Abstract Pancreatic ductal adenocarcinoma (PDAC) is highly resistant to immune checkpoint inhibitors (ICIs), largely due to an immune-excluded and stromal-dense microenvironment. MUC5AC, a gel-forming mucin aberrantly expressed in PDAC, is implicated in tumor progression and immune evasion. To define its role in shaping the tumor immune landscape, we investigated transcriptomic pathway, and immune infiltration features of MUC5AC-high versus MUC5AC-low PDACs. Transcriptomic data from TCGA, ICGC, and GEO PDAC cohorts (N=1047) were analyzed. Differential expression and pathway enrichment were assessed using Gene Ontology and KEGG. To ensure cross-platform robustness, immune cell infiltration was inferred using multiple transcriptomic deconvolution algorithms, including CIBERSORT, CIBERSORT-Abs, EPIC, MCPcounter, quanTIseq, xCell, ESTIMATE, and TIMER. Expression of immunomodulator and immune inhibitory genes was correlated with MUC5AC levels using median cut-offs, with cross-cohort validation. MUC5AC-high tumors showed enrichment of lipid and glycan metabolism, glycosyltransferase activity, extracellular vesicle secretion, and cytoskeletal/adhesion pathways, consistent with metabolic rewiring and stromal remodeling. Although KEGG immune pathways (T cell receptor, B cell receptor, NK cytotoxicity, chemokine signaling) were transcriptionally activated, functional signature evidence indicated immune suppression. Immune infiltration analysis revealed that MUC5AC-high tumors had significant associations (p0.05) with higher Tregs, resting memory CD4+ T cells, M0 macrophages, resting natural killer (NK) cells, memory B cells, plasma cells, and resting dendritic cells, and lower CD8+ T cells, activated NK cells, follicular helper T cells, activated memory CD4+ T cells, M1 macrophages, naïve B cells, γδ T cells, and M2 macrophages . Importantly, immunomodulator profiling demonstrated significant differences (p0.05) in inhibitory molecules, with positive associations with PD-L1, LGALS9, IL10/IL10RB, TGFB1/TGFBR1, and IDO1, and negative associations with PD-1, PD-L2, CTLA4, LAG3, and TIM-3.Thus, MUC5AC-high PDAC exhibits an “immune-inflamed but functionally restrained” phenotype, characterized by immune signaling engagement but dominance of stromal, metabolic, and ligand-driven suppressive programs. MUC5AC may serve as a biomarker of immune exclusion, guiding patient stratification for ICI-based therapies. Citation Format: Ashish Manne, Wancai Yang, Yongchen Guo, Vaibhav Sahai, Prachi Bajpai, Yonghua Bao, M Khalid Khan Niazi, Alejandro Leyva, Upender Manne. MUC5AC expression defines an immune-inflamed but functionally restrained tumor microenvironment in pancreatic ductal adenocarcinoma 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 1043.
Manne et al. (Fri,) studied this question.