Cancer-Associated Mesothelial Cells Drive Immune Escape and Therapy Resistance in Ovarian Cancer

ABSTRACT Cancer-associated mesothelial cells (CAMCs) are key modulators of the ovarian tumor microenvironment, contributing to tumor growth an immune evasion. Normal mesothelial cells play a role in peritoneal homeostasis and immune surveillance and represent the first point of contact during abdominal dissemination of ovarian cancers. Yet, their role in ovarian tumor immunity remains poorly understood. Here, we map the cellular states, spatial organization, and immune functions of CAMCs across ovarian cancer progression. Using lineage tracing and spatial transcriptomics, we demonstrate that CAMCs originate from mesothelial cells at the tumor surface and can progressively infiltrate the tumor core, undergoing a phenotypic transition towards fibroblast-like and immunosuppressive states. We characterize the function of an unrecognized CAMC subtype marked by SERPINB2 + expression, and a combination of markers absent in normal mesothelial cells. CAMC Serpinb2+ cells have reduced expression of pro-inflammatory cytokines (IL-2, IL-7, IL-12, IL-15) and increased expression of IL-10, TGFß1, and CCL17, promoting regulatory T cell recruitment and tolerogenic CD4 + T cell responses. Functionally, CAMC Serpinb2+ accelerate tumor growth, reduce CD4 + T and B cell infiltration, and expand Treg populations, ultimately leading to immunotherapy resistance. Together, our findings identify CAMCs as a potential therapeutic target in peritoneal carcinomatosis and as a means of restoring sensitivity to current treatments. Graphical abstract