Dipeptidyl peptidase 4 restoration facilitates anti-tumor immunity in KRAS–LKB1–mutant lung cancer

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 (ICIs). Despite their high tumor mutation burden, KL tumors exhibit low programmed cell death ligand 1 (PD-L1) expression, reduced immune cell infiltration, and suppressed immune signaling pathways. Through systematic genomic analyses, we found that LKB1 loss suppresses dipeptidyl peptidase 4 (DPP4) expression and activity in KRAS-mutant lung cancer. Therefore, we evaluated the therapeutic potential of restoring DPP4 function to improve the immune response in KL lung cancer 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 natural killer (NK) cell activation. Indeed, DPP4 restoration in three-dimensional microfluidic models enhanced NK cell chemotaxis and activity in targeting tumor spheroids. Furthermore, DPP4 restoration in syngeneic KL murine models synergized with anti-PD-1 therapy to achieve significant tumor regression. 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 highlight DPP4 as a key immune modulator and a promising therapeutic target, offering a novel strategy to overcome immune resistance and enhance immunotherapy outcomes in this challenging subset of lung cancer.