NAT10 promotes cisplatin resistance and immune escape by increasing the expression of DUSP1 and PD-L1 in gastric cancer.

Developing resistance to chemotherapy drugs and evading the killing effect of the immune system are the main obstacles in the clinical treatment of gastric cancer. However, the potential mechanism remains poorly understood. N-acetyltransferase 10 (NAT10) catalyzes the N4-acetylcytidine (ac4C) modification of mRNA and is associated with tumor occurrence, development and chemotherapy resistance. Here, we observed that elevated NAT10 levels promote cisplatin chemoresistance in gastric cancer cells. On the contrary, knockdown of NAT10 enhances the sensitivity of cisplatin-resistant gastric cancer cells to cisplatin, both in vitro and in vivo. Mechanistically, NAT10 binds to DUSP1 mRNA and catalyzes its ac4C modification at positions C327, C330, and C331 within the coding sequence (CDS) region, thereby enhancing the stability of DUSP1 mRNA and increasing the abundance of DUSP1 protein. Furthermore, NAT10 mediates resistance to cisplatin-induced apoptosis through DUSP1 via the JNK and ERK signaling pathways. Additionally, NAT10 can upregulate PD-L1 expression via FOSB. The combination of a NAT10 inhibitor and an anti-PD-1 antibody synergistically enhances the antitumor efficacy against cisplatin- resistant gastric cancer cells in murine models. Taken together, these findings offer novel insights into the role and mechanism of NAT10 in the crosstalk between cisplatin chemoresistance and immunosuppression in gastric cancer. NAT10 thus holds promise as a highly attractive target, with the potential to synergize with PD-1-based immunotherapy to reverse cisplatin resistance in gastric cancer.