STAT3 inhibitors synergize with KRAS G12C inhibitors in NSCLC by restricting adaptive resistance of STAT3 signaling and augmenting NK cell cytotoxicity

KRASG12C inhibitors have demonstrated clinical efficacy in KRASG12C-mutant non-small cell lung cancer (NSCLC), yet adaptive resistance limits their sustained therapeutic benefit. Through high-throughput screening of a pharmacological library, we identified a potent synergistic interaction between the KRASG12C inhibitor sotorasib and the signal transducer and activator of transcription 3 (STAT3) inhibitor napabucasin in KRASG12C-mutant NSCLC models. This combination exhibited superior anti-neoplastic activity compared to monotherapy in vitro and across diverse in vivo models. Mechanistically, KRASG12C inhibitor induced compensatory STAT3 activation, leading to adaptive resistance to sotorasib, which was abrogated by napabucasin. Notably, we elucidated a novel function of STAT3 in regulating HLA-B expression, an inhibitory ligand for natural killer (NK) cells, upon KRASG12C inhibition. The combination therapy enhanced NK cell-mediated cytotoxicity by disrupting the direct binding of phosphorylated STAT3 to the HLA-B promoter to downregulate its expression on neoplastic cells. Our findings unveiled an unexpected immunomodulatory mechanism underlying the synergism between KRAS and STAT3 inhibition, highlighting the potential of concurrently targeting oncogenic signaling cascades and the tumor microenvironment. This study provides a compelling rationale for the clinical evaluation of combined KRASG12C and STAT3 interruption in KRASG12C-mutant NSCLC patients, potentially offering a novel therapeutic strategy to overcome resistance and improve clinical outcomes.