Mechanistic insights into genomic basis of crosstalk between metabolic reprogramming and immune dysfunction in ovarian cancer.

Ovarian Cancer is one of the most lethal gynaecological malignancies, particularly due to late-stage diagnosis and high recurrence rate. The high lethality of ovarian cancer stems from a self-sustaining tumor microenvironment driven by metabolic reprogramming and immune suppression, which are the consequences of genomic alterations. Major genomic alterations such as TP53 mutations, amplification of MYC and hyperactivation of PI3K/Akt/mTOR pathway drive the cellular transformation towards aerobic glycolysis, glutamine addiction and anabolic lipogenesis. Additional genomic alterations such as BRCA1/2 deficiency and loss of PTEN enable immune evasion by triggering anti-tumor response via cGAS/STING pathway and recruitment of Myeloid-derived Suppressor Cells. Metabolic dysfunction generates oncometabolites such as lactate and kynurenine that reinforce immune suppression by causing exhaustion of cytotoxic T-cells. The clinical relevance of metabolic and immune combinations has not yet been demonstrated, while PARP inhibitor based strategies have already proven relevant in molecularly selected groups of ovarian cancer patients. Importantly, the number of mechanistic claims discussed in this review is based on preclinical models or on non-ovarian cancer studies, including oncometabolite-mediated immune regulation, the cGAS/STING pathway and metabolic immune crosstalk. Moreover, the clinical studies mentioned encompass both ovarian-cancer-specific trials and larger gynecological and mixed solid-tumor cohorts. Therefore, the conclusions of non-ovarian or early-phase studies should be interpreted as biologically informative and hypothesis-generating and not conclusive evidence of efficacy in ovarian cancer. These mechanisms must be confirmed in future ovarian cancer-specific, biomarker-driven translational studies and prospective clinical trials to see if rational combination strategies can provide durable clinical benefit.