Abstract P29: STAT3-Mediated Immune Dysfunction And BMI-Stratified Therapeutic Windows in Obesity-Associated Pancreatic Cancer
Arun Viswanathan, Shirly James, Aparna J S, Harikumar K BAbstract
Background:
Obesity increases pancreatic ductal adenocarcinoma (PDAC) incidence and aggressiveness by impairing antitumor immunity, yet mechanistic insights remain limited. We hypothesized that STAT3 integrates obesity-induced metabolic and immune dysfunctions, creating a therapeutic window during the overweight stage of disease.
Methods:
CPTAC PDAC RNA-seq data (n=140) were analyzed for BMI-correlated pathway alterations via KEGG enrichment and GSEA. T cell exhaustion markers positively correlated with BMI were validated in TCGA and mapped to STAT3–JAK signaling networks. Immune deconvolution (BayesPrism, TimiGP) profiled immune shifts across BMI categories. Kras^G12D; Pdx1-Cre (KP) mice with heterozygous or homozygous STAT3 deletion were fed a high-fat diet for 6 months. Spatial transcriptomics (NanoString GeoMX), proteomics (LC-MS/MS), immunofluorescence, and histopathology were performed. STAT3 inhibition was tested using TTI-101 in CD8+ T cell–tumor coculture assays.
Results:
Human PDAC showed progressive immune dysfunction with increasing BMI. Normal-weight patients retained intact ECM remodeling and TCR signaling with functional PAK/VAV-driven immunological synapse formation. Overweight patients exhibited proximal TCR hyperactivation but impaired downstream signaling and protein turnover. Obese patients displayed checkpoint activation (PD-1/CTLA-4), defective protein homeostasis, and PAK/VAV suppression despite TCR hyperactivation. STAT3 knockout mice showed near-complete PanIN prevention with marked reductions in ECM remodeling, glycolysis, fatty acid metabolism, inflammatory signaling, and ductal metaplasia. Spatial transcriptomics confirmed suppression of IL6–JAK–STAT and metabolic stress pathways. TTI-101 enhanced CD8+ cytotoxicity by >30% in vitro. Critically, immune regulation was restored with improved antioxidant defenses and stress resilience, highlighting STAT3’s central role in obesity-induced dysfunction.
Conclusions:
STAT3 orchestrates obesity-driven immune collapse through integrated immunometabolic reprogramming. Overweight PDAC represents a mechanistically defined therapeutic window. These findings support BMI-stratified clinical trials and early STAT3-targeted interventions in overweight patients to prevent irreversible disease progression.
Citation Format:
Arun Viswanathan, Shirly James, Aparna J S, Harikumar K B. STAT3-Mediated Immune Dysfunction And BMI-Stratified Therapeutic Windows in Obesity-Associated Pancreatic Cancer [abstract]. In: Proceedings of Frontiers in Cancer Science 2025; 2025 Nov 5-7; Singapore. Philadelphia (PA): AACR; Cancer Res 2026;86(13_Suppl):Abstract nr P29.