KRAS inhibition triggers coordinated neoplastic and immune remodeling in the tumor microenvironment

Abstract

Abstract KRAS inhibitors are a novel, recently approved class of small molecules that target cancers with KRAS mutations, and understanding molecular mechanisms by which these inhibitors stimulate anti-tumor immunity will improve patient outcomes. In this study, we utilized a multi-omic approach combining single-cell RNA-seq, spatial transcriptomics, and flow cytometry to define cell signatures and signaling events associated with response in a murine model expressing KRAS-G12C tumors. Treatment with KRAS inhibitors but not MEK inhibitors drove neoplastic differentiation toward cell states with increased oxidative stress and extracellular matrix remodeling capacity. These changes were accompanied by spatially-defined Notch and Integrin signaling patterns between neoplastic, stromal, and classical dendritic cell (cDC) niches, leading to accelerated cDC maturation and CD8 effector T-cell activation. Our multi-omic design distills the complex cellular consequences and intercellular communication patterns in the tumor microenvironment following KRAS inhibition and provides a framework for contextualizing and validating disease-relevant signatures to guide therapeutic strategy.