REVIEW article
Front. Immunol.
Sec. Cancer Immunity and Immunotherapy
This article is part of the Research TopicExploring key pathways in the progression of gastrointestinal diseases based on metabolic reprogramming and developing drugs targeting metabolismView all 9 articles
GPR35-Mediated Metabolic Reprogramming Promotes Tumorigenesis in Digestive Cancers
Provisionally accepted
Fang Wang1
Xin-xin Ding1Tao-hong Su1Jin Cao1Feng-qin Li1Zi-su Dong1Xin-zhi Guo1Yan Zhang1
Yang Chen2
Dong-Hua Yang3
Ping Luo1*- 1Jiangxi University of Traditional Chinese Medicine, Nanchang, China
- 2Chinese Academy of Sciences Dalian Institute of Chemical Physics, Dalian, China
- 3New York College of Traditional Chinese Medicine, Mineola, United States
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G protein-coupled receptor 35 (GPR35), a member of the largest druggable gene family, has emerged as a critical regulator of tumor metabolism and immune modulation. Aberrant expression of GPR35 is frequently observed in digestive system malignancies and is associated with poor prognosis. This review comprehensively explores GPR35's role in metabolic reprogramming, highlighting its regulatory functions in glucose, lipid, amino acid, and microbial metabolite metabolism. GPR35 shapes the tumor microenvironment through modulation of metabolite signaling, influencing angiogenesis, immune cell infiltration, and inflammation. It also acts as a key interface between host cells and the gut microbiota, contributing to cancer progression via microbial-derived metabolites. Pharmacological targeting of GPR35 shows promise, with several agonists and antagonists advancing through preclinical and early clinical development. However, challenges such as species-specific pharmacodynamics, ligand selectivity, and receptor isoform variability complicate drug development. Recent advances, including the creation of humanized GPR35 models, have facilitated translational research. Targeting GPR35-mediated metabolic reprogramming represents a novel therapeutic strategy, particularly for metabolically active digestive cancers. Future studies should focus on clarifying the metabolic pathways governed by GPR35 and optimizing receptor-specific therapeutics for clinical application
Keywords: GPR35, metabolic reprogramming, Digestive cancers, Tumor Microenvironment, Gut Microbiota
Received: 18 Jul 2025; Accepted: 27 Nov 2025.
Copyright: © 2025 Wang, Ding, Su, Cao, Li, Dong, Guo, Zhang, Chen, Yang and Luo. 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: Ping Luo
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