Targeted delivery of TGF-β inhibitor via LHRH-NanoTi reverses the NAT10/ac4C-mediated cisplatin-induced immunosuppressive tumor microenvironment in ovarian cancer

BACKGROUND: Platinum-based chemotherapy for ovarian cancer is frequently compromised by the development of drug resistance, which is often accompanied by an immunosuppressive tumor microenvironment. The molecular mechanisms linking cisplatin resistance to immune evasion remain poorly understood, hindering the development of effective combination therapies. RESULTS: This study revealed that cisplatin-induced resistance and immunosuppression were driven by reduced N-acetyltransferase 10 (NAT10)-mediated N4-acetylcytidine (ac4C) modification, which produced two distinct unfavorable effects: (1) activation of the DNA damage repair pathway, thereby promoting cisplatin resistance; and (2) activation of the TGF-β pathway through enhanced translation efficiency of Gdf6 and Inhba. Mechanistically, NAT10 bound to ribosomal proteins RPS3 and RPS6, creating a steric barrier that inhibited the loading of ac4C-modified mRNAs onto ribosomes. Elevated TGF-β signaling increased the infiltration of myeloid-derived suppressor cells, M2 macrophages, exhausted CD8 + T cells, and regulatory T cells within the tumor microenvironment. To target this pathway, we developed a luteinizing hormone-releasing hormone (LHRH) receptor-targeted nanodelivery system (NanoTi) for a TGF-β inhibitor, which synergized with cisplatin to achieve superior antitumor efficacy by effectively reversing the immunosuppressive microenvironment. CONCLUSIONS: Our findings suggest that cisplatin-induced NAT10/ac4C downregulation may contribute to platinum resistance and immunosuppression in ovarian cancer, and targeted TGF-β inhibition reverses cisplatin-induced immunosuppression in preclinical ovarian cancer models.