Role of tumor microenvironment in cancer promotion, development of drug resistance and cancer treatment

Abstract Cancer is a multifactorial disease and the second leading cause of death worldwide after cardiovascular disease. Initially, it was considered a genetic disease or gene expression disorder, but now it is regarded as a tumor microenvironment (TME) disease. The TME consists of cancer cells, endothelial cells, fibroblasts, and immune cells that interact with each other. These interactions support tumor growth by providing nutrients via altered metabolic mechanisms such as glutamine metabolism, aerobic glycolysis, and fatty acid metabolism. The by-products of these altered metabolic pathways interfere with the function of surrounding cells and thus lead to cancer progression. The role of metabolic crosstalk highlights the intricate relationship between the cancer cells and their TME. This review comprehensively analyzes recent studies to enhance understanding of the metabolic crosstalk in TME. It highlights how tumor-associated macrophages and fibroblasts reprogram lipid and glucose metabolism to create an immunosuppressive environment. This review also provides information about the role of hypoxia-induced HIF-1α signaling in the promotion of lactate accumulation. This factor in turn ensures tumor cells’ survival and makes them resistant to anti-cancer drugs. Further, we have discussed therapeutic approaches targeting TME, including use of PD-1, PD-L1 inhibitors, CAR-T cell therapy, and oncolytic viruses to improve patient outcomes. Besides this, clinical studies involving the estimation of lactate, GLUT1, and HIF-1α levels may help to recognize high-risk patients and develop guidance for personalized metabolism-targeting therapies. In the long run, such studies can ultimately improve patient outcomes and thus reduce disease burden.