Open Access
REVIEW
Metabolic Reprogramming in Gastric Cancer Immunity Mechanisms and Therapeutic Implications
Xiangyang Wang1,#, Ying Wu2,3,#, Yutong Fu3,4, Ejakpovi Emmanuel Oghenefejiro2,3, Zakari Shaibu3, Cunxi Li5, Qi Zhou6, Liang Yin2,*
1 Department of Traditional Chinese Medicine, Affiliated People’s Hospital of Jiangsu University, Zhenjiang, China
2 Department of Breast Surgery, Affiliated People’s Hospital of Jiangsu University, Zhenjiang, China
3 School of Medicine, Jiangsu University, Zhenjiang, China
4 Department of Rehabilitation, Danyang Hospital of Traditional Chinese Medicine, Danyang, China
5 Department of Endodontics and Dental Materials, Zhenjiang Stomatological Hospital, Zhenjiang, China
6 Department of Medical Oncology, Affiliated People’s Hospital of Jiangsu University, Zhenjiang, China
* Corresponding Author: Liang Yin. Email: 
# These authors have contributed equally to this work and share first authorship
Oncology Research https://doi.org/10.32604/or.2026.087144
Received 11 June 2026; Accepted 17 July 2026; Published online 07 August 2026
Abstract
Gastric cancer (GC) remains a leading cause of global cancer mortality, with progression and therapy resistance heavily influenced by the dynamic tumor microenvironment (TME). Despite advances in surgical techniques, chemotherapy, targeted therapy, and immunotherapy, overall survival for advanced disease remains poor, underscoring the need for a deeper understanding of resistance mechanisms. A hallmark of the TME is metabolic reprogramming, which sustains tumor growth and actively shapes an immunosuppressive landscape. This review aims to detail the coordinated metabolic adaptations of GC cells, cancer-associated fibroblasts (CAFs), and immune cells within the TME, focusing on nutrient competition, immunosuppressive metabolite accumulation, and dysregulated lipid metabolism. We analyze how glucose depletion, lactate accumulation, and amino acid deprivation establish a hostile metabolic niche that impairs cytotoxic T lymphocyte (CTL) function while paradoxically supporting regulatory T cells (Tregs), M2-like tumor-associated macrophages (TAMs), and myeloid-derived suppressor cells (MDSCs). We examine four major immunosuppressive metabolic pathways, lactate, adenosine, tryptophan-kynurenine, and arginine and demonstrate their convergence on immune checkpoint upregulation, forming an integrated metabolic-immune checkpoint axis. These pathways establish a self-reinforcing immunosuppressive circuit that drives T cell exhaustion and limits immune checkpoint blockade efficacy. We highlight emerging therapeutic strategies targeting this crosstalk, including inhibitors of glycolysis, glutaminolysis, indoleamine 2,3-dioxygenase 1 (IDO1), and adenosine signaling, often combined with immunotherapy. The metabolic supply-demand mismatch explains why certain interventions can revive effector cells while potentially harming other cell types. Finally, we discuss challenges and future directions, emphasizing the need for spatially resolved metabolic profiling, biomarker-driven patient stratification, and personalized therapies to overcome metabolic immunosuppression and improve clinical outcomes in GC.
Keywords
Gastric cancer (GC); tumor microenvironment (TME); metabolic reprogramming; immunometabolism; immunotherapy
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