KRAS proto-oncogene, GTPase (KRAS)-liver kinase B1 (LKB1)-mutant (KL) non-small cell lung cancer (NSCLC), characterized by a profoundly immunosuppressive tumor microenvironment (TME), is highly resistant to immune checkpoint inhibitors. Despite their high tumor mutation burden, KL tumors exhibit low expression of PD-L1, reduced immune cell infiltration, and suppressed immune signaling pathways. Systematic genome analyses revealed that LKB1 loss suppresses dipeptidyl peptidase 4 (DPP4) expression and activity in KRAS-mutant lung cancer. The therapeutic potential of restoring DPP4 function to improve the immune response in KL lung cancer was evaluated using patient-derived tumor samples and syngeneic mouse models. Restoration of DPP4 expression reprogrammed the TME and significantly increased immune-related gene signatures, including those involved in T-cell migration and NK-cell activation. Restoration of DPP4 expression in three-dimensional microfluidic models enhanced NK-cell chemotaxis and spheroid-targeting activity. Furthermore, DPP4 restoration was synergized with anti-PD-1 therapy to achieve significant tumor regression in syngeneic KL murine models. These findings suggest that LKB1 loss suppresses DPP4 expression, contributing to the immunosuppressive characteristics of the TME in KL-NSCLC cells, whereas restoring DPP4 expression promotes NK-cell recruitment, facilitates immune activation, and enhances the effects of anti-PD-1 therapy. These results suggest that DPP4 is a key immune modulator and a promising therapeutic target, providing a novel strategy to overcome immune resistance and improve immunotherapy outcomes in this challenging subset of lung cancer.
Significance: LKB1 loss suppresses DPP4 expression in KL-NSCLC; however, restoring DPP4 expression in vitro promotes NK-cell recruitment, mitigating the immunosuppressive TME and enhancing the efficacy of anti-PD-1 therapy in KL models.
©2025 The Authors; Published by the American Association for Cancer Research.