Authors
Kaizhao Chen, Qi Fu, Wei Zhang, Ziyang Lin, Longjun Chen, Youxi Zhou, Yongkun Huo, Ziqing Gao, Haoyang Wan, Caifang Wang, Xingxu Huang, Shuaishuai Zhang, Ming Liu, Xiaodong Ma
Published in
Science advances. Volume 12. Issue 41. Pages eaeh3957. Oct 09, 2026. Epub Oct 09, 2026.
Abstract
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-armored 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+ T cell-enriched and functionally active immune landscape. In humanized tumor models, TNC-scFv-armored CAR T cells mediate robust antitumor responses with minimal systemic toxicity. This extracellular matrix-targeted 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-directed armoring as a generalizable strategy to improve CAR T cell therapy for solid tumors.
PMID:
42853935
Bibliographic data and abstract were imported from PubMed on 10 Oct 2026.
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