Abstract The mechanisms controlling the extracellular abundance of tumor DNA (tDNA), which is increasingly recognized to modulate innate immunity and serves as a source of clinical biomarkers, remain poorly defined. Here, we show that oncogenic KRAS promotes tDNA clearance by inducing the tetraspanin CD9, which recruits FXR1 to remodel the actin cortex, lower plasma-membrane tension, and promote endocytic uptake of extracellular tDNA. This reduction in tDNA dampens ZBP1-dependent DNA sensing in tumor-associated macrophages (TAMs), shifting them toward an immunosuppressive state. Blockade of CD9 restores extracellular tDNA and DNA sensing, reprograms TAMs, and synergizes with PD-1 blockade in KRAS-mutant cancer models. These findings delineate a KRAS-CD9-FXR1 pathway that couples membrane mechanics to extracellular DNA clearance and immune evasion, providing a strong rationale for targeting CD9 to augment the efficacy of checkpoint blockade. Citation Format: Di Cao, Weiyi Zhou, Zhixiong Li, Shixun Lu, Zhenlin Hou, Long Yu, Yuanjun Guan, Guoqiang Wang, Yifan Liu, Zhijie Huang, Hao Wang, Jingyi Dai, Cong Li, Jing Wang, Gong Chen. Oncogenic KRAS suppresses DNA sensing via CD9 by remodeling membrane tension to clear extracellular tumor DNA abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts) ; 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86 (8Suppl): Abstract nr LB084.
Cao et al. (Fri,) studied this question.