Chen Enhong, Wang Qin, Wang Leisheng, Huang Zebo, Yang Dongjie, Zhao Changyong, Chen Wuqiang, Zhang Shuo, Xiong Shuming, He Youzhao, Mao Yong, Hu Hao
Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu, P. R. China.
School of Medicine, Jiangnan University, Wuxi, Jiangsu, P. R. China.
Cancer Commun (Lond). 2025 Jun 20. doi: 10.1002/cac2.70045.
N-acetyltransferase 10 (NAT10) was reported to be associated with the immune microenvironment in several cancers. However, it is not known in pancreatic ductal adenocarcinoma (PDAC). This study aimed to elucidate the roles and mechanisms of NAT10 in tumor malignancy and the tumor microenvironment (TME) in PDAC.
NAT10 expression and its role in tumor progression and clinical prognosis were analyzed using bioinformatics and functional assays. Downstream genes regulated by NAT10 and their underlying mechanisms were explored using acetylated RNA immunoprecipitation, quantitative polymerase chain reaction, RNA immunoprecipitation, and Western blotting. The role and mechanism of NAT10 in the PDAC TME were further explored using bioinformatics, single-cell RNA sequencing, multiplexed immunofluorescence, and flow cytometry. The association between NAT10 and immunotherapeutic response was investigated in a mouse model by inhibiting the programmed cell death 1/programmed cell death ligand 1(PD-1/PD-L1) axis with a PD-1/PD-L1 binding inhibitor, Naamidine J.
NAT10 was upregulated in PDAC tissues and cell lines, and was associated with poor progression-free survival of PDAC patients. NAT10 promoted tumor progression by enhancing the mRNA stability of laminin β3 (LAMB3) via N4-acetylation modification, thereby activating the focal adhesion kinase (FAK)/extracellular regulated protein kinases (ERK) pathway. NAT10 promoted subcutaneous tumor growth, increased the proportion of exhausted CD8 T cells (CD8 Tex), especially the intermediate CD8 Tex subset, and decreased the proportion of cytotoxic CD8 T cell (CD8 Tc) subset in the PDAC TME. Naamidine J treatment significantly enhanced the proportion of CD8 Tc subset and reduced the proportion of intermediate CD8 Tex subset in mice bearing subcutaneous tumors with high NAT10 expression. Regarding the regulatory mechanism, NAT10 increased PD-L1 expression and abundance in tumor cells by activating the LAMB3/FAK/ERK pathway, thereby reducing the cytotoxicity of CD8 T cells. Inhibition of the PD-1/PD-L1 axis with Naamidine J retrieved CD8 T cell cytotoxicity.
This study proposes a regulatory role of NAT10 in tumor progression and immune microenvironment via the LAMB3/FAK/ERK pathway in PDAC. These findings may favor the selection of candidates who may benefit from immunotherapy, optimize current therapeutic strategies, and improve the clinical prognosis of PDAC patients.
据报道，N - 乙酰基转移酶10（NAT10）与多种癌症的免疫微环境有关。然而，在胰腺导管腺癌（PDAC）中尚不清楚。本研究旨在阐明NAT10在PDAC肿瘤恶性程度和肿瘤微环境（TME）中的作用及机制。
使用生物信息学和功能分析方法分析NAT10的表达及其在肿瘤进展和临床预后中的作用。采用乙酰化RNA免疫沉淀、定量聚合酶链反应、RNA免疫沉淀和蛋白质免疫印迹法探索NAT10调控的下游基因及其潜在机制。利用生物信息学、单细胞RNA测序、多重免疫荧光和流式细胞术进一步探究NAT10在PDAC TME中的作用和机制。通过用PD - 1/PD - L1结合抑制剂纳米定J抑制程序性细胞死亡蛋白1/程序性细胞死亡配体1（PD - 1/PD - L1）轴，在小鼠模型中研究NAT10与免疫治疗反应之间的关联。
NAT10在PDAC组织和细胞系中上调，且与PDAC患者无进展生存期差相关。NAT10通过N4 - 乙酰化修饰增强层粘连蛋白β3（LAMB3）的mRNA稳定性，从而激活黏着斑激酶（FAK）/细胞外调节蛋白激酶（ERK）途径，促进肿瘤进展。NAT10促进皮下肿瘤生长，增加耗竭性CD8 T细胞（CD8 Tex）的比例，尤其是中间型CD8 Tex亚群，并降低PDAC TME中细胞毒性CD8 T细胞（CD8 Tc）亚群的比例。纳米定J治疗显著增加了高表达NAT10的皮下肿瘤小鼠中CD8 Tc亚群的比例，并降低了中间型CD8 Tex亚群的比例。关于调控机制，NAT10通过激活LAMB3/FAK/ERK途径增加肿瘤细胞中PD - L1的表达和丰度，从而降低CD8 T细胞的细胞毒性。用纳米定J抑制PD - 1/PD - L1轴可恢复CD8 T细胞的细胞毒性。
本研究提出NAT10在PDAC中通过LAMB3/FAK/ERK途径对肿瘤进展和免疫微环境具有调控作用。这些发现可能有助于选择可能从免疫治疗中获益的患者，优化当前治疗策略，并改善PDAC患者的临床预后。
