You Li, Wang Qian, Zhang Tianxue, Xiao Hongwei, Lv Mengjiao, Lv Hong, Deng Li, Zhang Xuyao, Zhang Yu
Department of Gastric Surgery, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
Department of Obstetrics and Gynecology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China.
Oncogene. 2025 Apr 23. doi: 10.1038/s41388-025-03425-w.
Resistance to anti-PD-1 therapy remains a significant challenge in gastric cancer (GC) treatment. Here, we revealed that the USP14-IMP2-CXCL2 axis in tumor-associated macrophages (TAMs) drove resistance by recruiting myeloid-derived suppressor cells (MDSCs). Endoscopic biopsy samples were obtained from patients with inoperable GC who were candidates for anti-PD-1 therapy. Single-cell RNA sequencing (scRNA-seq) analysis showed a higher prevalence of USP14 TAMs in therapy-resistant cases, where USP14 was linked to the immunosuppressive phenotype of TAMs. Clinically, GC samples with elevated USP14 TAM infiltration exhibited decreased CD8 T cell presence and increased MDSC infiltration. In vivo experiments further confirmed that USP14 TAMs facilitated resistance to anti-PD-1 therapy in GC, reduced the infiltration of CD8 T cells, and significantly increased the infiltration of MDSCs. In particular, USP14 TAMs markedly enhanced the recruitment of MDSCs into the GC microenvironment through the secretion of CXCL2. Mechanistically, USP14 stabilized the m6A reader IMP2 through deubiquitination, thus enhancing CXCL2 expression and secretion. Conversely, the E3 ligase RNF40 facilitated IMP2 degradation via increasing its ubiquitination, with USP14 and RNF40 dynamically balancing IMP2's protein abundance. Furthermore, animal experiments demonstrated that targeted intervention of USP14 markedly enhanced the sensitivity of GC to anti-PD-1 therapy. This study provided a comprehensive exploration of USP14's oncogenic roles in TAMs, suggesting a novel strategy to enhance the efficacy of anti-PD-1 therapy by inhibiting the USP14/IMP2/CXCL2 signaling axis in GC.
对抗程序性死亡蛋白1（PD-1）疗法产生耐药性仍然是胃癌（GC）治疗中的一项重大挑战。在此，我们揭示了肿瘤相关巨噬细胞（TAM）中的泛素特异性蛋白酶14（USP14）-胰岛素样生长因子2信使核糖核酸结合蛋白2（IMP2）-CXC趋化因子配体2（CXCL2）轴通过募集髓源性抑制细胞（MDSC）来驱动耐药性。从符合抗PD-1治疗条件的不可切除GC患者中获取内镜活检样本。单细胞RNA测序（scRNA-seq）分析显示，在治疗耐药病例中USP14阳性TAM的比例更高，其中USP14与TAM的免疫抑制表型相关。在临床上，USP14阳性TAM浸润增加的GC样本显示CD8 T细胞数量减少，MDSC浸润增加。体内实验进一步证实，USP14阳性TAM促进了GC对抗PD-1治疗的耐药性，减少了CD8 T细胞的浸润，并显著增加了MDSC的浸润。特别是，USP14阳性TAM通过分泌CXCL2显著增强了MDSC向GC微环境的募集。从机制上讲，USP14通过去泛素化作用稳定了m6A阅读蛋白IMP2，从而增强了CXCL2的表达和分泌。相反，E3泛素连接酶RNF40通过增加IMP2的泛素化促进其降解，USP14和RNF40动态平衡IMP2的蛋白质丰度。此外，动物实验表明，对USP14进行靶向干预可显著增强GC对抗PD-1治疗的敏感性。本研究全面探讨了USP14在TAM中的致癌作用，提示通过抑制GC中的USP14/IMP2/CXCL2信号轴来提高抗PD-1治疗疗效的新策略。
