NOTCH3/JAG1 signaling is associated with immunosuppressive tumor microenvironment features in ovarian cancer: links to nutritional risk, CD163+ macrophages, and CD8+ T cell exclusion

Background NOTCH3 signaling is frequently dysregulated in ovarian cancer and has been linked to tumor progression and treatment resistance. We investigated the prognostic significance of NOTCH3 expression and its associations with immune-cell infiltration, nutritional risk, tumor-associated biomarkers, and transcriptional programs in public single-cell RNA-sequencing datasets. Methods We retrospectively analyzed 186 patients with epithelial ovarian cancer stratified by immunohistochemistry-assessed NOTCH3 expression ( n = 93 per group). Clinicopathological variables, nutritional measures (BMI, serum albumin, and NRS-2002), tumor-associated biomarkers (CA-125 and HE4), immune markers (CD8+, CD4+, CD163+, FOXP3+, and PD-L1), treatment response, and survival were evaluated. Public scRNA-seq datasets were used for complementary exploratory analysis of NOTCH3-associated transcriptional patterns. Results NOTCH3-high expression was associated with shorter overall survival, lower CD8+ TIL density, higher CD163+ tumor-associated macrophage density, lower chemotherapy response, and higher platinum resistance. High nutritional risk and hypoalbuminaemia were also associated with an immune-excluded phenotype after adjustment for clinicopathological covariates. The combined NOTCH3-high/NRS-2002 ≥ 3 subgroup had the poorest observed clinical outcomes. In the scRNA-seq analysis, epithelial cells showed the highest NOTCH3-related signature scores, and JAG1 showed the strongest co-expression with NOTCH3 among the evaluated ligands. These findings are associative and do not establish functional ligand-receptor signaling or a causal nutrition-mediated mechanism. Conclusion High NOTCH3 expression is associated with an immunosuppressive tumor microenvironment, adverse treatment response, and poorer survival in ovarian cancer. Nutritional risk identifies an additional clinically relevant correlate of immune and survival outcomes. The observational clinical design and exploratory public scRNA-seq analysis do not establish causality; functional validation and prospective studies are required before specific nutritional or NOTCH3-targeted interventions can be recommended.