Immunometabolic reprogramming reshapes the tumor microenvironment in PARPi-resistant ovarian cancer towards predictive, preventive, and personalized medicine approaches

Ovarian cancer is a highly lethal gynecologic malignancy that affects women worldwide. Its clinical symptoms are often insidious, and its recurrence rate remains high. Patient prognosis is severely limited by these factors. Poly(ADP-ribose) polymerase inhibitors (PARPi) have achieved remarkable clinical efficacy and are commonly used for treating ovarian cancer with homologous recombination deficiency by inducing synthetic lethality. However, acquired resistance remains a major clinical challenge in modern practice. Genomic alterations and the restoration of DNA repair capacity have been the primary focus of traditional research on resistance mechanisms. Recent studies have pointed to the tumor microenvironment (TME) as a key player, and its immunometabolic reprogramming has been recognized as crucial for driving PARPi resistance and enabling tumor immune evasion. However, the strength of this evidence varies substantially across experimental contexts. This review therefore distinguishes acute or ongoing effects of PARPi exposure from phenotypes associated with established acquired resistance and explicitly separates direct evidence in ovarian cancer from mechanistic observations extrapolated from other tumor types. The dynamic immunometabolic changes seen in the TME of PARPi-resistant ovarian cancer are reviewed. It highlights context-dependent metabolic plasticity involving glycolysis and oxidative phosphorylation (OXPHOS), and discusses how nutrient competition and metabolites such as lactate and acetyl-CoA may influence immune cell function. Specifically, this review explores metabolic exhaustion of effector T cells and natural killer (NK) cells, as well as metabolically driven mechanisms underlying heterogeneous tumor-associated macrophage (TAM) states, rather than a simple M1-to-M2 switch. Finally, it introduces the emerging Predictive, Preventive, and Personalized Medicine (PPPM/3PM) paradigm and discusses how early metabolic profiling, precise immunometabolic modulation, and multi-target combinatorial interventions may reshape the tumor immune microenvironment and potentially overcome PARPi resistance, although most proposed interventions still require prospective clinical validation.