Metformin is a widely used antidiabetic drug for cancer prevention and treatment. However, the overproduction of lactic acid and its inefficiency in cancer therapy limit its application. Here, we demonstrate the synergistic effects of the lactate/GPR81 blockade (3-hydroxy-butyrate, 3-OBA) and metformin on inhibiting cancer cells growth in vitro. Simultaneously, this combination could inhibit glycolysis and OXPHOS metabolism, as well as inhibiting tumor growth and reducing serum lactate levels in tumor-bearing mice. Interestingly, we observed that this combination could enhance the functions of Jurkat cells in vitro and CD8⁺ T cells in vivo. In addition, considering that 3-OBA could recover the inhibitory effects of metformin on PD-1 expression, we further determined the dual blockade effects of PD-1/PD-L1 and lactate/GPR81 on the antitumor activity of metformin. Our results suggested that this dual blockade strategy could remarkably enhance the anti-tumor effects of metformin, or even lead to tumor regression. In conclusion, our study has proposed a novel and robust strategy for a future application of metformin in cancer treatment.

中文翻译：

---

乳酸/GPR81和PD-1/PD-L1通路的双重阻断增强二甲双胍的抗肿瘤作用

二甲双胍是一种广泛用于癌症预防和治疗的抗糖尿病药物。然而，乳酸的过量生产及其在癌症治疗中的低效限制了其应用。在这里，我们展示了乳酸/GPR81 阻断剂（3-羟基丁酸酯，3-OBA）和二甲双胍在体外抑制癌细胞生长的协同作用。同时，这种组合可以抑制糖酵解和 OXPHOS 代谢，以及抑制肿瘤生长和降低荷瘤小鼠的血清乳酸水平。有趣的是，我们观察到这种组合可以增强体外 Jurkat 细胞的功能和 CD8 ⁺体内的 T 细胞。此外，考虑到3-OBA可以恢复二甲双胍对PD-1表达的抑制作用，我们进一步确定了PD-1/PD-L1和乳酸/GPR81对二甲双胍抗肿瘤活性的双重阻断作用。我们的研究结果表明，这种双重阻断策略可以显着增强二甲双胍的抗肿瘤作用，甚至导致肿瘤消退。总之，我们的研究为二甲双胍在癌症治疗中的未来应用提出了一种新颖而稳健的策略。