Acquired resistance to immunotherapy by physical barriers with cancer cell–expressing collagens in non–small cell lung cancer

Sep 23, 2026

Uploaded by Fahsai

Immunotherapy is widely used, yet many patients develop acquired immunotherapy resistance (AIR) after an initial response. This study reconstructed the full immunotherapy-to-AIR process in non–small cell lung cancer (NSCLC) mouse models and used implanted tumor organoids with serial transplants to show tumor cell–intrinsic contributions. Single-cell RNA sequencing and electron microscopy identified resistant tumor cell–expressing collagens (Col3a1, Col6a1) that formed physical barriers blocking T cell infiltration and attack. Collagen disruption and TGFβ pathway targeting resensitized tumors, suggesting collagen barrier interference as a clinical option.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages11

Reading Time28 min

AccessFree to download

Abstract

Background

Methods and models

Key findings on collagen barriers

Mechanistic role of TGFβ

Clinical implications

RESEARCH ARTICLE MEDICAL SCIENCES Acquired resistance to immunotherapy by physical barriers with cancer cell–expressing collagens in non–small cell lung cancer Manli Wanga,1, Yiyun Wangb,1, Xiangyu Panb,1, Bo Wangb,1, Yuying Wangb,1, Xiangmeng Luob,1, Xiaofeng Dengb, Li Liub, Xuelan Chenb, Xiaoqian Zhaib,c, Baohong Wub, Qi Zhangb, Yifeng Rend,e, Jia Lid, Xiaoyu Lif, Fujun Caob, Yang Yangb, Xintong Dengb, Runhong Lib, Zhenghao Lug, Ping Tanb, Jingyao Chenb, Yan Lic, Yanyang Liuc, Jiewei Liuc, Yuan Wangb , Hongxin Dengb, Zhaoming Sub , Weiya Wangh, Yongsheng Wangf, Shengyong Yangb, Chengjian Zhaob, Jianxin Xuea, Yuquan Weib, Kang Zhangi,2, Feifei Naa, b,2, Yu Liub,j,2, and Chong Chena, b, k, l,2 Affiliations are included on p. 10. Edited by Gordon Freeman, Dana-Farber Cancer Institute, Boston, MA; received January 7, 2025; accepted May 1, 2025 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. NSCLC | immunotherapy | acquired resistance | collagens | physical barrier Cancer treatment has entered the era of immunotherapy (1) . The immune checkpoint inhibitor (ICI) treatment itself or combined with other treatments is routine for most patients with more than 20 different types of cancers, including non–small cell lung cancer (NSCLC) (2–4) . Despite the enthusiasm for these new treatments, resistance is very common to ICIs (5, 6) . It is reported that about 60 to 80% of patients had no or little response to ICI treatment, which is called primary resistance. Previously, it was believed that immunotherapy should achieve a durable response, even a lasting cure for those who had an initial response, or in other terms, acquired resistance might be rare for immunotherapy (7, 8). However, with the increasingly widespread use of ICI, there is accumulating evidence indicating that cases with acquired resistance to ICIs are explosively observed in clinic (4, 9) . For example, more than 65% of advanced NSCLC patients who achieved initial response to PD-1 blockade relapsed in 4 y (9, 10). To understand the mechanisms underlying acquired resistance is urgently needed to improve the outcomes of these patients. The effect of immunotherapy can be affected by many factors, including both tumor cell–intrinsic and extrinsic features and the dynamic interactions of tumor cells and their microenvironment (5, 11–14). Evidence suggests that scarcity of potential tumor-suppressive immune cells, especially cytotoxic T cells, abundance of immunosuppressive Tregs, M2 macrophages, myeloid-derived suppressor cells, erythroid differentiated myeloid cells and cancer-associated fibroblasts, and various their secreted

FAQs

What is acquired immunotherapy resistance (AIR) in this study?

AIR refers to the development of resistance after an initial response to immunotherapy. The study models the transition from response to AIR in NSCLC mice.

How do collagens contribute to AIR according to the results?

Resistant tumor cells expressing Col3a1 and Col6a1 form physical barriers that limit T cell infiltration and directly protect tumor cells from T cell attack.

How does targeting collagen barriers or the TGFβ pathway affect immunotherapy?

Disrupting collagen barriers with collagenase or knocking out Col3a1 and Col6a1 sensitizes tumors, while upregulation of the TGFβ pathway increases collagen expression and TGFβ treatment boosts Col3a1 and Col6a1 levels.

Sep 23, 2026

Uploaded by Fahsai