2. Academic Validation
  3. Repurposed Acarbose Targets Nidogen-1 to Remodel the Tumor Stroma and Suppress Portal Vein Tumor Thrombus in Hepatocellular Carcinoma

Repurposed Acarbose Targets Nidogen-1 to Remodel the Tumor Stroma and Suppress Portal Vein Tumor Thrombus in Hepatocellular Carcinoma

  • Research (Wash D C). 2026 Feb 25:9:1161. doi: 10.34133/research.1161.
Tao Han 1,  Lujun Chen 2,  Ning Liu 3,  Ying Chen Han 1,  Zhi Zhu 4,  Shuyi Wang 1,  Haoran Song 1,  Ziming Gao 4,  Lin Su 5,  Qilin Hu 1,  Linda Hammerich 6,  Timothy M Pawlik 7,  Yuhan Zhang 8,  Masatoshi Kudo 9,  Hao Li 10,  Lei Ma 1,  Giorgio Valabrega 11,  Guang Wang 12,  Zhengqiang Yang 13,  Qiuhua Luo 14,  Donatella Marino 11,  Zihang Xu 5,  Meng Niu 15,  Tingsong Chen 16,  Heming Li 1,  Kai Li 4 17
Affiliations

Affiliations

  • 1 Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, Liaoning, China.
  • 2 Laboratory of Gastrointestinal Onco-Pathology, Cancer Institute and General Surgery Institute, The First Hospital of China Medical University, Shenyang, China.
  • 3 Department of Pancreatic and Biliary Surgery, The First Hospital of China Medical University, Shenyang, Liaoning, China.
  • 4 Department of Surgical Oncology, The First Hospital of China Medical University, Shenyang, Liaoning, China.
  • 5 Shanghai Key Laboratory of Health Identification and Assessment, School of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
  • 6 Department of Hepatology and Gastroenterology, Campus Charité Mitte and Campus Virchow-Klinikum, Charité-Universitätsmedizin Berlin, Berlin, Germany.
  • 7 Department of Surgery, Division of Surgical Oncology, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
  • 8 Shenzhen Engineering Center for Translational Medicine of Precision Cancer Immunodiagnosis and Therapy, YuceBio Technology Co., Ltd, Shenzhen, China.
  • 9 Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka, Japan.
  • 10 Department of Interventional Radiology, The First Hospital of China Medical University, Shenyang, Liaoning, China.
  • 11 Department of Oncology, University of Turin, Medical Oncology, Ordine Mauriziano Hospital, Turin, Italy.
  • 12 Department of Hepatobiliary Surgery, The First Hospital of China Medical University, Shenyang, Liaoning, China.
  • 13 Department of Interventional Therapy, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
  • 14 Department of Pharmacy, The First Hospital of China Medical University, Shenyang, Liaoning, China.
  • 15 Department of Interventional Radiology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China.
  • 16 Department of Interventional Oncology, Seventh People's Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai, China.
  • 17 Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, The First Hospital of China Medical University, Shenyang, China.
PMID: 41756725 DOI: 10.34133/research.1161
Abstract

Portal vein tumor thrombus (PVTT) is among the most lethal complications of hepatocellular carcinoma (HCC), yet its molecular mechanisms and immune features remain poorly characterized. To address this gap, we performed a comprehensive multi-omics analysis of 99 specimens from 47 patients, integrating nCounter profiling, single-cell RNA Sequencing, digital spatial profiling, and proteomics to construct the first spatial map of the PVTT microenvironment. These analyses revealed marked intratumoral heterogeneity and enrichment of myofibroblast-like cancer-associated fibroblasts (myCAFs) arising through a macrophage-to-myofibroblast transition. Nidogen-1 (NID1) was identified as a stromal driver of immune barriers, highly expressed in PVTT cores and associated with impaired antitumor immunity. Guided by these mechanistic insights, we repurposed acarbose, a Food and Drug Administration-approved drug, to inhibit the NID1 axis. Functional assays demonstrated that acarbose disrupted myCAF-mediated immune barriers, suppressed PVTT progression, and synergized with anti-programmed death-1 (anti-PD-1) therapy in preclinical models. Furthermore, analysis of an independent clinical cohort of 810 HCC patients revealed a substantially lower incidence of PVTT among those receiving acarbose, underscoring its translational potential. Collectively, these findings establish the immune-stromal landscape of PVTT, uncover NID1-driven stromal remodeling as a mechanism of immune evasion, and highlight drug repurposing as an immediately actionable strategy to improve outcomes in HCC with PVTT.

Figures
Products