Barriers to Immunotherapy in Ovarian Cancer: Metabolic, Genomic, and Immune Perturbations in the Tumour Microenvironment

Simple Summary Immunotherapy hinges on stimulating patients’ immune system to fight cancer. This treatment has led to improved survival in patients with malignancies such as melanoma and lung cancer but, disappointingly, its benefits have not been as forthcoming in ovarian cancer. This review summarises how the ovarian cancer tumour microenvironment hinders the efficacy of immunotherapy by modulating immunoregulatory pathways, reorchestrating metabolism and featuring specific cancer cell genomic aberrations. The impact of novel targeted drugs and combination therapies aiming to overcome these obstacles and improve the clinical success of immunotherapy in ovarian cancer are considered. Abstract A lack of explicit early clinical signs and effective screening measures mean that ovarian cancer (OC) often presents as advanced, incurable disease. While conventional treatment combines maximal cytoreductive surgery and platinum-based chemotherapy, patients frequently develop chemoresistance and disease recurrence. The clinical application of immune checkpoint blockade (ICB) aims to restore anti-cancer T-cell function in the tumour microenvironment (TME). Disappointingly, even though tumour infiltrating lymphocytes are associated with superior survival in OC, ICB has offered limited therapeutic benefits. Herein, we discuss specific TME features that prevent ICB from reaching its full potential, focussing in particular on the challenges created by immune, genomic and metabolic alterations. We explore both recent and current therapeutic strategies aiming to overcome these hurdles, including the synergistic effect of combination treatments with immune-based strategies and review the status quo of current clinical trials aiming to maximise the success of immunotherapy in OC.