2. Academic Validation
  3. DB75 targets PRMT1 to suppress liver metastasis and synergizes with PD-L1 blockade for enhanced therapeutic efficacy

DB75 targets PRMT1 to suppress liver metastasis and synergizes with PD-L1 blockade for enhanced therapeutic efficacy

  • Int Immunopharmacol. 2025 Aug 8:164:115327. doi: 10.1016/j.intimp.2025.115327.
Sumin Sun 1,  Haili Hu 1,  Peihua Sun 2,  Yuan Gao 2,  Yu Huang 3,  Xue Gong 4,  Liming Chen 5
Affiliations

Affiliations

  • 1 Department of Biochemistry, School of Life Sciences, Nanjing Normal University, Nanjing, China; Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, China; Jiangsu Key Laboratory of Innovative Cancer Diagnosis & Therapeutics, Cancer Institute of Jiangsu Province, Nanjing, China.
  • 2 Department of Biochemistry, School of Life Sciences, Nanjing Normal University, Nanjing, China.
  • 3 Department of Biochemistry, School of Life Sciences, Nanjing Normal University, Nanjing, China; Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, China; Jiangsu Key Laboratory of Innovative Cancer Diagnosis & Therapeutics, Cancer Institute of Jiangsu Province, Nanjing, China. Electronic address: 90888@njnu.edu.cn.
  • 4 Nanjing Women and Children's Healthcare Institute, Women's Hospital of Nanjing Medical University, Nanjing Women and Children's Healthcare Hospital, 123 Tianfei Alley, Mochou Road, Nanjing, China. Electronic address: gongxue@njmu.edu.cn.
  • 5 Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, China; Jiangsu Key Laboratory of Innovative Cancer Diagnosis & Therapeutics, Cancer Institute of Jiangsu Province, Nanjing, China. Electronic address: chenliming1981@u.nus.edu.
PMID: 40782428 DOI: 10.1016/j.intimp.2025.115327
Abstract

Liver metastasis represents a major clinical challenge, primarily attributed to its unfavorable prognosis and scarce therapeutic alternatives. This study investigated protein arginine methyltransferase 1 (PRMT1) and its highly selective inhibitor furamidine (DB75), exploring their roles in liver metastasis and their potential for combination therapy with anti-programmed death-ligand 1 monoclonal antibody (anti-PD-L1 mAb). PRMT1 regulates malignant phenotypes of tumour cells through asymmetric dimethylation of arginine residues in various cancers. Using multiple liver metastasis models, including breast Cancer liver metastasis (BCLM), we demonstrated that PRMT1 expression was upregulated in liver metastases and highly metastatic cells, while DB75 effectively suppressed tumour proliferation, clonogenicity, and hepatic colonization. RNA Sequencing analysis revealed significant upregulation of Tmem196 within the tumour microenvironment following DB75 treatment. Functionally, Tmem196 exhibited tumour-suppressive effects in Cancer cells but paradoxically promoted α-smooth muscle actin expression in cancer-associated fibroblasts (CAFs), driving a pro-tumorigenic phenotype through TMEM196. Notably, DB75 selectively upregulated TMEM196 in CAFs but not in tumour cells. Given previous reports linking activated CAFs to elevated PD-L1 expression and immunosuppression, we combined DB75 with anti-PD-L1 mAb and observed synergistic inhibition of metastatic progression, which was significantly superior to anti-PD-L1 mAb monotherapy. This study elucidates the mechanism by which DB75 suppresses BCLM and provides preclinical evidence for PD-L1 blockade-based combinatorial immunotherapy.

Keywords

Anti-PD-L1 mAb; Cancer-associated fibroblasts; DB75; Liver metastasis; Protein arginine methyltransferase 1; TMEM196.

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