机构：[1]Department of Thoracic Oncology, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.四川大学华西医院[2]State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.四川大学华西医院[3]Lung Cancer Treatment Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.四川大学华西医院[4]Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 610072, China.[5]Traditional Chinese Medicine Regulating Metabolic Diseases Key Laboratory of Sichuan Province, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 610072, China.[6]Division of Thoracic Tumor Multimodality Treatment Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.四川大学华西医院[7]Chengdu OrganoidMed Medical Laboratory, West China Health Valley, Chengdu, Sichuan 610041, China.[8]Department of Pathology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.四川大学华西医院[9]Faculty of Medicine, Macau University of Science and Technology, Macau 999078, China.[10]Department of Hematology and Institute of Hematology, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.四川大学华西医院[11]Frontiers Medical Center, Tianfu Jincheng Laboratory, Chengdu, Sichuan 610213, China.[12]Children's Medicine Key Laboratory of Sichuan Province, West China Second Hospital, Sichuan University, Chengdu, Sichuan 610041, China.
Immunotherapy has become the standard treatment for many types of cancers, but an increasing number of patients who initially respond to these treatments develop acquired immunotherapy resistance (AIR). Here, we recapitulated the entire process of immunotherapy from response to AIR in mice with non-small cell lung cancer (NSCLC). With implanted tumor organoids derived from these models and serial transplants, we demonstrated that tumor cell-intrinsic mechanisms contributed significantly to AIR. Single-cell RNA sequencing and electron microscope assays revealed that resistant tumor cell-expressing collagens, including Col3a1 and Col6a1, formed multiple physical barriers surrounding tumor cells. Disruption of these barriers by collagenase or knockout of both Col3a1 and Col6a1 in tumor cells could sensitize the tumors of AIR. Mechanistically, the TGFβ pathway was upregulated upon immunotherapy, and treatment with TGFβ significantly increased the expression levels of both Col3a1 and Col6a1 in tumor cells. COL3A1 formed a castle-like barrier for a cluster of tumor cells and prevented T cell infiltration, while COL6A1 formed an armor-like barrier surrounding individual tumor cells to protect them against direct T cell attack. Our data reveal a tumor cell-intrinsic mechanism of AIR, mediated by collagen-containing physical barriers, which immediately suggests a clinical treatment option.
基金：
This work was supported by the National Natural Science
Foundation of China (82330087; T2221004; 82130007; 82303880; 82170171;
82470188; 82472783; 82300186; and 82300185), the Noncommunicable
Chronic Diseases-National
Science and Technology Major Project (2023ZD0500500),
the Sichuan Science and Technology Program (2023ZYD0057; 2025NSFTD0030;
2025ZNSFSC0047; 2023NSFSC1904; 2025NSFSC1997; 24CXTD05; and
2024NSFSC1699), the China Postdoctoral Science Foundation (2023M732457;
2023TQ0226; 2024T170604; and 2023M732465), the Frontiers Medical Center,
Tianfu Jincheng Laboratory Foundation (TFJC2023010004); the 1.3.5. Project for
Disciplines of Excellence, West China Hospital, Sichuan University (ZYGD22012),
National Clinical Research Center for Geriatrics, West China Hospital, Sichuan
University (Z2024JC001), the Post-Doctor
Research Project of Sichuan University
(JCXK2215 and 2024SCU12033), and the Post-Doctor
Research Project, West China
Hospital, Sichuan University (2023HXBH018).
语种：
外文
PubmedID：
中科院(CAS)分区：
出版当年[2025]版：
大类|1 区综合性期刊
小类|1 区综合性期刊
最新[2025]版：
大类|1 区综合性期刊
小类|1 区综合性期刊
第一作者：
第一作者机构：[1]Department of Thoracic Oncology, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.
共同第一作者：
通讯作者：
通讯机构：[1]Department of Thoracic Oncology, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.[2]State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.[10]Department of Hematology and Institute of Hematology, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.[11]Frontiers Medical Center, Tianfu Jincheng Laboratory, Chengdu, Sichuan 610213, China.[12]Children's Medicine Key Laboratory of Sichuan Province, West China Second Hospital, Sichuan University, Chengdu, Sichuan 610041, China.
推荐引用方式(GB/T 7714)：
Wang Manli,Wang Yiyun,Pan Xiangyu,et al.Acquired resistance to immunotherapy by physical barriers with cancer cell-expressing collagens in non-small cell lung cancer[J].Proceedings Of The National Academy Of Sciences Of The United States Of America.2025,122(24):e2500019122.doi:10.1073/pnas.2500019122.
APA：
Wang Manli,Wang Yiyun,Pan Xiangyu,Wang Bo,Wang Yuying...&Chen Chong.(2025).Acquired resistance to immunotherapy by physical barriers with cancer cell-expressing collagens in non-small cell lung cancer.Proceedings Of The National Academy Of Sciences Of The United States Of America,122,(24)
MLA：
Wang Manli,et al."Acquired resistance to immunotherapy by physical barriers with cancer cell-expressing collagens in non-small cell lung cancer".Proceedings Of The National Academy Of Sciences Of The United States Of America 122..24(2025):e2500019122
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