ACVR2A attenuation impacts lactate production and hyperglycolytic conditions attracting regulatory T cells in hepatocellular carcinoma
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.
Authors
- Akira Shimizu (ORCID: https://orcid.org/0000-0002-5015-1697)
- Keiichi Akahoshi (ORCID: https://orcid.org/0000-0003-3792-5659)
- Shu Tsukihara (ORCID: https://orcid.org/0000-0003-2537-719X)
- Kentaro Umemura (ORCID: https://orcid.org/0000-0003-1259-5438)
- Yuji Soejima (ORCID: https://orcid.org/0000-0001-5539-9280)
- Tomohiko Taniai (ORCID: https://orcid.org/0000-0001-8911-5530)
- Atsushi Kamachi (ORCID: https://orcid.org/0000-0002-4012-0459)
- Yoshiaki Tanji (ORCID: https://orcid.org/0009-0004-6585-3220)
- Shinji Tanaka (ORCID: https://orcid.org/0000-0002-7718-3453)
- Koya Yasukawa (ORCID: https://orcid.org/0000-0002-3643-0921)
- Yosuke Igarashi (ORCID: https://orcid.org/0000-0003-1998-8074)
- Shu Shimada (ORCID: https://orcid.org/0000-0002-4962-0636)
- Minoru Tanabe (ORCID: https://orcid.org/0000-0003-4875-1471)
- Atsushi Nara (ORCID: https://orcid.org/0000-0001-9233-8911)
- Masahiro Yamane (ORCID: https://orcid.org/0009-0004-6251-8654)
- Yoshimitsu Akiyama
Institutions
- Jikei University School of Medicine (JP)
- Tokyo Medical and Dental University (JP)
- Shinshu University (JP)
Publication Details
- Journal
- Cell Reports Medicine
- Published
- 2025-03-26
- DOI
- https://doi.org/10.1016/j.xcrm.2025.102038
- Citations
- 8
- Primary Topic
- Cancer Immunotherapy and Biomarkers
- Type
- article
- Field-Weighted Citation Impact
- 8.36
Funders
- Japan Agency for Medical Research and Development
- Ministry of Education, Culture, Sports, Science and Technology
- Princess Takamatsu Cancer Research Fund