Jia Yuchen, Li Jie, Mei Wentong, Zhang Haoyu, Wang Zheng, Xie Xiaozhou, Gao Chongchong, Xu Xiaoqing, Li Fei
Department of General Surgery, Xuanwu Hospital, Capital Medical University, No.45 Changchun Street, Beijing, China.
Department of General Surgery, Xuanwu Hospital, Capital Medical University, No.45 Changchun Street, Beijing, China; Department of Gastrointestinal Surgery, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China.
Int Immunopharmacol. 2025 May 8;154:114528. doi: 10.1016/j.intimp.2025.114528. Epub 2025 Mar 29.
Pancreatic cancer is the seventh leading cause of cancer-related deaths worldwide, with a dismal 5-year survival rate. New drugs targeting pancreatic ductal adenocarcinoma (PDAC), the primary pathological subtype, are urgently needed. LAQ824, a novel pan-histone deacetylase inhibitor (HDACi), has shown anti-tumor activity in various cancers, but its effects on PDAC remain unexplored. This study investigates the therapeutic potential of LAQ824 in PDAC and its role in modulating immune escape mechanisms. Using a subcutaneous tumor model in C57BL/6 J mice, LAQ824's anti-tumor effects were evaluated. In vitro and in vivo experiments-including IHC, flow cytometry, RNA sequencing, and single-cell RNA sequencing-demonstrated that LAQ824 inhibits tumor proliferation, suppresses the epithelial-mesenchymal transition (EMT), and induces apoptosis. LAQ824 also enhances immunogenicity by upregulating MHC-I-mediated antigen presentation, increasing immune cell infiltration, and promoting CD8 T cell maturation and differentiation. Mechanistically, LAQ824 upregulated MHC-I expression by enhancing chromatin accessibility of related genes, with HDAC1 identified as a key repressor of MHC-I in PDAC cells. In conclusion, we found that LAQ824 has a significant anti-tumor effect in PDAC. LAQ824 not only directly affects general biological behaviors such as proliferation, apoptosis, and EMT, but also increases the immunogenicity of tumor cells by upregulating the expression of MHC-I in PDAC, which promotes the antigen presentation process and enhances anti-tumor immunity. By showcasing LAQ824's potential as a therapeutic target against PDAC, the present study provides novel insights into the link between epigenetic regulation and immunogenicity in PDAC.
胰腺癌是全球癌症相关死亡的第七大主要原因，5年生存率极低。迫切需要针对主要病理亚型胰腺导管腺癌（PDAC）的新药。LAQ824是一种新型的泛组蛋白去乙酰化酶抑制剂（HDACi），已在多种癌症中显示出抗肿瘤活性，但其对PDAC的作用仍未得到探索。本研究调查了LAQ824在PDAC中的治疗潜力及其在调节免疫逃逸机制中的作用。使用C57BL/6 J小鼠的皮下肿瘤模型评估了LAQ824的抗肿瘤作用。体外和体内实验，包括免疫组化、流式细胞术、RNA测序和单细胞RNA测序，表明LAQ824抑制肿瘤增殖、抑制上皮-间质转化（EMT）并诱导凋亡。LAQ824还通过上调MHC-I介导的抗原呈递、增加免疫细胞浸润以及促进CD8 T细胞成熟和分化来增强免疫原性。机制上，LAQ824通过增强相关基因的染色质可及性上调MHC-I表达，HDAC1被确定为PDAC细胞中MHC-I的关键抑制因子。总之，我们发现LAQ824在PDAC中具有显著的抗肿瘤作用。LAQ824不仅直接影响增殖、凋亡和EMT等一般生物学行为，还通过上调PDAC中MHC-I的表达增加肿瘤细胞的免疫原性，这促进了抗原呈递过程并增强了抗肿瘤免疫力。通过展示LAQ824作为针对PDAC的治疗靶点的潜力，本研究为PDAC中表观遗传调控与免疫原性之间的联系提供了新的见解。
