Mutant KRAS Suppresses DNA Sensing by Remodeling Membrane Tension to Clear Extracellular Tumor DNA

Abstract Extracellular tumor-derived DNA (tDNA) has emerged as an important biomarker for cancer diagnosis and monitoring. A better understanding of the mechanisms controlling the abundance of tDNA could help improve biomarker and treatment strategies. Here, we identified oncogenic KRAS as a critical regulator of tDNA levels. Mutant KRAS promoted tDNA clearance by inducing the tetraspanin CD9, which recruited FXR1 to remodel the actin cortex, lower plasma-membrane tension, and promote endocytic uptake of extracellular tDNA. The reduction in tDNA dampened ZBP1-dependent DNA sensing in tumor-associated macrophages (TAMs), shifting them toward an immunosuppressive state. Blockade of CD9 restored extracellular tDNA and DNA sensing, reprogrammed TAMs, and synergized 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 immune checkpoint blockade therapy.