was not predicted by canonical damage-associated molecular pattern (DAMP) signatures but instead correlated with antigen availability and processing capacity. In human basal-like breast cancer, higher expression of genes involved in TA generation and antigen processing\/presentation correlated with improved survival. Conclusions: Our findings establish an antigen-centric mechanism underlying chemo\u2013TLR agonist synergy: chemotherapy liberates a broadened repertoire of tumor antigens, which CR108 then leverages via innate immune activation to drive potent, T-cell-mediated antitumor immunity. This framework for rational selection of chemotherapy partners for TLR7\/8\/9 agonism and support clinical evaluation to convert \u201ccold\u201d tumors into immunologically responsive disease.<\/jats:p>","DOI":"10.3390\/cancers17193277","type":"journal-article","created":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T16:54:31Z","timestamp":1760028871000},"page":"3277","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Chemotherapy Liberates a Broadening Repertoire of Tumor Antigens for TLR7\/8\/9-Mediated Potent Antitumor Immunity"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-3815-6528","authenticated-orcid":false,"given":"Cheng","family":"Zu","sequence":"first","affiliation":[{"name":"Shanghai Institute of Infectious Disease and Biosecurity, Fudan University, Shanghai 200032, China"},{"name":"Key Laboratory of Medical Molecular Virology (MOE\/NHC\/CAMS), School of Basic Medical Sciences, Fudan University, Shanghai 200032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiwei","family":"Zhong","sequence":"additional","affiliation":[{"name":"Shanghai Institute of Infectious Disease and Biosecurity, Fudan University, Shanghai 200032, China"},{"name":"Key Laboratory of Medical Molecular Virology (MOE\/NHC\/CAMS), School of Basic Medical Sciences, Fudan University, Shanghai 200032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuting","family":"Wu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Medical Molecular Virology (MOE\/NHC\/CAMS), School of Basic Medical Sciences, Fudan University, Shanghai 200032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9945-1818","authenticated-orcid":false,"given":"Bin","family":"Wang","sequence":"additional","affiliation":[{"name":"Shanghai Institute of Infectious Disease and Biosecurity, Fudan University, Shanghai 200032, China"},{"name":"Key Laboratory of Medical Molecular Virology (MOE\/NHC\/CAMS), School of Basic Medical Sciences, Fudan University, Shanghai 200032, China"},{"name":"Advaccine Biopharmaceuticals Suzhou Co., Ltd., Suzhou 215000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,9]]},"reference":[{"key":"ref_1","first-page":"433","article-title":"The evolving landscape of tissue-agnostic therapies in precision oncology","volume":"74","author":"Subbiah","year":"2024","journal-title":"CA Cancer J. 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