ORIGINAL RESEARCH article
Front. Immunol.
Sec. Cancer Immunity and Immunotherapy
Collagen-mediated pro-tumorigenic MAPK activation drives stromal-immune reprogramming in solid cancers
Junli Ding 1
Hongxin Lin 2
Hanfang Fan 1
Liangfeng Xu 3
Haihua Zhou 4
Huning Jiang 1
Zeyu Wang 1
Tiansong Xia 2
Yun Cai 5
Yichao Zhu 6
Junying Xu 1
1. Wuxi People's Hospital, Wuxi, China
2. The First Affiliated Hospital With Nanjing Medical University, Nanjing, China
3. Sheyang County People's Hospital, Yancheng, China
4. The Affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou, China
5. Jintan Affiliated Hospital of Jiangsu University, Changzhou, China
6. Nanjing Medical University, Nanjing, China
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Abstract
Intratumoral collagen deposition is a hallmark of solid cancers and plays a critical role in shaping the tumor microenvironment (TME). This study aimed to characterize the clinical and molecular implications of collagen deposition and elucidate its role in modulating TME components and signaling pathways. In this research, we found that high levels of intratumoral collagen deposition were related to poor clinical outcomes and advanced tumor stages in gastric cancer. Collagen deposition showed strong positive correlations with the abundance of vascular endothelial cells and M2-polarized macrophages, suggesting its role in promoting angiogenesis and immunosuppression. In addition, the correlations between collagen deposition and endothelial cells as well as M2-polarized macrophages were also confirmed in lung cancer. Moreover, pathway analysis revealed that collagen activated the MAPK signaling pathway, and in vitro and in vivo functional assays confirmed that collagen-mediated MAPK activation enhanced tumor cell invasion, angiogenesis, and M2 macrophage polarization. Our findings demonstrate that intratumoral collagen deposition is a key regulator of the TME in gastric cancer, promoting tumor progression through MAPK signaling pathway activation. These results demonstrate the promise of collagen as both a prognostic indicator and a therapeutic target, offering fresh perspectives on the underlying mechanisms of TME remodeling and tumor progression across various solid tumors.
Summary
Keywords
collagen deposition, M2 macrophage, MAPK, Microvessel density, Pan-cancer
Received
11 November 2025
Accepted
10 February 2026
Copyright
© 2026 Ding, Lin, Fan, Xu, Zhou, Jiang, Wang, Xia, Cai, Zhu and Xu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Junying Xu
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