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Background Immune checkpoint blockade (ICB) has revolutionized treatment for cancers like melanoma and non-small cell lung cancer by reactivating antitumor T cells. However, its impact in ovarian cancer remains limited due to a highly immunosuppressive tumor microenvironment. A key barrier is immune exclusion, where tumors block cytotoxic CD8+ T cell infiltration. This is driven by factors such as abnormal vasculature, stromal changes, and tumor-intrinsic barriers. 1 Identifying the molecular drivers of immune exclusion is essential to enhance immune infiltration and improve ICB response in ovarian cancer.2 Methods To uncover new therapeutic targets, we investigated ADGRL2, a member of the adhesion G-protein coupled receptor subfamily, for its role in ovarian cancer. Using single-cell RNA sequencing, spatial transcriptomics, and survival analyses across ovarian cancer patients, we assessed the expression pattern of ADGRL2 and its correlation with immune cell infiltration, tumor progression, and patient survival. Special attention was given to the impact of ADGRL2 in both TP53 mutant and wild-type tumors.Results ADGRL2 was significantly overexpressed in malignant epithelial cells ( figure 1), especially within a cancer cell cluster marked by high S100A4 and CASC1, genes linked to invasiveness and treatment resistance. scRNA-seq showed ADGRL2 was mainly tumor-specific, with minimal expression in non-cancerous cells. Clinically, high ADGRL2 correlated with worse overall survival irrespective of TP53 status. Spatial transcriptomics revealed CD8+ T cells localized to tumor margins but were excluded from ADGRL2+ tumor areas, indicating immune exclusion (figure 2). Moreover, ADGRL2 expression was positively associated with immunosuppressive cells such as regulatory T cells, M2 macrophages, myeloid-derived suppressor cells, and cancer-associated fibroblasts, highlighting its role in fostering an immunosuppressive environment. Mechanistically, ADGRL2 interacts with occludin, a tight junction protein, and their expression levels were positively correlated across ovarian cancer samples. This interaction may contribute to the formation of physical or signaling barriers that prevent T cell infiltration into the tumor core. Together, these findings suggest that ADGRL2 contributes to tumor progression and immune evasion in ovarian cancer.Conclusions Our findings highlight ADGRL2 as a novel immunomodulatory factor and a potential therapeutic target in ovarian cancer. Its restricted expression to malignant cells, association with immune evasion, and correlation with aggressive phenotypes support its relevance in tumor progression. Unlike current ICB targets, ADGRL2 possesses a large extracellular domain, making it amenable to targeting via nanobodies, monoclonal antibodies, or protein-protein interaction inhibitors. Targeting ADGRL2 may help overcome immune resistance in ovarian cancer and enhance the efficacy of immune checkpoint blockade, offering a promising combinatorial therapeutic approach.References Jiang Y, Wang C, Zhou S. Targeting tumor microenvironment in ovarian cancer: premise and promise. Biochimica et Biophysica Acta (BBA) - Reviews on Cancer. 2020;1873:188361.Balan D, Kampan NC, Plebanski M, Abd Aziz NH. Unlocking ovarian cancer heterogeneity: advancing immunotherapy through single-cell transcriptomics. Front Oncol. 2024;14:1388663.Abstract 1232 Figure 1Single cell analysis of ADGRL2 expression in ovarian cancer patients cohort. All sites n=160 tumors, 42 patientsAbstract 1232 Figure 2Spatial transcriptomics analysis of Ovarian cancer patients. In red ADGRL2, in blue CD8