The controversial role of metabolic reprogramming in anti-tumor therapy resistance

Anti-tumor therapies, including chemotherapy, immunotherapy, targeted therapy and endocrine therapy highlight an increasingly important role, but drug resistance limits their efficacy. In the nutrient-poor tumor microenvironment (TME), tumor cells resist the anti-tumor therapies by turning into ‘resistance continuum’. Metabolic reprogramming serves an essential character in the cellular ‘resistance continuum’. The process of metabolic reprogramming is heterogeneous, dynamic and complex in drug-resistant tumor cells. Some resist the killing effects of anti-tumor drugs by enhancing glycolysis, some by heightening lipid metabolism, some by boosting amino acid metabolism, and some even by potentiating OXPHOS which is contrary to the traditional Warburg effect. These metabolic reprogrammed processes could help tumor cells to maintain intracellular redox homeostasis and evade ferroptosis under anti-tumor treatments. This review has attempted to describe the common mechanisms in drug-resistant tumor cells under chemotherapy, immunotherapy, targeted therapy and endocrine therapy from the perspective of metabolic reprogramming, and summarizes recent advances in research on targeting metabolism to overcome drug resistance.