Tang Jing, Wei Wei, Xu Yaoqing, Chen Kexin, Miao Yaping, Fan Weining, Huang Zhi, Liu Jie, Chen Ping, Luo Honghao, Wang Lexin
Department of Gastroenterology, Guangyuan Central Hospital, Guangyuan, China.
Department of Oncology, Chongqing General Hospital, Chongqing University, Chongqing, China.
Biofactors. 2025 Jan-Feb;51(1):e2130. doi: 10.1002/biof.2130. Epub 2024 Oct 21.
G-protein-coupled receptors (GPRs) are critical regulators of various biological behaviors, and their role in gastric cancer (GC) progression is gaining increasing attention. Among them, the immune regulatory mechanisms mediated by chemokine receptor 4 (CXCR4) remain insufficiently understood. This study aims to explore the immune regulatory functions of CXCR4 and the heterogeneity of the tumor microenvironment (TME) by examining GPR-related gene expression in GC. Through multi-omics approaches, including spatial transcriptomics and single-cell RNA sequencing, we investigated the oncogenic mechanisms of CXCR4, particularly its role in T cell immune exhaustion. In vitro experiments, including ELISA, PCR, CCK8 assays, cell scratch assays, and colony formation assays, were used to validate the role of CXCR4 in the migration and invasion of AGS and SNU-1 cell lines. CXCR4 silencing using siRNA further demonstrated its regulatory effects on these cellular processes. Our results revealed a strong correlation between elevated CXCR4 expression and increased exhaustion of regulatory T cells (Tregs) in the TME. Furthermore, heightened CXCR4 expression was linked to increased TME heterogeneity, driven by oxidative stress and activation of the NF-κB pathway, promoting immune evasion and tumor progression. Silencing CXCR4 significantly inhibited the invasive and proliferative abilities of AGS and SNU-1 cells, while also reducing the expression of pro-inflammatory cytokines IL-1β and interleukin-6, thus alleviating chronic inflammation and improving TME conditions. In conclusion, our comprehensive investigation highlights CXCR4 as a key mediator of TME dynamics and immune modulation in GC. Targeting CXCR4 presents a promising therapeutic strategy to slow tumor progression by reducing Tregs-mediated immune exhaustion and TME heterogeneity, positioning it as a novel therapeutic target in GC treatment.
G蛋白偶联受体（GPRs）是各种生物学行为的关键调节因子，其在胃癌（GC）进展中的作用日益受到关注。其中，趋化因子受体4（CXCR4）介导的免疫调节机制仍未得到充分了解。本研究旨在通过检测GC中GPR相关基因表达，探索CXCR4的免疫调节功能及肿瘤微环境（TME）的异质性。通过多组学方法，包括空间转录组学和单细胞RNA测序，我们研究了CXCR4的致癌机制，特别是其在T细胞免疫耗竭中的作用。体外实验，包括ELISA、PCR、CCK8检测、细胞划痕实验和集落形成实验，用于验证CXCR4在AGS和SNU-1细胞系迁移和侵袭中的作用。使用siRNA沉默CXCR4进一步证明了其对这些细胞过程的调节作用。我们的结果显示，TME中CXCR4表达升高与调节性T细胞（Tregs）耗竭增加之间存在强烈相关性。此外，CXCR4表达升高与TME异质性增加有关，这是由氧化应激和NF-κB途径激活驱动的，促进了免疫逃逸和肿瘤进展。沉默CXCR4显著抑制了AGS和SNU-1细胞的侵袭和增殖能力，同时还降低了促炎细胞因子IL-1β和白细胞介素-6的表达，从而减轻了慢性炎症并改善了TME条件。总之，我们的全面研究突出了CXCR4作为GC中TME动态变化和免疫调节的关键介质。靶向CXCR4提出了一种有前景的治疗策略，可通过减少Tregs介导的免疫耗竭和TME异质性来减缓肿瘤进展，使其成为GC治疗中的一个新的治疗靶点。
