胃癌（GC）的高患病率和对患者预后的不利影响使之成为国际上持续存在的重大健康问题。现有的治疗方式效果有限，促使人们探索免疫检查点抑制剂作为一种新的治疗方法。然而，对免疫治疗的抵抗对GC治疗提出了重大挑战，需要深入掌握内在的分子途径。本研究重点研究GC中静止癌细胞（QCC）的免疫抑制机制，特别是它们对T细胞介导的免疫抑制机制免疫反应。利用小鼠模型、基因编辑技术和转录组测序，我们的目标是阐明 QCC、免疫细胞和 HIF1A 等关键调控因子之间的相互作用。功能富集分析将进一步强调糖酵解相关基因在介导 QCC 免疫抑制中的作用。接受 T 细胞疗法治疗的 GC 中幸存的癌细胞失去了增殖能力。 QCC作为免疫治疗的主要抵抗力量，对CD8 T细胞攻击表现出更强的抵抗力，并具有更高的致癌潜力。单细胞测序分析显示，QCCs区域的微环境含有更多的M2型肿瘤相关巨噬细胞和更少的T细胞。 QCC 区域的这种微环境导致 T 细胞免疫激活下调并改变巨噬细胞代谢功能。 QCC 的转录组测序鉴定出与化疗耐药、缺氧和糖酵解相关的上调基因。体外细胞实验表明，HIF1A促进糖酵解相关基因的转录，沉默QCC中的HIF1A可增强共培养系统中T细胞的增殖和活化，诱导QCC凋亡，并增加QCC对免疫检查点抑制剂的敏感性。体内动物实验表明，沉默 QCC 中的 HIF1A 可以抑制 GC 生长和转移。揭示 QCC 通过免疫抑制抵抗 T 细胞介导的免疫反应的分子机制，对于完善治疗策略和改善 GC 患者的治疗效果具有重要意义。通过描述这些错综复杂的相互作用，这项研究为精准医疗和改善 GC 管理的治疗结果提供了重要见解。© 2024。作者。

The high prevalence and detrimental effects on patient outcomes make gastric cancer (GC) a significant health issue that persists internationally. Existing treatment modalities exhibit limited efficacy, prompting the exploration of immune checkpoint inhibitors as a novel therapeutic approach. However, resistance to immunotherapy poses a significant challenge in GC management, necessitating a profound grasp of the intrinsic molecular pathways.This study focuses on investigating the immunosuppressive mechanisms of quiescent cancer cells (QCCs) in GC, particularly their resistance to T-cell-mediated immune responses. Utilizing mouse models, gene editing techniques, and transcriptome sequencing, we aim to elucidate the interactions between QCCs, immune cells, and key regulatory factors like HIF1A. Functional enrichment analysis will further underscore the role of glycolysis-related genes in mediating immunosuppression by QCCs.The cancer cells that survived GC treated with T-cell therapy lost their proliferative ability. QCCs, as the main resistance force to immunotherapy, exhibit stronger resistance to CD8+ T-cell attack and possess higher cancer-initiating potential. Single-cell sequencing analysis revealed that the microenvironment in the QCCs region harbors more M2-type tumor-associated macrophages and fewer T cells. This microenvironment in the QCCs region leads to the downregulation of T-cell immune activation and alters macrophage metabolic function. Transcriptome sequencing of QCCs identified upregulated genes related to chemo-resistance, hypoxia, and glycolysis. In vitro cell experiments illustrated that HIF1A promotes the transcription of glycolysis-related genes, and silencing HIF1A in QCCs enhances T-cell proliferation and activation in co-culture systems, induces apoptosis in QCCs, and increases QCCs' sensitivity to immune checkpoint inhibitors. In vivo, animal experiments showed that silencing HIF1A in QCCs can inhibit GC growth and metastasis.Unraveling the molecular mechanisms by which QCCs resist T-cell-mediated immune responses through immunosuppression holds promising implications for refining treatment strategies and enhancing patient outcomes in GC. By delineating these intricate interactions, this study contributes crucial insights into precision medicine and improved therapeutic outcomes in GC management.© 2024. The Author(s).