2. Academic Validation
  3. CD146+ CAFs mediate immunosuppression in gastric cancer via COL4A1: potential therapeutic targets

CD146+ CAFs mediate immunosuppression in gastric cancer via COL4A1: potential therapeutic targets

  • J Immunother Cancer. 2025 Dec 21;13(12):e013577. doi: 10.1136/jitc-2025-013577.
Jia Chen # 1 2,  Peng Xu # 1,  Qingyuan Wang # 1,  Juncheng Dai 3 4,  Shuang Liang 3 4,  Sheng Yang 4 5,  Guiping Xie 6,  Xiang Li 6,  Yaohui Wang 7,  Hongjin Hua 8,  Xiaochun Ping 9,  Jiajia Shen 9,  Lizong Shen 9
Affiliations

Affiliations

  • 1 Department of General Surgery, the First Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu, China.
  • 2 Department of General Surgery, Northern Jiangsu People's Hospital, Yangzhou, Jiangsu, China.
  • 3 Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, China.
  • 4 State Key Laboratory Cultivation Base of Biomarkers for Cancer Precision Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine and China International Cooperation Center for Environment and Human Health, Nanjing Medical University, Nanjing, Jiangsu, China.
  • 5 Department of Biostatistics, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, China.
  • 6 Department of Surgical Oncology, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China.
  • 7 Department of Pathology, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China.
  • 8 Department of Pathology, the First Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu, China.
  • 9 Department of General Surgery, the First Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu, China [email protected] [email protected] [email protected].
  • # Contributed equally.
PMID: 41423274 DOI: 10.1136/jitc-2025-013577
Abstract

Background: The immunomodulatory roles of cancer-associated fibroblasts (CAFs) in gastric Cancer have been increasingly recognized. This study aimed to identify specific CAF subpopulations and to elucidate the mechanisms underlying their immunosuppressive effects.

Methods: We developed a single-cell RNA Sequencing (scRNA-seq) protocol to enrich CAFs and matched normal fibroblasts (NFs) from stomach tissues. Bioinformatics analyses, along with in vitro and in vivo experiments, were performed to functionally validate a distinct CAF subset.

Results: We profiled 8,322 high-quality fibroblasts from nine patient-matched tumor and adjacent normal tissue pairs. A unique CAF subset, CD146+ CAFs, was identified. CD146+ CAFs were significantly enriched in the tumor microenvironment and associated with poor survival and M2-like macrophage infiltration. Tumor cells promoted CD146+ CAFs expansion via JAG1-NOTCH3 and LGALS3-CD146 signaling. Mechanistically, NOTCH3 acted as a master regulator in CD146+ CAFs. Tumor cell-derived JAG1 engaged NOTCH3 on CD146+ CAFs, which triggered PI3K/AKT-mediated CD146 transcription and enhanced COL4A1 secretion. Functionally, CD146+ CAF-derived COL4A1 bound macrophage CD44/IL7R to drive macrophage M2-like polarization, thereby suppressing CD8+ T-cell function. Therapeutic blockade of CD146 or COL4A1 in vivo impaired M2 polarization, reinvigorated CD8+ T-cell activity, and restrained tumor growth.

Conclusions: Our findings underscore the pivotal role of CD146+ CAFs in shaping an immunosuppressive microenvironment and highlight CD146+ CAFs and COL4A1 as promising candidates for targeted therapy in gastric Cancer.

Keywords

Gastric Cancer; Immunosuppression.

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