ORIGINAL RESEARCH article
Front. Immunol.
Sec. Cancer Immunity and Immunotherapy
Volume 16 - 2025 | doi: 10.3389/fimmu.2025.1618591
This article is part of the Research TopicCommunity Series in The Immunosuppressive Tumor Microenvironment and Strategies to Revert its Immune Regulatory Milieu for Cancer Immunotherapy: Volume IIView all 7 articles
Identification of a Stromal Immunosuppressive Barrier Orchestrated by SPP1 + /C1QC + Macrophages and CD8 + Exhausted T Cells Driving Gastric Cancer Immunotherapy Resistance
Provisionally accepted
Guichuang Ma
Xiaohan Liu
Qinrui JiangShaowei LiQijing WuBishan LiangFei Sun
Chunhui Gu
Wangjun LiaoZhihua Zhang
Min Shi*
Qiong Huang*- Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province, China
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The heterogeneity of immune cells is a critical manifestation of gastric cancer (GC) heterogeneity and significantly contributes to immune therapy resistance. Although previous studies have focused on the roles of specific myeloid cells and exhausted CD8 + T cells in immune resistance, the immune cell interaction network and its spatiotemporal distribution in GC immune resistance remain underexplored.This study integrated multiple GC single-cell RNA sequencing, spatial transcriptomics, bulk-RNA sequencing, and single-cell immunotherapy datasets of our cohort (NFHGC Cohort). Methods such as single-cell subpopulation identification, transcriptomic analysis, spatial colocalization, cell communication network analysis and tissue immunofluorescence of gastric cancer were employed to investigate immune cell interactions and their molecular mechanisms in immune resistance.By leveraging a comprehensive approach that integrates single-cell RNA sequencing, spatial transcriptomics, and bulk RNA-seq profiles, we identified 20 immune subsets with potential prognostic and therapeutic implications. Our findings suggest a stromal immunosuppressive network orchestrated by Macro_SPP1/C1QC macrophages and CD8_Tex_C1 T cells, which may form a barrier impeding antitumor immunity. Macrophagederived MIF signaling appears to drive immunosuppression via the MIF-CD74/CXCR4/CD44 axis. Based on these observations, we developed a preliminary TME classification system using a gene signature derived from barrier-associated immune cell markers and unsupervised clustering.Our study identified a potential stromal immunosuppressive barrier in gastric cancer, driven by Macro_SPP1/C1QC macrophages and CD8_Tex_C1 T cells, which may contribute to immune dysfunction and therapy resistance. Molecular subtyping based on this barrier's presence could inform personalized immune therapy strategies.
Keywords: gastric cancer, immune microenvironment, Immunotherapy resistance, Macrophages, exhausted CD8 + T cells, Cellular interaction network
Received: 26 Apr 2025; Accepted: 01 Jul 2025.
Copyright: © 2025 Ma, Liu, Jiang, Li, Wu, Liang, Sun, Gu, Liao, Zhang, Shi and Huang. 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:
Min Shi, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong Province, China
Qiong Huang, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong Province, China
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