Recent studies have shown that oxidative phosphorylation (OXPHOS) is a target for the effective attenuation of
cancer drug resistance. OXPHOS inhibitors can improve treatment responses to anticancer
therapy in certain
cancers, such as
melanomas,
lymphomas,
colon cancers,
leukemias and pancreatic ductal
adenocarcinoma (PDAC). However, the effect of OXPHOS on
cancer drug resistance is complex and associated with cell types in the tumor microenvironment (TME).
Cancer cells universally promote OXPHOS activity through the activation of various signaling pathways, and this activity is required for resistance to
cancer therapy. Resistant
cancer cells are prevalent among cancer stem cells (CSCs), for which the main metabolic phenotype is increased OXPHOS. CSCs depend on OXPHOS to survive targeting by anticancer drugs and can be selectively eradicated by OXPHOS inhibitors. In contrast to that in
cancer cells, mitochondrial OXPHOS is significantly downregulated in
tumor-infiltrating T cells, impairing antitumor immunity. In this review, we summarize novel research showing the effect of OXPHOS on
cancer drug resistance, thereby explaining how this metabolic process plays a dual role in
cancer progression. We highlight the underlying mechanisms of metabolic reprogramming in
cancer cells, as it is vital for discovering new drug targets.