Abstract 6745: NAT10-MYC loop induces MHC-I loss through autophagy to promote immune evasion and immunotherapy resistance in colorectal cancer

Abstract Background: Immune checkpoint inhibitors (ICIs) have significantly improved therapeutic outcomes in colorectal cancer (CRC), particularly for metastatic tumors with microsatellite instability-high (MSI-H) or deficient mismatch repair (dMMR). While patients with metastatic CRC have a median overall survival of only 21 months, MSI-H/dMMR patients treated with ICIs can achieve durable responses and even long-term survival. However, the vast majority are microsatellite-stable (MSS) and remain profoundly resistant to immunotherapy, underscoring a critical unmet clinical need. Therefore, elucidating and overcoming the mechanisms that drive immune resistance is essential to broaden the therapeutic benefit of immunotherapy. Methods: We investigated the role of the RNA acetyltransferase NAT10, responsible for N4-acetylcytidine (ac4C) modification, in mediating immune escape in CRC. MYC-mediated transcriptional regulation and NAT10-dependent mRNA stabilization were analyzed. The stability of autophagy-related transcripts and MHC class I expression was assessed. The effects of NAT10 inhibition, achieved through genetic knockdown or pharmacological Remodelin treatment, on immune cell infiltration and response to immune checkpoint blockade were evaluated. Results: NAT10 was found to be significantly upregulated in CRC across multiple cohorts, with higher expression in MSS tumors compared to MSI-H tumors (p<0.01-0.001). Elevated NAT10 expression correlated with immune-cold phenotypes, poorer predicted immunotherapy response, and was negatively associated with T-cell activation genes (p<0.01). NAT10 positively regulated autophagy-lysosome genes, including BECN1, ATG3, and ATG5, through direct ac4C modification, enhancing their mRNA stability (p<0.05). NAT10 knockout reduced autophagic flux (p<0.001), increased MHC-I expression (p<0.01), and promoted infiltration and activation of CD8+ and CD4+ T cells, leading to enhanced tumor cytotoxicity and suppressed tumor growth, effects that were abrogated by CD8 depletion. A combination of NAT10 knockout with anti-PD-1 therapy resulted in 80% complete tumor regression. MYC was identified as an upstream activator of NAT10, with MYC mRNA itself modified by ac4C. MYC deletion reduced NAT10 expression, global ac4C levels, and autophagy. Remodelin synergized with anti-PD-1 treatment, underscoring NAT10 as a druggable epitranscriptomic-autophagy checkpoint. Conclusion: Our findings reveal a novel NAT10-MYC-autophagy axis that drives MHC-I degradation and orchestrates tumor immune evasion and resistance to immunotherapy in CRC. Targeting NAT10 represents a promising therapeutic strategy to overcome immune resistance and enhance the efficacy of immunotherapy in CRC. Citation Format: Junyong Weng, Tianchen Xiong, Zilan Ye, Zezhi Shan, Rui Su, Jianhua Yu, Michael A. Caligiuri, Xinxiang Li, Ajay Goel. NAT10-MYC loop induces MHC-I loss through autophagy to promote immune evasion and immunotherapy resistance in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 6745.