Abstract 923: The role of NNMT in anti-tumor immunity in LKB1 deficient NSCLCs

Abstract Lung cancer is the leading cause of cancer-related deaths with non-small cell lung cancer (NSCLC)accounting for 85% of all lung cancers. Loss or inactivating mutations of serine/threonine kinase STK11 encoding the LKB1 protein occurs in approximately 20% of lung adenocarcinoma (LUAD). Although treatment of NSCLCs with immune checkpoint inhibitors (ICI) has responded in overall survival in a subset of patients, studies have revealed that co-occurring KRAS/LKB1 mutations promote primary resistance to ICIs in NSCLCs, the mechanism of which is still not completely understood. Nicotinamide N-methyltransferase (NNMT) is a metabolic enzyme that catalyzes the methylation of nicotinamide (Nam) using the co-factor S-adenosyl-L-methionine to form 1-methyl-nicotinamide (1-MNA). In this study, we discovered that levels of NNMT and its product 1-MNA are elevated inNSCLCs with loss of function of LKB1. Mechanistically, we found that LKB1-SIK1/2/3 axisdirectly suppresses NNMT expression transcriptionally. Therefore, loss of function of LKB1 leadsto upregulation of NNMT and its products 1-MNA. Interestingly, knockout of NNMT or 1-MNA treatment did not impact cell proliferation or survival in NSCLC cells with or without functionalLKB1. Global metabolomic and transcriptomic studies revealed that 1-MNA promotes FOXP3induction and regulatory T cell (Treg) expansion, consequently leading to reduced CD8 T cellfunction both in vitro and in vivo. Knockout of NNMT in KPL cells (KrasG12DTp53/LKB1 KO)enhanced anti-tumor immune response and promoted ICI efficacy by suppressing Tregaccumulation in vivo. Importantly, NNMT inhibitor improves the therapeutic efficacy of anti-PD-1antibody in KPL model in vivo. The present study revealed that NNMT/1-MNA signaling plays animportant role in regulating Treg function in LKB1 deficient NSCLC. Targeting NNMT with smallmolecular inhibitor may hold promise to improve the efficacy of ICIs for LKB1 deficient NSCLCs. Citation Format: Thi Na Nguyen, Wenjing Na, Pawel Nowialis, Thi Kim Ngan Bui, Kunyang Li, Ryan Clay, Lina Song, Lingtao Jin. The role of NNMT in anti-tumor immunity in LKB1 deficient NSCLCs. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 923.