Yasukawa Koya, Shimada Shu, Akiyama Yoshimitsu, Taniai Tomohiko, Igarashi Yosuke, Tsukihara Shu, Tanji Yoshiaki, Umemura Kentaro, Kamachi Atsushi, Nara Atsushi, Yamane Masahiro, Akahoshi Keiichi, Shimizu Akira, Soejima Yuji, Tanabe Minoru, Tanaka Shinji
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.
Department of Molecular Oncology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo 113-8519, Japan.
Cell Rep Med. 2025 Apr 15;6(4):102038. doi: 10.1016/j.xcrm.2025.102038. Epub 2025 Mar 25.
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.
尽管激活素受体2A（ACVR2A）突变在非病毒性肝细胞癌（HCC）中普遍存在，但其潜在机制仍未阐明。我们的分子研究表明，ACVR2A功能受损通过SMAD信号通路的失活诱导糖酵解增强。利用同基因移植模型和人类临床样本，我们阐明了ACVR2A缺陷的HCC细胞通过上调乳酸脱氢酶A（LDHA）和单羧酸转运蛋白4（MCT4）的表达水平来产生和分泌乳酸，这促进了调节性T（Treg）细胞的积累，进而获得对免疫检查点抑制剂的抗性。值得注意的是，MCT4的基因敲低和药物抑制改善了ACVR2A缺陷型HCC中的高乳酸环境，导致肿瘤内Treg细胞募集的抑制以及对PD-1阻断敏感性的恢复。这些发现提供了令人信服的证据，表明乳酸会削弱抗肿瘤免疫力，并且针对该途径的治疗方法为减轻ACVR2A缺陷型HCC中的免疫治疗抗性提供了一种有前景的策略。
