Inhibition of tumor-intrinsic NAT10 enhances antitumor immunity by triggering type I interferon response via MYC/CDK2/DNMT1 pathway

Abstract Posttranslational modifications add tremendous complexity to cancer progression; however, gaps remain in knowledge regarding the function and immune regulatory mechanism of newly discovered mRNA acetylation modification. Here, we discovered an unexpected role of N4-acetylcytidine (ac4C) RNA acetyltransferase-NAT10 on reshaping tumor immune microenvironment. Based on analyses of patient datasets, we found that NAT10 was upregulated in tumor tissues, and negatively correlated with overall survival and immune cells infiltration. Inhibition of NAT10 significantly suppressed tumor growth in vivo and in vitro. NAT10 deficiency in cancer cells significantly upregulated immune cells infiltration and stimulated tumor-specific cellular immune responses, leading to the establishment of robust anti-tumor immunity. Mechanistically, we identified MYC as a key downstream target of NAT10, and then induced CDK2-DNMT1 expression. Meanwhile, inhibition of NAT10 down-regulated MYC-CDK2-DNMT1 expression, which enhanced double-stranded RNAs (dsRNA) formation to induce type I IFN (IFN-I) and trigger immune responses of CD8+ T cells. In terms of clinical significance, we demonstrated that inhibition of NAT10 using Remodelin or PEI/PC7A/siRNA nanoparticles combined with anti-PD1 treatment synergistically improved tumor immune microenvironment and repressed tumor progression in vivo. Therefore, inhibition of NAT10 in cancer cells improve tumor immunogenicity, resulting in tumor suppression by enhancing anti-tumor immune responses. Our study uncovers a crucial role of NAT10 in re-modulating tumor immunogenicity and demonstrates a novel concept for targeting NAT10 in cancer immunotherapy.