Oncogenic KRAS suppresses DNA sensing via CD9 by remodeling membrane tension to clear extracellular tumor DNA

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.