2. Academic Validation
  3. GPRC5A+ myCAFs promote ESCC progression via TGF-β-induced fibroblast activation and ANXA1-mediated M2 macrophage polarization

GPRC5A+ myCAFs promote ESCC progression via TGF-β-induced fibroblast activation and ANXA1-mediated M2 macrophage polarization

  • Int Immunopharmacol. 2025 Oct 11:167:115663. doi: 10.1016/j.intimp.2025.115663.
Xiang Lv 1,  Ming Liu 1,  Jing Chen 2,  Xiamin He 1,  Jiamiao Weng 1,  Yanhui Lin 1,  Yaocheng Wang 1,  Rongzhao Zhang 3,  Minjian Huang 3,  Lilan Zhao 4,  Fan Lin 5,  Chundong Yu 6,  Yi Huang 7
Affiliations

Affiliations

  • 1 Shengli Clinical Medical College, Fujian Medical University, Fuzhou 350001, China; Department of Clinical Laboratory, Fujian Provincial Hospital, Fuzhou 350001, China.
  • 2 Shengli Clinical Medical College, Fujian Medical University, Fuzhou 350001, China; Department of Clinical Laboratory, Fuzhou First General Hospital Affiliated with Fujian Medical University, Fuzhou 350009, China.
  • 3 Shengli Clinical Medical College, Fujian Medical University, Fuzhou 350001, China; Center for Experimental Research in Clinical Medicine, Fujian Provincial Hospital, Fuzhou 350001, China.
  • 4 Shengli Clinical Medical College, Fujian Medical University, Fuzhou 350001, China; Department of Thoracic Surgery, Fujian Provincial Hospital, Fuzhou 350001, China.
  • 5 Shengli Clinical Medical College, Fujian Medical University, Fuzhou 350001, China; Department of Geriatric Medicine, Fujian Provincial Hospital, Fuzhou 350001, China; Fujian Provincial Center for Geriatrics, Fujian Provincial Hospital, Fuzhou 350001, China.
  • 6 Shengli Clinical Medical College, Fujian Medical University, Fuzhou 350001, China; Center for Experimental Research in Clinical Medicine, Fujian Provincial Hospital, Fuzhou 350001, China; State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen 361102, China. Electronic address: cdyu@xmu.edu.cn.
  • 7 Shengli Clinical Medical College, Fujian Medical University, Fuzhou 350001, China; Department of Clinical Laboratory, Fujian Provincial Hospital, Fuzhou 350001, China; Center for Experimental Research in Clinical Medicine, Fujian Provincial Hospital, Fuzhou 350001, China; Central Laboratory, Fujian Provincial Hospital, Fuzhou 350001, China; Fujian Provincial Key Laboratory of Cardiovascular Disease, Fujian Provincial Key Laboratory of Critical Care Medicine, Fuzhou 350001, China. Electronic address: hyi8070@126.com.
PMID: 41082840 DOI: 10.1016/j.intimp.2025.115663
Abstract

Cancer-associated fibroblasts (CAFs) play a pivotal regulatory role in the immune microenvironment of esophageal squamous cell carcinoma (ESCC), reshaping the tumor microenvironment and promoting disease progression through the secretion of various factors. Utilizing single-cell RNA Sequencing (scRNA-seq) on 15 ESCC and 11 normal tissues, we identified a distinct terminally differentiated myofibroblast (myCAF_1) subset that was significantly expanded in tumors and correlated with poor patient prognosis. This subpopulation was specifically marked by GPRC5A, a gene we validated as a myCAF_1-specific marker through bulk transcriptomic deconvolution of large cohorts. Functional studies revealed that GPRC5A+ myCAFs drive ESCC progression via a dual mechanism: (1) Activating the TGF-β/SMAD2/3 pathway to promote the transformation of normal fibroblasts (NFs) into CAFs, and (2) Secreting ANXA1 to recruit monocytes and polarize them into M2-type tumor-associated macrophages (TAMs), thereby fostering an immunosuppressive microenvironment. These findings were confirmed using primary CAFs and NFs models. Our study unveils GPRC5A as a key mediator in ESCC and proposes the GPRC5A/TGF-β/ANXA1 axis as a promising therapeutic target for ESCC treatment.

Keywords

ANXA1; CAFs; ESCC; GPRC5A; M2 macrophages.

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