Targeting the N-acetyltransferase 10/DKK2 axis enhances CD8+ T cell antitumor activity in colorectal cancer models
Mengmeng Li, Xiaoya Zhao, Jun Wu, Shimeng Zhou, Yao Fu, Chen Chen, Zhuang Ma, Jiawen Xu, Yun Qian, Zhangding Wang, Bo Wang, Qiang Wang, Qingqing Ding, Changyu Chen, Honggang Wang, Xiaozhong Yang, Weijie Dai, Wenjie Zhang, Shouyu Wang
Mengmeng Li, Xiaoya Zhao, Jun Wu, Shimeng Zhou, Yao Fu, Chen Chen, Zhuang Ma, Jiawen Xu, Yun Qian, Zhangding Wang, Bo Wang, Qiang Wang, Qingqing Ding, Changyu Chen, Honggang Wang, Xiaozhong Yang, Weijie Dai, Wenjie Zhang, Shouyu Wang
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Research Article Gastroenterology Immunology Oncology

Targeting the N-acetyltransferase 10/DKK2 axis enhances CD8+ T cell antitumor activity in colorectal cancer models

Abstract

Despite overexpression of N-acetyltransferase 10 (NAT10) in colorectal cancer (CRC), its immunomodulatory role in the tumor microenvironment remains elusive. Here, we reveal that NAT10 promotes immune evasion through N4-acetylcytosine–dependent (ac4C-dependent) mRNA stabilization. Using syngeneic mouse models (MC38/CT-26), intestinal epithelial-cell specific Nat10 conditional KO (Nat10cKO) mice, patient-derived organoids, and clinical specimens, we show that Nat10 ablation enhanced CD8+ T cell–mediated antitumor immunity. Single-cell RNA-seq revealed increased cytotoxic CD8+ T cell infiltration in Nat10cKO tumors, which was corroborated by the inverse correlation of tumoral NAT10 expression and CD8+ T cell number in clinical specimens. Multi-omics integration analysis identified DKK2 as the predominant NAT10-regulated transcript. NAT10 stabilized DKK2 mRNA via ac4C modification, leading to high expression of the DKK2 protein. Secreted DKK2 engaged LRP6 receptors to activate AKT-mTOR signaling, inducing cholesterol accumulation in CD8+ T cells and impairing their cytotoxicity. Pharmacological NAT10 inhibition (Remodelin treatment) or DKK2 neutralization restored CD8+ T cell function and synergized with anti–PD-1 therapy. Our findings establish the NAT10/DKK2/LRP6/AKT-mTOR/cholesterol axis as a critical regulator of CD8+ T cell dysfunction in CRC, positioning NAT10/DKK2 as a potential target to enhance immunotherapy efficacy.

Authors

Mengmeng Li, Xiaoya Zhao, Jun Wu, Shimeng Zhou, Yao Fu, Chen Chen, Zhuang Ma, Jiawen Xu, Yun Qian, Zhangding Wang, Bo Wang, Qiang Wang, Qingqing Ding, Changyu Chen, Honggang Wang, Xiaozhong Yang, Weijie Dai, Wenjie Zhang, Shouyu Wang

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Figure 9

Dual targeting of NAT10 or DKK2 synergizes with PD1 blockade to suppress CRC.

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Dual targeting of NAT10 or DKK2 synergizes with PD1 blockade to suppress...
(A) Tumor growth curves. Data are shown as the mean ± SEM of 7 mice/group. (B and C) Flow cytometry analysis of tumor-infiltrating CD8+ T cells (B) and GzmB+ and IFN-γ+CD8+ T cell populations (C) in tumors form each group (n = 7 mice/group). (D) Tumor growth curves. Data are shown as the mean ± SEM of 7 mice/group. (E and F) Flow cytometry analysis of tumor-infiltrating CD8+ T cells (E) and GzmB+ and IFN-γ+CD8+ T cell populations (F) in tumors form each group (n = 5 mice/group). (G) Proposed model: tumor-intrinsic NAT10 stabilizes DKK2 mRNA via ac4C modification, enabling DKK2-LRP6/AKT-mTOR signaling to drive cholesterol accumulation and dysfunction in CD8+ T cells, thereby promoting CRC progression. Dual targeting of NAT10 or DKK2 synergizes with anti–PD-1 therapy to suppress CRC. Data are shown as the mean ± SD of indicated mice per group. All statistical analysis was performed by 2-way ANOVA. ns, P ≥ 0.05. P < 0.05 was considered to indicate statistical significance.