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Review Open Access

Tumor microenvironment in gastric cancer immune tolerance and its therapeutic relevance in immunomodulation (Review)

  • Authors:
    • Zihe Guan
    • Lichao Han
    • Baojiang Chen
    • Yijia Ma
    • Qianyue Ni
    • Zijian Wang
    • Jingyu Yang
    • Zheng Liu
  • View Affiliations / Copyright

    Affiliations: School of Basic Medical Sciences, Heilongjiang University of Chinese Medicine, Harbin, Heilongjiang 150040, P.R. China, First Clinical Medical College, Heilongjiang University of Chinese Medicine, Harbin, Heilongjiang 150040, P.R. China
    Copyright: © Guan et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 108
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    Published online on: January 13, 2026
       https://doi.org/10.3892/ol.2026.15461
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Abstract

Gastric cancer (GC) is a highly heterogeneous malignancy and the formation of an immunotolerant tumor microenvironment (TME) is an important promoter of tumor progression, treatment resistance and a poor prognosis. The TME is composed of cellular components including immune cells as well as non‑cellular elements (such as the extracellular matrix) which induce immune tolerance through numerous mechanisms. Comprehensive exploration of TME regulatory pathways in GC has established the theoretical foundation for targeted immunomodulatory strategies. TME‑targeted immunotherapies have demonstrated efficacy in reversing immune tolerance and enhancing antitumor immunity. Additionally, when combined with chemotherapy, radiotherapy and/or targeted agents, these therapies notably improve response rates in patients with GC. The present review evaluates the impact of the TME on the development of immune tolerance in GC and the therapeutic implications of immunomodulation. The components of the GC TME were systematically characterized, and the present review discusses the contributions of cellular components to establishing an immunosuppressive microenvironment, investigates the molecular mechanisms underlying immune tolerance in GC, identifies key immune cells and their crosstalk within the TME and summarizes current treatments targeting TME‑mediated immune tolerance, all with the aim to provide insights into optimized immunotherapeutic strategies and improve patient outcomes.

View Figures

Figure 1

Schematic diagram of immune
regulatory mechanisms in the tumor microenvironment of gastric
cancer. MDSCs suppress the activity of immune effector cells
through metabolic pathways. This leads to increased immune energy
depletion and enhanced immunosuppression within the tumor
microenvironment. The red arrow indicates inhibition, the black
arrows indicate promotion, and the dotted arrow represents indirect
metabolic signaling. MDSC, myeloid-derived suppressor cell; CAF,
cancer-associated fibroblast; DC, dendritic cell; C3-C3AR1,
complement C3-complement C3a receptor 1; CCL2, C-C motif chemokine
ligand 2; APC, antigen-presenting cell; TAM, tumor-associated
macrophage; HIF-1α, hypoxia-inducible factor 1α; PD-1, programmed
cell death protein 1; Treg, regulatory T-cell; PD-L1, programmed
death-ligand 1.

Figure 2

Mechanistic diagram of cell-cell
interactions in the immune tolerance network within the gastric
cancer tumor microenvironment. The red arrows indicate inhibition
and the black arrows indicate promotion. TAM, tumor-associated
macrophage; NK, natural killer; Treg, regulatory T-cell; CAF,
cancer-associated fibroblast; EMT, epithelial-mesenchymal
transition; ECM, extracellular matrix; A2A, adenosine A2A
receptor.
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Copy and paste a formatted citation
Spandidos Publications style
Guan Z, Han L, Chen B, Ma Y, Ni Q, Wang Z, Yang J and Liu Z: <p>Tumor microenvironment in gastric cancer immune tolerance and its therapeutic relevance in immunomodulation (Review)</p>. Oncol Lett 31: 108, 2026.
APA
Guan, Z., Han, L., Chen, B., Ma, Y., Ni, Q., Wang, Z. ... Liu, Z. (2026). <p>Tumor microenvironment in gastric cancer immune tolerance and its therapeutic relevance in immunomodulation (Review)</p>. Oncology Letters, 31, 108. https://doi.org/10.3892/ol.2026.15461
MLA
Guan, Z., Han, L., Chen, B., Ma, Y., Ni, Q., Wang, Z., Yang, J., Liu, Z."<p>Tumor microenvironment in gastric cancer immune tolerance and its therapeutic relevance in immunomodulation (Review)</p>". Oncology Letters 31.3 (2026): 108.
Chicago
Guan, Z., Han, L., Chen, B., Ma, Y., Ni, Q., Wang, Z., Yang, J., Liu, Z."<p>Tumor microenvironment in gastric cancer immune tolerance and its therapeutic relevance in immunomodulation (Review)</p>". Oncology Letters 31, no. 3 (2026): 108. https://doi.org/10.3892/ol.2026.15461
Copy and paste a formatted citation
x
Spandidos Publications style
Guan Z, Han L, Chen B, Ma Y, Ni Q, Wang Z, Yang J and Liu Z: <p>Tumor microenvironment in gastric cancer immune tolerance and its therapeutic relevance in immunomodulation (Review)</p>. Oncol Lett 31: 108, 2026.
APA
Guan, Z., Han, L., Chen, B., Ma, Y., Ni, Q., Wang, Z. ... Liu, Z. (2026). <p>Tumor microenvironment in gastric cancer immune tolerance and its therapeutic relevance in immunomodulation (Review)</p>. Oncology Letters, 31, 108. https://doi.org/10.3892/ol.2026.15461
MLA
Guan, Z., Han, L., Chen, B., Ma, Y., Ni, Q., Wang, Z., Yang, J., Liu, Z."<p>Tumor microenvironment in gastric cancer immune tolerance and its therapeutic relevance in immunomodulation (Review)</p>". Oncology Letters 31.3 (2026): 108.
Chicago
Guan, Z., Han, L., Chen, B., Ma, Y., Ni, Q., Wang, Z., Yang, J., Liu, Z."<p>Tumor microenvironment in gastric cancer immune tolerance and its therapeutic relevance in immunomodulation (Review)</p>". Oncology Letters 31, no. 3 (2026): 108. https://doi.org/10.3892/ol.2026.15461
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