Folate-targeted nanoparticles for glutamine metabolism inhibition enhance anti-tumor immunity and suppress tumor growth in ovarian cancer.

Ovarian cancer (OC) is a highly malignant gynecological tumor, and its effective treatment is frequently impeded by drug resistance and recurrent tumor growth. The reprogramming of glutamine metabolism in ovarian cancer is closely associated with tumor progression and the immunosuppressive tumor microenvironment. Recently, targeting metabolic reprogramming has emerged as a promising approach for cancer therapy. However, the application of such therapies is often constrained by their significant toxicity to normal tissues. In this study, we fabricated folate-targeted nanoparticles (FA-DCNPs) that co-encapsulate the glutamine metabolism inhibitor 6-diazo-5-oxo-L-norleucine (DON) and calcium carbonate (CaCO). These nanoparticles alleviate damage to normal tissues by specifically targeting tumor cells via folate receptors (FOLR) mediation. Under acidic conditions, the FA-DCNPs release DON and Ca, generating a synergistic anti-tumor effect by impeding glutamine metabolism and inducing calcium overload. Additionally, FA-DCNPs target M2 phenotype tumor-associated macrophages (TAMs) via FOLR2, attenuating M2-TAMs activity. When partially phagocytosed by M0-TAMs, the nanoparticles restrict glutamate production, inhibiting polarization towards the M2 phenotype. This resulted in an increased proportion of M1-TAMs, thereby improving the tumor immune microenvironment. Our study explores a nanotherapeutic strategy that enhances the biosafety of anti-glutamine metabolism therapy through folate targeting, effectively suppresses tumor cell proliferation, and enhances the anti-tumor immune response.