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
  • 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: [email protected].
  • 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: [email protected].
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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