GGT5: a potential immunotherapy response inhibitor in gastric cancer by modulating GSH metabolism and sustaining memory CD8+ T cell infiltration

Sep 22, 2026

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Variable immunotherapy outcomes in gastric cancer (GC) are driven by the complex tumor microenvironment. Glutathione (GSH) metabolism influences GC initiation and progression, making it a promising target to improve immune checkpoint inhibitor (ICI) efficacy. Using pan-cancer TCGA datasets and GSH metabolism–related genes from MSigDB, the study integrates prognosis selection, scRNA-seq tumor heterogeneity, and validation by multiplex immunohistochemistry. Results identify GGT5 as a hub gene linked to memory CD8+ T cell infiltration and suboptimal immunotherapy response. The work supports GGT5 inhibition as a therapeutic strategy and provides new insight for optimizing GC immunotherapy.

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Cancer Immunology, Immunotherapy (2024) 73:131 [https://doi.org/10.1007/s00262-024-03716-3](https://doi.org/10.1007/s00262-024-03716-3) GGT5: a potential immunotherapy response inhibitor in gastric cancer by modulating GSH metabolism and sustaining memory CD8+ T cell infiltration Wenjing Zhao1 · Ziwei Liang1 · Yongshi Yao1 · Yang Ge1 · Guangyu An1 · Ling Duan2 · Jiannan Yao1 Received: 3 November 2023 / Accepted: 24 April 2024 / Published online: 15 May 2024 © The Author(s) 2024 Abstract Purpose The variable responses to immunotherapy observed in gastric cancer (GC) patients can be attributed to the intricate nature of the tumor microenvironment. Glutathione (GSH) metabolism significantly influences the initiation and progression of gastric cancer. Consequently, targeting GSH metabolism holds promise for improving the effectiveness of Immune checkpoints inhibitors (ICIs) . Methods We investigated 16 genes related to GSH metabolism, sourced from the MSigDB database, using pan-cancer datasets from TCGA. The most representative prognosis-related gene was identified for further analysis. ScRNA-sequencing analysis was used to explore the tumor heterogeneity of GC, and the results were confirmed by Multiplex immunohistochemistry (mIHC) . Results Through DEGs, LASSO, univariate and multivariate Cox regression analyses, and survival analysis, we identified GGT5 as the hub gene in GSH metabolism with the potential to promote GC. Combining CIBERSORT, ssGSEA, and scRNA analysis, we constructed the immune architecture of GC. The subpopulations of T cells were isolated, revealing a strong association between GGT5 and memory CD8+ T cells. Furthermore, specimens from 10 GC patients receiving immunotherapy were collected. mIHC was used to assess the expression levels of GGT5 and memory CD8+ T cell markers. Our results established a positive correlation between GGT5 expression, the enrichment of memory CD8+ T cells, and a suboptimal response to immunotherapy. Conclusions Our study identifies GGT5, a hub gene in GSH metabolism, as a potential therapeutic target for inhibiting the response to immunotherapy in GC patients. These findings offer new insights into strategies for optimizing immunotherapy of GC. Keywords GGT5 · Gastric cancer · GSH · Memory CD8+ T cells · Immunotherapy · Immune checkpoints inhibitors Abbreviations GC Gastric cancer GSH Glutathione ICIs Immune checkpoint inhibitors ROS Reactive oxygen species TCM Central memory CD8+ T cells Wenjing Zhao and Ziwei Liang contributed equally to this work. * Jiannan Yao [yaojiannan@mail.ccmu.edu.cn](yaojiannan@mail.ccmu.edu.cn) 1 Beijing Chaoyang Hospital, Capital Medical University, Beijing, China 2 Beijing Tiantan Hospital, Capital Medical University, Beijing, China TEM Effector memory CD8+ T cells TME Tumor microenvironment Introduction Gastric cancer (GC) is one of the most prevalent digestive malignancies, ranking fifth in terms of tumor morbidity and fourth in terms of mortality [1] . Its incidence is particularly high in East Asia [2] . Although reports indicate a decline in its incidence rates over the past few years, advanced GC still has an adverse prognosis, with a five-year survival rate of 10% to 30%[3, 4] . In recent years, immunotherapy has shown promise for improving the clinical outcome of patients with GC. However, due to the strong tumor heterogeneity of GC, tumor immune escape events occur frequently, and the efficacy of immunotherapy remains limited and uncertain. According to the results of CheckMate-649 [5], patients with GC who received Nivolumab in combination with chemotherapy had better clinical benefits than those treated with chemotherapy alone, regardless of the PD-L1 Combined Positive Score (CPS) . In the combination treatment group, the two-year overall survival (OS) rate was nearly 40%, progression-free survival (PFS) was significantly increased, and the objective response rate (ORR) was almost 70% . However, the r

FAQs

Why is GSH metabolism considered important for gastric cancer immunotherapy response?

GSH metabolism affects gastric cancer initiation and progression and can influence how tumors respond to immune checkpoint inhibitors by shaping immune and tumor microenvironment processes.

How did the study identify GGT5 as a key gene?

It analyzed 16 GSH metabolism–related genes from MSigDB using TCGA pan-cancer datasets, then applied gene selection and statistical approaches (including Cox regression and survival analyses) and validated immune associations using scRNA-seq and multiplex immunohistochemistry.

What relationship did the results show between GGT5 and T cells?

Higher GGT5 expression correlated with enriched memory CD8+ T cells and with a suboptimal response to immunotherapy in gastric cancer patients.

Sep 22, 2026

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