KRAS G12C inhibition combined with CD47 and immune checkpoint blockage overcomes intrinsic resistance to concomitant KRAS G12C and immune checkpoint inhibitor therapy

Although KRAS G12C inhibitors have altered the treatment strategy of patients with KRAS G12C mutant lung cancer, their efficacy is insufficient to eliminate tumors. Here, we identified that inhibition of mutant KRAS promotes escape from macrophage phagocytosis by upregulating the expression of 'don't eat me' signal proteins, including CD47. CD47 was induced by the binding of FOXA1 to the super-enhancer of CD47. The addition of an anti-CD47 antibody restored macrophage phagocytosis and phenotype of macrophages. Overall design: LLC Nras KO syngeneic lung tumors were treated with vehicle, sotorasib (100mg/kg), anti-CD47 (100µg/body), or the combination of these drugs at the same doses for 3 days. Tumors were harvested and subjected to spatial transcriptomics analyses.