Unraveling the effects of genetic and pharmacological Complex I targeting on the ovarian cancer microenvironment

Mitochondria-targeted anticancer therapy, particularly via inhibition of respiratory Complex I (CI), a key enzyme of oxidative phosphorylation (OXPHOS), has emerged as a promising anticancer strategy. Apart from hampering tumor progression, CI dysfunction is associated with tumor microenvironment (TME) remodelling but it is unclear whether it promotes tumor suppression or pro-tumorigenic effects. Importantly, CI inhibition has not been explored in High-Grade Serous Ovarian Cancer (HGSOC), the most aggressive gynecological malignancy. We aimed to demonstrate that both genetic and pharmacological targeting of CI reduces tumor progression in HGSOC in vivo models and define whether CI deficiency–induced TME alterations elicit pro- or anti-tumorigenic effects. We generated a functional CI knockout (KO) in OV90 cells, together with an inducible CI KO model, and evaluated their tumorigenic potential in NOD/SCID mice. Moreover, pharmacological CI inhibition was evaluated in a preliminary study by treating orthotopic ID8 tumors in immunocompetent C57BL/6J mice with EVP-4593 and QA-2. Finally, CI targeting effects on TME were evaluated by histological and cytometric analyses. Genetic targeting of CI in OV90 demonstrated lower tumorigenic potential of KO masses compared to wild-type controls. However, CI-deficient tumors continued to grow, suggesting compensatory mechanisms. Pharmacological CI inhibition revealed no significant survival improvement, but a tendency toward less aggressive disease in QA-2-treated animals. Both genetic and pharmacologic CI targeting are associated with TME remodelling. Specifically, OV90 KO xenografts presented with higher macrophage infiltration and increased stroma abundance, whereas QA-2–treated syngenic ID8-VEGF tumors showed increased T-cell infiltration and a higher proportion of activated, antigen-presenting macrophages. These findings demonstrate that genetic CI ablation is associated with reduced tumorigenicity, whereas the pharmacological approach applied here does not significantly improve survival in ID8-VEGF ovarian tumor-bearing mice. Interestingly, our data suggest targeting CI may be exploited for TME-mediated therapeutic strategies. Further studies are required to corroborate these findings.