Immune Resistance and Anti-Tumor Immunity in the Ovarian Tumor Microenvironment

Ovarian cancer is a lethal gynecologic malignancy with limited effective treatment options. It is expected that in 2026 there will be about 21,010 new cases of ovarian cancer diagnosed and about 12,450 deaths within the United States. Unfortunately, conventional therapies such as chemotherapy and radiation have limited efficacy for high-grade serous ovarian cancer (HGSOC) and also produce significant toxicity. HGSOC is characterized by an ovarian tumor microenvironment (TME) consisting of immune inhibitory T regulatory cells and inhibitory tumor-associated macrophages, including myeloid-derived suppressor cells (MDSCs) and M2 cells, which confer immune suppression. Immunocompetent T cells, tumor-suppressing M1 cells, natural killer cells, and other cellular subsets are also present. The TME is further shaped by soluble molecules, extracellular matrix, and other structural components, as well as the presence of blood vessels and ascitic fluid in the peritoneal cavity, which aid in the distribution of cancer cells to the omentum where more lesions soon develop. This review outlines the heterogenous immune cell subsets in the ovarian TME and other structural targets that promote or reduce cancer burden. Most single-agent immune strategies have shown limited efficacy in unselected HGSOC populations due to the complex immune-suppressive nature of the TME. Here, we also discuss novel combination treatments in clinical trials or in clinical practice for HGSOC. Advances in understanding the ovarian TME will reveal new immunotherapy and drug targets for translational medicine and aid in determining effective drug and immunotherapy combinations, which may ultimately lead to improved overall survival in HGSOC.