Single-cell multi-omics reveal coordinated neoplastic and immune remodeling following KRAS inhibition

Allele-specific KRAS inhibitors are approved for KRAS-mutant cancers, and efforts to maximize patient responses are ongoing. Previous work suggests that KRAS inhibition can modulate anti-tumor immunity, but the critical cellular players and molecular pathways have not been clearly defined. Here we perform multi-omic profiling using single-cell RNA-seq, spatial transcriptomics, and flow cytometry to profile intratumoral changes after KRASG12C inhibition (KRAS(G12C)i), MEK inhibition (MEKi), and combination therapy with KRAS(G12C)i and PD-1 blockade. Treatment with KRAS(G12C)i but not MEKi drove neoplastic adaptation toward increased oxidative stress, integrin signaling, and upregulation of extracellular matrix remodeling factors. These changes were accompanied by enhanced intercellular communication with classical dendritic cells, leading to robust cDC maturation and CD8 effector T-cell activation. Combination treatment with anti-PD-1 further expands T-cell responses, as well as macrophage states associated with increased cancer survival. Our findings connect KRAS inhibition with the coordination of subsequent immune activation and reveal molecular mechanisms that promote and sustain tumor control.