Department of Neurology and Stroke Center, The First Affiliated Hospital, Department of Chemistry, Jinan University, Guangzhou 510632, China.
ACS Appl Mater Interfaces. 2022 Jun 22;14(24):27651-27665. doi: 10.1021/acsami.2c05533. Epub 2022 Jun 8.
Rapid glycolysis of tumor cells produces excessive lactate to trigger acidification of the tumor microenvironment (TME), leading to the formation of immunosuppressive TME and tumor-associated macrophage (TAM) dysfunction. Therefore, reprogramming TAMs by depleting lactate with nanodrugs is expected to serve as an effective means of tumor-targeted immunotherapy. Herein, we report the use of lactic acid dehydrogenase (LDH)-mimicking SnSe nanosheets (SnSe NSs) loaded with a carbonic anhydrase IX (CAIX) inhibitor to reconstruct an acidic and immunosuppressive TME. As expected, this nanosystem could reprogram the TAM to achieve M1 macrophage activation and could also restore the potent tumor-killing activity of macrophages while switching their metabolic mode from mitochondrial oxidative phosphorylation to glycolysis. In addition, the repolarizing effect of SnSe NSs on macrophages was validated in a coculture model of bone marrow-derived macrophages, in three patient-derived malignant pleural effusion and in vivo mouse model. This study proposes a feasible therapeutic strategy for depleting lactate and thus ameliorating acidic TME employing Se-containing nanosheets, which could further amply the effects of TAM-based antitumor immunotherapy.
肿瘤细胞的快速糖酵解会产生过量的乳酸，从而引发肿瘤微环境（TME）酸化，导致免疫抑制性 TME 的形成和肿瘤相关巨噬细胞（TAM）功能障碍。因此，通过纳米药物耗竭乳酸来重新编程 TAMs，有望成为肿瘤靶向免疫治疗的有效手段。在此，我们报告了使用乳酸脱氢酶（LDH）模拟的 SnSe 纳米片（SnSe NSs）负载碳酸酐酶 IX（CAIX）抑制剂来重建酸性和免疫抑制性 TME。正如预期的那样，这种纳米系统可以重新编程 TAM 以实现 M1 巨噬细胞激活，还可以恢复巨噬细胞的强大肿瘤杀伤活性，同时将其代谢模式从线粒体氧化磷酸化切换到糖酵解。此外，在骨髓来源的巨噬细胞共培养模型、三种患者来源的恶性胸腔积液和体内小鼠模型中验证了 SnSe NSs 对巨噬细胞的再极化作用。本研究提出了一种利用含硒纳米片耗竭乳酸从而改善酸性 TME 的可行治疗策略，这可能进一步增强基于 TAM 的抗肿瘤免疫治疗效果。
