{
  "abstract": "Background Chimeric antigen receptor (CAR) T cell therapy has shown remarkable success in hematologic malignancies but faces substantial challenges in solid tumors. One of the main obstacles is the extracellular matrix (ECM), which serves as the physical barrier that hinders T cell infiltration into tumor tissues.Methods We engineered CAR-T cells targeting mesothelin or B7H3 to co-express matrix metalloproteinase-3 (MMP3). We evaluated the effects of MMP3 overexpression on CAR-T cell proliferation, activation, cytotoxicity, and tumor infiltration using both in vitro Matrigel-based assays and in vivo xenograft and syngeneic models enriched with cancer-associated fibroblasts (CAFs).Results MMP3 overexpression did not impair CAR-T cell proliferation, activation, or cytotoxicity. However, it significantly enhanced their capacity to invade through ECM and improved tumor cell killing in vitro. In CAF-enriched xenograft models, MMP3-engineered CAR-T cells demonstrated superior tumor infiltration, expansion, and antitumor activity. Notably, MMP3 overexpression rescued the function of B7H3 CAR-T cells in the stringent CAF-enriched tumor microenvironment, while conventional CAR-T cells showed limited activity. Importantly, MMP3 overexpression also conferred potent antitumor activity in an immunocompetent mouse model, underscoring its therapeutic benefit in a more physiologically and clinically related setting.Conclusions These findings suggest that MMP3 engineering is a simple yet effective strategy to overcome stromal barriers and enhance the efficacy of CAR-T cell therapy in solid tumors.",
  "authors": [
    {
      "affiliations": [
        "Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Thoracic Surgery II, Peking University Cancer Hospital & Institute, Beijing, People's Republic of China"
      ],
      "name": "Yuge Zhu"
    },
    {
      "affiliations": [
        "Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Biochemistry and Molecular Biology, Peking University Cancer Hospital & Institute, Beijing, People's Republic of China"
      ],
      "name": "Jiaxin Tu"
    },
    {
      "affiliations": [
        "Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Biochemistry and Molecular Biology, Peking University Cancer Hospital & Institute, Beijing, People's Republic of China"
      ],
      "name": "Shance Li"
    },
    {
      "affiliations": [
        "Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Thoracic Surgery II, Peking University Cancer Hospital & Institute, Beijing, People's Republic of China"
      ],
      "name": "Bufan Xiao"
    },
    {
      "affiliations": [
        "Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Thoracic Surgery II, Peking University Cancer Hospital & Institute, Beijing, People's Republic of China"
      ],
      "name": "Xuantong Zhou"
    },
    {
      "affiliations": [
        "Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Biochemistry and Molecular Biology, Peking University Cancer Hospital & Institute, Beijing, People's Republic of China"
      ],
      "name": "Xia Teng"
    },
    {
      "affiliations": [
        "Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Biochemistry and Molecular Biology, Peking University Cancer Hospital & Institute, Beijing, People's Republic of China"
      ],
      "name": "Guanyu Zhang"
    },
    {
      "affiliations": [
        "Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Biochemistry and Molecular Biology, Peking University Cancer Hospital & Institute, Beijing, People's Republic of China"
      ],
      "name": "Huimin Xie"
    },
    {
      "affiliations": [
        "Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Biochemistry and Molecular Biology, Peking University Cancer Hospital & Institute, Beijing, People's Republic of China"
      ],
      "name": "Kang Sun"
    },
    {
      "affiliations": [
        "Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Biochemistry and Molecular Biology, Peking University Cancer Hospital & Institute, Beijing, People's Republic of China"
      ],
      "name": "Xinyu Li"
    },
    {
      "affiliations": [
        "Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Biochemistry and Molecular Biology, Peking University Cancer Hospital & Institute, Beijing, People's Republic of China"
      ],
      "name": "You He"
    },
    {
      "affiliations": [
        "Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Laboratory Animal, Peking University Cancer Hospital & Institute, Beijing, People's Republic of China"
      ],
      "name": "Yunan Ma"
    },
    {
      "affiliations": [
        "Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Biochemistry and Molecular Biology, Peking University Cancer Hospital & Institute, Beijing, People's Republic of China"
      ],
      "name": "Zheming Lu"
    },
    {
      "affiliations": [
        "State Key Laboratory of Molecular Oncology, Frontiers Science Center for Cancer Integrative Omics, Department of Thoracic Surgery II, Beijing Key Laboratory of Carcinogenesis and Translational Research, Peking University Cancer Hospital & Institute, Beijing, People's Republic of China",
        "Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, Peking University Cancer Hospital Yunnan, Yunnan, People's Republic of China"
      ],
      "name": "Nan Wu"
    },
    {
      "affiliations": [
        "Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Biochemistry and Molecular Biology, Peking University Cancer Hospital & Institute, Beijing, People's Republic of China"
      ],
      "name": "Chaoting Zhang"
    }
  ],
  "title": "MMP3 overexpression enhances CAR-T cell infiltration and antitumor activity in a CAF-enriched solid tumor model",
  "uid": "8a23658b-6f6d-5dde-bfff-e339f9d9f00c"
}