2. Academic Validation
  3. ACVR2A attenuation impacts lactate production and hyperglycolytic conditions attracting regulatory T cells in hepatocellular carcinoma

ACVR2A attenuation impacts lactate production and hyperglycolytic conditions attracting regulatory T cells in hepatocellular carcinoma

  • Cell Rep Med. 2025 Apr 15;6(4):102038. doi: 10.1016/j.xcrm.2025.102038.
Koya Yasukawa 1,  Shu Shimada 2,  Yoshimitsu Akiyama 3,  Tomohiko Taniai 4,  Yosuke Igarashi 4,  Shu Tsukihara 5,  Yoshiaki Tanji 4,  Kentaro Umemura 1,  Atsushi Kamachi 1,  Atsushi Nara 6,  Masahiro Yamane 6,  Keiichi Akahoshi 7,  Akira Shimizu 8,  Yuji Soejima 8,  Minoru Tanabe 7,  Shinji Tanaka 9
Affiliations

Affiliations

  • 1 Department of Molecular Oncology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo 113-8519, Japan; Division of Gastroenterological, Hepato-Biliary-Pancreatic, Transplantation and Pediatric Surgery, Department of Surgery, Shinshu University School of Medicine, Matsumoto 390-8621, Japan.
  • 2 Department of Molecular Oncology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo 113-8519, Japan. Electronic address: shimada.monc@tmd.ac.jp.
  • 3 Department of Molecular Oncology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo 113-8519, Japan.
  • 4 Department of Molecular Oncology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo 113-8519, Japan; Division of Hepatobiliary and Pancreas Surgery, Department of Surgery, The Jikei University School of Medicine, Tokyo 105-8471, Japan.
  • 5 Department of Molecular Oncology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo 113-8519, Japan; Department of Surgery, The Jikei University School of Medicine, Tokyo 105-8471, Japan.
  • 6 Department of Molecular Oncology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo 113-8519, Japan; Department of Hepato-Biliary-Pancreatic Surgery, Tokyo Medical and Dental University, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo 113-8519, Japan.
  • 7 Department of Hepato-Biliary-Pancreatic Surgery, Tokyo Medical and Dental University, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo 113-8519, Japan.
  • 8 Division of Gastroenterological, Hepato-Biliary-Pancreatic, Transplantation and Pediatric Surgery, Department of Surgery, Shinshu University School of Medicine, Matsumoto 390-8621, Japan.
  • 9 Department of Molecular Oncology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo 113-8519, Japan; Department of Hepato-Biliary-Pancreatic Surgery, Tokyo Medical and Dental University, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo 113-8519, Japan. Electronic address: tanaka.monc@tmd.ac.jp.
PMID: 40139191 DOI: 10.1016/j.xcrm.2025.102038
Abstract

Although ACVR2A mutations are prevalent in non-viral hepatocellular carcinomas (HCCs), the underlying mechanism remains unelucidated. Our molecular investigation reveals that ACVR2A impairment induces hyperglycolysis through the inactivation of the SMAD signaling pathway. Using syngeneic transplantation models and human clinical samples, we clarify that ACVR2A-deficient HCC cells produce and secrete lactate via the upregulation of Lactate Dehydrogenase A (LDHA) and Monocarboxylate Transporter 4 (MCT4) expression levels, which promotes regulatory T (Treg) cell accumulation and then acquires resistance to immune checkpoint inhibitors. Remarkably, genetic knockdown and pharmacological inhibition of MCT4 ameliorate the high-lactate milieu in ACVR2A-deficient HCC, resulting in the suppression of intratumoral Treg cell recruitment and the restoration of the sensitivity to PD-1 blockade. These findings furnish compelling evidence that lactate attenuates anti-tumor immunity and that therapeutics targeting this pathway present a promising strategy for mitigating immunotherapy resistance in ACVR2A-deficient HCC.

Keywords

ACVR2A; LDHA; MCT4; PD-1; hepatocellular carcinoma; immunotherapy; lactate; regulatory T cell.

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