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

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. In this study, 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 (TAM), 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. SIGNIFICANCE: KRAS activates CD9-FXR1 signaling that reduces membrane tension to promote extracellular tumor DNA uptake and reduce innate DNA sensing, reshaping the immune landscape and opening opportunities for KRAS-mutant cancer diagnosis and treatment. See related commentary by McAndrews, p. 3371.