2. Academic Validation
  3. Cancer-associated fibroblasts (CAFs) derived from MFAP2 promote CRC proliferation and metastasis while suppressing CD8+ T cell-mediated antitumor immunity

Cancer-associated fibroblasts (CAFs) derived from MFAP2 promote CRC proliferation and metastasis while suppressing CD8+ T cell-mediated antitumor immunity

  • Cell Death Dis. 2026 Jan 30;17(1):159. doi: 10.1038/s41419-026-08413-w.
Xu Zhang # 1,  Yuxiang Fei # 2,  Chunqi Xie # 3,  Tao Li 4,  Ben Niu 3,  Zihao Yang 3,  Mengwei Song 3,  Fanjun Meng 5,  Hongting Diao 6,  Jing Ji 7,  Qianming Du 8 9,  Chao Liu 10 11
Affiliations

Affiliations

  • 1 Department of Pharmacy, Chengdu Integrated TCM & Western Medicine Hospital, Chengdu University of TCM, 18# Wanxiang East Road, Chengdu, 610041, P.R. China.
  • 2 Department of Pharmacy, Nanjing First Hospital, Nanjing Medical University, Nanjing, 210006, P.R. China. [email protected].
  • 3 Jiangsu Key Laboratory of Marine Pharmaceutical Compound Screening, College of Pharmacy, Jiangsu Ocean University, Lianyungang, 222001, P.R. China.
  • 4 General Clinical Research Center, Nanjing First Hospital, Nanjing Medical University, Nanjing, 210006, P.R. China.
  • 5 School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, 211198, P.R. China.
  • 6 School of Nursing, Nanjing Medical University, Nanjing, 211168, P.R. China. [email protected].
  • 7 College of Pharmacy, Taizhou University, Taizhou, 225300, P.R. China. [email protected].
  • 8 General Clinical Research Center, Nanjing First Hospital, Nanjing Medical University, Nanjing, 210006, P.R. China. [email protected].
  • 9 School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, 211198, P.R. China. [email protected].
  • 10 Department of Pharmacy, Nanjing First Hospital, Nanjing Medical University, Nanjing, 210006, P.R. China. [email protected].
  • 11 School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, 211198, P.R. China. [email protected].
  • # Contributed equally.
PMID: 41617683 DOI: 10.1038/s41419-026-08413-w
Abstract

Colorectal Cancer (CRC) ranks among the most prevalent malignancies of the digestive system, with the intricate tumor immune microenvironment (TIME) emerging as a key determinant of poor prognosis. Cancer-associated fibroblasts (CAFs), a central constituent of the tumor microenvironment, critically influence tumorigenesis and progression by orchestrating immunosuppression through cytokine secretion and Other mechanisms. This study investigates the multifaceted interplay between CAFs and the immune system to identify novel therapeutic targets and improve prognostic outcomes for CRC patients. Through comprehensive analyses of clinical samples and public database data, we identified elevated MFAP2 expression in both CRC tissues and fibroblasts. Mechanistically, we established that CAFs-derived MFAP2 interacts with Integrin β8 (ITGB8) on Cancer cell surfaces, activating the integrin-FAK-ERK1/2 signaling cascade to drive CRC progression. Furthermore, ERK1/2 phosphorylates and activates the transcription factor ETS2, which upregulates the expression of CYP27A1, an enzyme that modulates lipid metabolism and suppresses CD8+ T cell function via liver X receptor beta (LXRβ) signaling. These findings elucidate a novel MFAP2-ITGB8-FAK-ERK1/2-ETS2-CYP27A1-LXRβ signaling axis, significantly activated by CAFs-derived MFAP2 in both in vitro and in vivo models, contributing to immune exhaustion and tumor progression. This axis offers significant therapeutic and prognostic potential for CRC, providing critical insights into CAF-mediated immune modulation and paving the way for targeted immunotherapeutic strategies.

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