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Adv."],"published-print":{"date-parts":[[2026,10,9]]},"abstract":"<jats:p>\n                    Chimeric antigen receptor T cell (CAR T cell) therapy has shown limited efficacy in solid tumors, largely due to physical and immunosuppressive barriers imposed by the tumor microenvironment (TME). Tenascin-C (TNC), an extracellular matrix protein highly expressed in multiple solid malignancies, contributes to immune exclusion and T cell dysfunction. Here, we engineer an armored CAR T cell platform that locally targets the extracellular matrix by secreting a TNC-specific single-chain variable fragment (TNC-scFv) linked to conventional CAR architecture. TNC-scFv\u2013armored CAR T cells exhibit enhanced cytotoxic activity, improved persistence, and reduced exhaustion in vitro and in xenograft tumor models. Single-cell transcriptomic analysis reveals that TNC targeting reprograms the TME toward a CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cell\u2013enriched and functionally active immune landscape. In humanized tumor models, TNC-scFv\u2013armored CAR T cells mediate robust antitumor responses with minimal systemic toxicity. This extracellular matrix\u2013targeted armoring framework is compatible with additional immunomodulatory payloads, as illustrated by combinatorial armoring with interleukin-2, which further enhances efficacy while mitigating cytokine-associated toxicity. Together, these results establish extracellular matrix\u2013directed armoring as a generalizable strategy to improve CAR T cell therapy for solid tumors.\n                  <\/jats:p>","DOI":"10.1126\/sciadv.aeh3957","type":"journal-article","created":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T18:06:59Z","timestamp":1791569219000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":0,"title":["Extracellular matrix\u2013targeted TNC-scFv armoring enhances CAR T cell persistence and antitumor activity in solid tumors"],"prefix":"10.1126","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1819-2453","authenticated-orcid":true,"given":"Kaizhao","family":"Chen","sequence":"first","affiliation":[{"name":"Key Laboratory of Brain, Cognition and Education Sciences, Institute for Brain Research and Rehabilitation, Guangdong Key Laboratory of Mental Health and Cognitive Science, Ministry of Education, South China Normal University, Guangzhou 510631, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-0415-0493","authenticated-orcid":true,"given":"Qi","family":"Fu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Brain, Cognition and Education Sciences, Institute for Brain Research and Rehabilitation, Guangdong Key Laboratory of Mental Health and Cognitive Science, Ministry of Education, South China Normal University, Guangzhou 510631, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-6333-4138","authenticated-orcid":true,"given":"Wei","family":"Zhang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Brain, Cognition and Education Sciences, Institute for Brain Research and Rehabilitation, Guangdong Key Laboratory of Mental Health and Cognitive Science, Ministry of Education, South China Normal University, Guangzhou 510631, 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China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-2180-9195","authenticated-orcid":true,"given":"Youxi","family":"Zhou","sequence":"additional","affiliation":[{"name":"Key Laboratory of Brain, Cognition and Education Sciences, Institute for Brain Research and Rehabilitation, Guangdong Key Laboratory of Mental Health and Cognitive Science, Ministry of Education, South China Normal University, Guangzhou 510631, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongkun","family":"Huo","sequence":"additional","affiliation":[{"name":"Key Laboratory of Brain, Cognition and Education Sciences, Institute for Brain Research and Rehabilitation, Guangdong Key Laboratory of Mental Health and Cognitive Science, Ministry of Education, South China Normal University, Guangzhou 510631, 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China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caifang","family":"Wang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Brain, Cognition and Education Sciences, Institute for Brain Research and Rehabilitation, Guangdong Key Laboratory of Mental Health and Cognitive Science, Ministry of Education, South China Normal University, Guangzhou 510631, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8934-1247","authenticated-orcid":true,"given":"Xingxu","family":"Huang","sequence":"additional","affiliation":[{"name":"Laboratory of Pancreatic Disease, The First Affiliated Hospital, and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou 310000, 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