2. Academic Validation
  3. Pan-HDAC inhibitor LAQ824 inhibits the progression of pancreatic ductal adenocarcinoma and suppresses immune escape by promoting antigen presentation

Pan-HDAC inhibitor LAQ824 inhibits the progression of pancreatic ductal adenocarcinoma and suppresses immune escape by promoting antigen presentation

  • Int Immunopharmacol. 2025 May 8:154:114528. doi: 10.1016/j.intimp.2025.114528.
Yuchen Jia 1,  Jie Li 1,  Wentong Mei 2,  Haoyu Zhang 1,  Zheng Wang 1,  Xiaozhou Xie 1,  Chongchong Gao 3,  Xiaoqing Xu 4,  Fei Li 5
Affiliations

Affiliations

  • 1 Department of General Surgery, Xuanwu Hospital, Capital Medical University, No.45 Changchun Street, Beijing, China.
  • 2 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.
  • 3 Department of General Surgery, Xuanwu Hospital, Capital Medical University, No.45 Changchun Street, Beijing, China. Electronic address: scientificsalon@sina.com.
  • 4 Department of General Surgery, Xuanwu Hospital, Capital Medical University, No.45 Changchun Street, Beijing, China. Electronic address: xiaoqingxu@cams.cn.
  • 5 Department of General Surgery, Xuanwu Hospital, Capital Medical University, No.45 Changchun Street, Beijing, China. Electronic address: feili36@ccmu.edu.cn.
PMID: 40158429 DOI: 10.1016/j.intimp.2025.114528
Abstract

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.

Keywords

Histone deacetylase; LAQ824; MHC-I; Pancreatic ductal adenocarcinoma; Single-cell RNA sequencing; TME.

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