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Targeting KRAS reprograms a Treg-dominant immunosuppressive microenvironment and sensitizes KRAS-mutant gastric adenocarcinoma to CTLA-4 immunotherapy 期刊论文

编号：

849EE70A62AFC24DC42C10EAD9D8CD97
作者：

Tang, Xiaohuan#^[1]Yang, Peiyao#^[1]Guo, Xiaoyong#^[1]Wei, Shuhua#^[2]Cheng, Xiaojing#^[3]Li, Mengyuan(李梦园)^[4]Bao, Yigang^[5,6];Nomura, Sachiyo^[7];Sun, Yu^[8];Huangfu, Longtao^[1];Xing, Xiaofang^[1];Jia, Yongning^[1];Shan, Fei^[1];Gao, Xiangyu*^[1]Han, Chuanhui*^[9,10]Li, Ziyu*^[1]
语种：

英文
期刊：

SCIENCE CHINA-LIFE SCIENCES ISSN：1674-7305 2026 年 ; 2026 SEP 3
收录：
关键词：

gastric adenocarcinoma <italic>KRAS</italic> mutation tumor microenvironment TGF-beta Treg targeted immunotherapy
摘要：

Oncogenic KRAS mutations define a distinct molecular subset of gastric adenocarcinoma (GA), yet their impact on the tumor immune microenvironment remains incompletely understood. In this study, we established a genetically faithful and immunocompetent KRAS G12D-driven mouse model of GA, together with matched organoids and cell lines, to investigate how oncogenic KRAS shapes tumor-immune interactions. KRAS-mutant tumors consistently developed an immunosuppressive microenvironment characterized by enrichment of regulatory T cells (Tregs), accompanied by reduced cytotoxic lymphocyte infiltration and intrinsic resistance to PD-1 blockade. Although pharmacologic targeting of KRAS effectively suppressed tumor growth and increased immune cell infiltration, functional immune analyses revealed persistent Treg-mediated immunosuppression that limited effective antitumor immunity. Mechanistically, TGF-beta signaling was required to maintain Treg dominance and suppress effector T cell function in KRAS-driven tumors. Importantly, disruption of this suppressive axis through combined KRAS inhibition and CTLA-4 blockade attenuated TGF-beta activity, impaired Treg function, and enhanced antitumor immune responses in vivo. Collectively, these findings identify oncogenic KRAS as a key regulator of TGF-beta-dependent immune suppression in GA and provide mechanistic insight into immune evasion within this molecular subtype.
推荐引用方式
GB/T 7714：

Tang Xiaohuan,Yang Peiyao,Guo Xiaoyong, et al. Targeting KRAS reprograms a Treg-dominant immunosuppressive microenvironment and sensitizes KRAS-mutant gastric adenocarcinoma to CTLA-4 immunotherapy [J].SCIENCE CHINA-LIFE SCIENCES,2026.
APA：

Tang Xiaohuan,Yang Peiyao,Guo Xiaoyong,Wei Shuhua,&Li Ziyu.(2026).Targeting KRAS reprograms a Treg-dominant immunosuppressive microenvironment and sensitizes KRAS-mutant gastric adenocarcinoma to CTLA-4 immunotherapy .SCIENCE CHINA-LIFE SCIENCES.
MLA：

Tang Xiaohuan, et al. "Targeting KRAS reprograms a Treg-dominant immunosuppressive microenvironment and sensitizes KRAS-mutant gastric adenocarcinoma to CTLA-4 immunotherapy" .SCIENCE CHINA-LIFE SCIENCES(2026).
入库时间：

2026/9/23 9:46:24
更新时间：

2026/9/23 9:46:24

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