C118S Redox Modulation of KRASG12D Suppresses Obesity-Driven Pancreatic Tumorigenesis

Background: Pancreatic ductal adenocarcinoma (PDAC) is frequently driven by oncogenic KRASG12D/+ and exacerbated by obesity-induced metabolic inflammation, driving immune suppression and metabolic reprogramming. The concurrent rise in global obesity and PDAC incidence demands mechanistic strategies specifically tailored to the unique biology of obesity-associated KRAS-mutant tumors. Redox-sensitive regulation of KRAS at cysteine118 (C118) plays a critical role in signaling activity, and mutation to serine (C118S) has been shown to attenuate KRAS function in other tumor models. However, the impact of C118S on the immunometabolism landscape of KRASG12D/+ driven PDAC particularly in the context of obesity remains unexplored. This study aims to characterize how the C118S mutation alters immune and metabolic dynamics in obese versus lean PDAC settings. Methods & Results: Using in-house genetically engineered mouse models (KRASG12D/+ and KRASG12D+C118S/+ on a KC (KrasCre) background) fed with high-fat or standard normal diets to examine tumor progression. We found changes related to the C118S modification in the KRAS-G12D allele slowed the progression of PDAC. H&E staining showed reduced high-grade PanIN lesion. Alcian Blue and Sirius Red staining revealed a marked reduction in mucin production and fibrosis, indicating an alleviation of the desmoplastic response. Immunohistochemistry for Ki67 showed decreased cell proliferation, CK19 staining confirmed reduced ductal marker expression, and MIST1 staining indicated preservation of acinar cell identity. We also examined the related immune infiltration (CD8+ T cells, PD-1/PD-L1, myeloid cells), metabolic markers (GLUT1, CPT1A). We found that KRASG12D+C118S/+ tumors had improved antitumor Immune and Metabolic profile components of TIME, particularly under obese conditions. Elucidating the redox-dependent mechanisms linking KRASG12D+C118S/+ to immune-metabolic reprogramming. We quantified ROS and GTP-bound KRAS activity, and downstream signaling (PI3K/AKT/mTOR, ERK). We found that C118S reduced ROS-dependent KRAS activity, suppresses oncogenic signaling, and restore metabolic immune fitness. Conclusion: This study pioneers a paradigm shift in pancreatic cancer research by combining redox-based KRAS mutation, metabolic stress (obesity), and immunometabolism signaling. It aims to show that targeting KRAS redox regulation can reshape the immune-metabolic microenvironment to impede tumor progression. Findings could lead to novel redox-immunometabolism therapeutic strategies for obesity-associated KRAS-driven cancers. Citation Format: Zahid Rafiq, Weiqin Lu. C118S-mediated redox modulation of KRASG12D mutation reprograms immunometabolism to suppress obesity-driven pancreatic tumorigenesis [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 5565.