Targeted delivery of TGF-ß inhibitor via LHRH-NanoTi reverses the NAT10/ac4C-mediated cisplatin-induced immunosuppressive tumor microenvironment in ovarian cancer [RNA-Seq]
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 investigate the potential molecular mechanisms underlying the reduction of DNA damage associated with decreased NAT10/ac4C levels, this study performed RNA-seq analysis on ID8 cells stably transfected with sgNC (control group) and sgNat10 (NAT10 knockdown group). By comparing the whole-genome expression profiles between the two groups, we aim to systematically reveal the transcriptome changes triggered by NAT10 depletion and the consequent reduction in ac4C modification, thereby identifying key differentially expressed genes and signaling networks related to the DNA damage response pathway. This analysis will provide transcript-level evidence to elucidate the role of NAT10/ac4C in maintaining genome stability.