Abstract IA01: Spatial and molecular control of tumor immune microenvironments

Abstract Elucidating the spatial organization and local interactions of immune cells in the pancreatic ductal adenocarcinoma (PDAC) microenvironment is essential to identify biomarkers of disease initiation and progression, and to uncover targets for PDAC immunotherapy. By combining high-resolution spatial transcriptomics and functional experiments, we discovered key principles of architecture and function of pathogenic immune niches in human and mouse pancreatic cancer. We identified IL-1β+ tumor-associated macrophages (TAMs) as central organizers of inflammatory niches, as these cells engage in reciprocal crosstalk with multiple tumor, stromal and immune cell subsets via the production and sensing of prostaglandins and innate immune cytokines. Spatial analyses showed that pathogenic IL-1β+ TAM niches are composed of multiple cell types sharing a conserved inflammatory signature, highlighting spatial coordination of functional programs as well as spatial biomarkers of disease. Our analyses also identified specific factors and actionable targets driving defective differentiation of B cells and their organization in aberrant tertiary lymphoid structures (TLSs) lacking germinal centers and enriched in extrafollicular response programs. Together, our findings provide an integrated spatial and functional map of immune dysregulation in PDAC, highlighting local multicellular programs that shape tumor progression, inflammation and immune suppression. Targeting these niches may offer new strategies to restore anti-tumor immunity and overcome immunotherapy resistance in PDAC. Citation Format: Renato Ostuni. Spatial and molecular control of tumor immune microenvironments [abstract]. In: Proceedings of the AACR Immuno-Oncology Conference (AACR IO): Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2026 Feb 18-21; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2026;14(2 Suppl):Abstract nr IA01.