Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington DC 20007, United States.
Shanghai Proton and Heavy Ion Center, Shanghai 201321, China.
Curr Med Chem. 2020;27(24):4002-4015. doi: 10.2174/0929867325666180601101145.
The Tumor Microenvironment (TME) comprising stromal cells, fibroblasts and various components of the immune system forms a pro-tumorigenic cocoon around the tumor cells with the reprogramming of the metabolism in the form of Warburg phenotype (enhanced aerobic glycolysis) in tumor as well as non-tumor cells. This reprogramming plays a significant role in suppressing the immune response leading to the survival and proliferation of tumor cells and resistance to therapies. Therefore, there is a considerable interest in developing strategies involving metabolic modifiers to improve the therapeutic efficacy that restores immune competence, besides enhancing the direct effects on tumor cells. Inhibitors of glycolysis like 2-deoxy-D-glucose (2-DG; a hexokinase inhibitor), dichloroacetate and small molecule inhibitors of lactate transport (MCT-1) are some of the metabolic modifiers investigated for their therapeutic as well as adjuvant potential. Among these, 2-DG has been widely investigated and established as an ideal adjuvant in the radio- and chemotherapy of tumors. Modulation of the immuno-biome in the form of cytokine shifts, differential transcriptional regulation, abrogation of immunosuppressive network and reduced accumulation of lactate are some of the contributing factors for immune stimulation linked to the radio- and chemosensitization by glycolytic inhibitors.
肿瘤微环境（TME）由基质细胞、成纤维细胞和各种免疫系统成分组成，在肿瘤细胞周围形成一个促肿瘤形成的“茧”，同时肿瘤细胞和非肿瘤细胞的代谢发生重编程，表现为瓦博格表型（增强的有氧糖酵解）。这种重编程在抑制免疫反应方面起着重要作用，导致肿瘤细胞的存活和增殖以及对治疗的耐药性。因此，人们对开发涉及代谢调节剂的策略产生了浓厚的兴趣，这些策略旨在改善免疫功能恢复的治疗效果，同时增强对肿瘤细胞的直接作用。已研究了一些代谢调节剂，如 2-脱氧-D-葡萄糖（2-DG；己糖激酶抑制剂）、二氯乙酸盐和乳酸转运的小分子抑制剂（MCT-1），它们具有治疗和辅助作用。其中，2-DG 已被广泛研究，并被确立为肿瘤放射和化学治疗的理想辅助剂。免疫生物组的调节形式为细胞因子转移、差异转录调控、抑制免疫抑制网络和减少乳酸积累，这些都是与糖酵解抑制剂的放射和化学增敏相关的免疫刺激的促成因素。
