Abstract 7950: Targeting the OSM-OSMR signaling axis to reprogram the tumor microenvironment and overcome immune suppression in pancreatic cancer

Abstract Pancreatic ductal adenocarcinoma (PDA) is one of the deadliest malignancies, characterized by a dense, fibrotic, and immune-excluded tumor microenvironment (TME) that resists current therapies. Emerging evidence implicates the Oncostatin M (OSM)-Oncostatin M receptor (OSMR) signaling axis, a member of the IL-6 cytokine family, as a key driver of PDA progression through regulation of tumor-stroma-immune interactions. My research aims to define how OSM-OSMR signaling orchestrates the immune-suppressive microenvironment in PDA and to evaluate whether its inhibition can reprogram tumors toward immune responsiveness.Spatial transcriptomics analysis of treatment-naïve human PDA revealed high OSMR expression associated with cancer-associated fibroblast (CAF) activation, stromal stiffness, and enrichment of macrophage and monocyte gene signatures, alongside reduced CD8+ T-cell infiltration. Integrated transcriptomic analyses identified OSMR-associated genes enriched for NF-κB, JAK-STAT, and IFN-γ pathways. Functional studies showed that OSM-OSMR signaling promotes PDA cell proliferation, migration, and invasion, while driving CAF activation and polarization of monocytes toward immunosuppressive CD163+/CD206+ macrophages. In ex vivo human PDA slice cultures, recombinant OSM enhanced proliferation and STAT3 phosphorylation, effects reversed by OSM or OSMR neutralizing antibodies.To dissect the underlying mechanisms, I employed CRISPR-engineered OSMR knockout and rescue PDA cell lines, OSMR-overexpressing CAFs, and 3D co-cultures with monocyte-derived macrophages, integrated with single-cell RNA-seq, phospho-proteomics, and spatial transcriptomics. Parallel translational studies will test OSM/OSMR-neutralizing antibodies in patient-derived organoids, tumor slice cultures, and genetically engineered mouse models (GEMMs), alone or in combination with FDA-approved chemotherapies. These studies will assess the effects of OSM-OSMR signaling on tumor growth, stromal remodeling, immune infiltration, and metastasis.By defining how OSM-OSMR signaling sustains PDA’s fibrotic and immune-suppressive TME and establishing its therapeutic vulnerability, this work aims to develop rational strategies that reprogram the TME, enhance immunotherapy responsiveness, and improve outcomes for patients with pancreatic cancer. Citation Format: Yuan Sui, Tony Hunter. Targeting the OSM-OSMR signaling axis to reprogram the tumor microenvironment and overcome immune suppression in pancreatic cancer [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 7950.