Extracellular matrix–targeted TNC-scFv armoring enhances CAR T cell persistence and antitumor activity in solid tumors
- 1Key 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.
- 2Laboratory of Pancreatic Disease, The First Affiliated Hospital, and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou 310000, China.
- 3National Center for Respiratory Medicine, National Clinical Research Center for Respiratory Disease, State Key Laboratory of Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou 510120, China.
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.
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BibTeX
@article{chen2026extracellular,
title = {{Extracellular matrix–targeted TNC-scFv armoring enhances CAR T cell persistence and antitumor activity in solid tumors}},
author = {Kaizhao Chen and Qi Fu and Wei Zhang and Ziyang Lin and Longjun Chen and Youxi Zhou and Yongkun Huo and Ziqing Gao and Haoyang Wan and Caifang Wang and Xingxu Huang and Shuaishuai Zhang and Ming Liu and Xiaodong Ma},
journal = {Science Advances},
year = {2026},
month = oct,
doi = {10.1126/sciadv.aeh3957},
url = {https://www.science.org/doi/10.1126/sciadv.aeh3957},
note = {CC BY-NC},
}
RIS
TY - JOUR
TI - Extracellular matrix–targeted TNC-scFv armoring enhances CAR T cell persistence and antitumor activity in solid tumors
AU - Kaizhao Chen
AU - Qi Fu
AU - Wei Zhang
AU - Ziyang Lin
AU - Longjun Chen
AU - Youxi Zhou
AU - Yongkun Huo
AU - Ziqing Gao
AU - Haoyang Wan
AU - Caifang Wang
AU - Xingxu Huang
AU - Shuaishuai Zhang
AU - Ming Liu
AU - Xiaodong Ma
PY - 2026
DA - 2026/10/09
JO - Science Advances
DO - 10.1126/sciadv.aeh3957
UR - https://www.science.org/doi/10.1126/sciadv.aeh3957
AB - 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.
SN - 2375-2548
ER -