Abstract A113: Cachexia and Depression in Pancreatic Cancer (PC) Associate with Myeloid Inflammation and Tumor-Intrinsic Metabolic Stress

Abstract Background: Cachexia and depression are common in pancreatic cancer (PC) and portend poor outcomes. While their links to systemic inflammation are established, their relationship to the tumor immune microenvironment (TME) remains underexplored. We investigated the immunologic and metabolic correlates of cachexia and depression in PC, focusing on systemic and tumor-intrinsic features. Methods: We retrospectively analyzed 685 patients with PC to assess associations between baseline neutrophil-to-lymphocyte ratio (NLR), cachexia (>5% BMI loss in 6 months) and depression (diagnosis or antidepressant use). Odds ratios (OR) and 95% confidence intervals (CI) were calculated. To explore tumor-associated immune and metabolic features, gene set enrichment and immune cell deconvolution were performed on bulk RNAseq (N=39). Validation was conducted using single-nucleus RNAseq (snRNAseq, N=6) and single-cell RNAseq (scRNAseq, N=31). Results: In the clinical cohort (N=685), baseline NLR was significantly associated with both cachexia (OR 1.13, 95% CI: 1.03-1.25; p=0.012) and depression (OR 1.22, 95% CI: 1.14-1.31; p<0.001). Bulk RNAseq (N= 39) revealed that depression (N=10) was associated with increased CSF3 expression (p=0.001) and enrichment of inflammatory (TNFa, IL6-JAK-STAT3), interferon (IFN-r, IFN-a) and lipid metabolism pathways. GDF15 correlated with NLR (R=0.32, p=0.045) and trended with M2 macrophage enrichment (p=0.062) and dendritic cell depletion (p=0.035). Depression was also associated with cytokine elevation (TNF p=0.005, IL1B p=0.004, CD36 p=0.037), along with T cell exclusion, suggesting TME remodeling. M2 abundance was independently associated with worse overall survival (p=0.03). Cachexia was associated with catabolic processes with suppressed myogenesis and epithelial-mesenchymal transition. snRNAseq revealed tumor-intrinsic upregulation of stress-related genes (TXNIP, FASN, GDF15, IL1B, TNF), primarily in malignant cells and macrophages. TXNIP emerged as the top differentially expressed gene in both depression and cachexia, implicating oxidative stress and nutrition depletion. Cortisol-regulated genes were also enriched in depression. scRNAseq confirmed M2 macrophage and N2 neutrophils in cachexia cases, along with metabolic reprogramming in tumor cells. Conclusion: Cachexia and depression in PC are linked to immunosuppressive myeloid polarization and tumor-intrinsic metabolic stress. Elevated NLR reflects systemic inflammation and tracks with GDF15-associated M2/N2/Treg TME remodeling. TXNIP and cortisol-regulated stress pathways may bridge tumor metabolism with systemic wasting and neuroinflammation. Targeting this psycho-immunologic axis, via GDF15, TXNIP or myeloid reprogramming, may improve quality of life and survival outcomes in PC. Citation Format: Junmin Song, Marc Hilmi, Catherine O'Connor, Helen Martirosova, Joshua Schoenfeld, Anabelle Hilmi, Yu Kenneth, Han Sang Kim, Jeffrey Zwicker, Yesne Alici, James Flory, Christine Iacobuzio-Donahue, Eileen O'Reilly, Wungki Park. Cachexia and Depression in Pancreatic Cancer (PC) Associate with Myeloid Inflammation and Tumor-Intrinsic Metabolic Stress [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research—Emerging Science Driving Transformative Solutions; Boston, MA; 2025 Sep 28-Oct 1; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl_3):Abstract nr A113.