Targeted delivery of TGF-ß 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 resistance, a process 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 reveals that cisplatin-induced immunosuppression and resistance are driven by a reduction in N-acetyltransferase 10 (NAT10)-mediated N4-acetylcytidine (ac4C) modification, which produces two parts of unfavorable effects: 1) activating the DNA damage repair pathway, thereby confers resistance to cisplatin; 2) enhancing the expression of TGF-ß via NAT10's interaction with ribosomal proteins RPS3 and RPS6. The elevated TGF-ß increases the infiltration of myeloid-derived suppressor cells (MDSCs), M2 macrophages, exhausted CD8+ T cells, and regulatory T cells (Tregs) within the tumor microenvironment. To target this pathway, we developed a LHRH receptor-targeted nanodelivery system for a TGF-ß inhibitor, which synergized with cisplatin to achieve superior antitumor efficacy by effectively reversing the immunosuppressive microenvironment. Conclusions: Our study defines the NAT10/ac4C–TGF-ß axis as a pivotal mechanism coordinating cisplatin resistance and immunosuppression in ovarian cancer. These findings propose targeted inhibition of TGF-ß signaling as a promising therapeutic strategy to overcome platinum resistance by revitalizing the antitumor immune response. Overall design: To explore the role of NAT10/ac4C-mediated mRNA regulation under cisplatin treatment, we conducted acRIP-seq on cisplatin-treated ID8 cells.