Abstract 4324: Dipeptidyl peptidase 4 restoration facilitates anti-tumor immunity in KRAS-LKB1-mutant lung cancer

Abstract KRAS-liver kinase B1 (LKB1)-mutant (KL) non-small cell lung cancer (NSCLC) represents an aggressive subtype characterized by a profoundly immunosuppressive tumor microenvironment (TME) and poor response to immune checkpoint inhibitors (ICIs). Despite harboring a high tumor mutation burden, KL tumors exhibit reduced immune cell infiltration, low PD-L1 expression, and suppressed interferon and cytotoxic signaling. To elucidate the molecular basis of this immune resistance, we performed multi-omics analyses and found that loss of LKB1 suppresses the mRNA, protein, and enzymatic activity of dipeptidyl peptidase 4 (DPP4), a membrane-bound glycoprotein involved in immune modulation. Restoration of DPP4 expression in KRAS-mutant lung cancer cells reprogrammed the TME and markedly increased immune-related gene signatures associated with T-cell migration and natural killer (NK) cell activation. In three-dimensional microfluidic models, DPP4 overexpression enhanced NK cell chemotaxis and spheroid targeting. In syngeneic KL murine models, DPP4 restoration synergized with anti-PD-1 therapy, leading to significant tumor regression and immune activation. These findings provide the first evidence that LKB1 actively regulates DPP4, establishing DPP4 as a pivotal immune modulator in KRAS-mutated NSCLC. The loss of LKB1 may represent an active mechanism of immune evasion, wherein tumor cells suppress DPP4-mediated immune activation to create an immune-cold TME. Consistent with recent observations linking STK11 and KEAP1 co-mutations to PD-L1-negative or immune desert phenotypes, our data support the concept that DPP4 suppression contributes to immune exclusion in KL-NSCLC. Conversely, DPP4 restoration promoted NK cell migration and enhanced responsiveness to PD-1 blockade, underscoring its role in reprogramming the TME. While DPP4 has context-dependent functions in cancer immunity, our study demonstrates that restoring, rather than inhibiting, DPP4 enhances immune effector recruitment and facilitates antitumor immunity. Collectively, these findings highlight DPP4 as a key immune regulator and promising therapeutic target to overcome ICI resistance and improve immunotherapy outcomes in KRAS-LKB1-mutant lung cancer. Citation Format: Hiraku Yanada, . Dipeptidyl peptidase 4 restoration facilitates anti-tumor immunity in KRAS-LKB1-mutant lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4324.