Metabolic Targeting of SREBP1 Reprograms the Obesity-Driven Ascites Immune Microenvironment and Enhances Chemotherapy Response in Obesity-Associated Ovarian Cancer

Obesity negatively impacts the survival of women diagnosed with ovarian cancer (OC), suggesting a connection between obesity, metastasis, and treatment response. However, the underlying mechanisms remain unclear. In preclinical studies involving mice fed a high-fat diet (HFD) and ovarian cancer, the tumors grew significantly larger than those in mice on a low-fat diet (LFD), and the HFD mice were less responsive to standard-of-care (SOC) chemotherapy.

Both the HFD-induced tumors and tumors from obese women showed heightened SREBP1 expression and nuclear localization, a protein that governs lipid production and transport. The researchers aimed to determine if inhibiting SREBP1 processing could improve the response to SOC chemotherapy in obesity-associated OC. They tested the FDA-approved drug Nelfinavir (NFV), which acts as a pharmacological inhibitor of site-2 protease, blocking SREBP1 processing, in combination with SOC (paclitaxel+carboplatin) in preclinical models of diet-induced obesity and OC.

The results revealed a marked enhancement in therapeutic response, alterations in the tumor's fat cells, and a reprogramming of the immune environment surrounding the tumor in the ascites fluid, all of which are driven by NFV-mediated inhibition of SREBP1 processing. These findings propose a model wherein NFV's action disrupts metabolic pathways associated with immune evasion and treatment resistance, thus boosting the efficacy of SOC chemotherapy in obesity-linked OC.

Overall, these results underscore the potential of metabolic targeting as a therapeutic strategy to improve outcomes in obesity-associated ovarian cancer.