Due to the proliferative nature of cancer cells, they utilize more dietary extracellular nutrients via one-carbon metabolism for the various metabolic processes, including the synthesis of antioxidants such as glutathione (GSH) and hydrogen sulfide (H2S). Indeed, several studies have found that specific cancer types produce significantly higher levels of GSH and H2S than normal healthy cells, which may serve as a protective mechanism, allowing them to resist stress, survive, and grow. This metabolic heterogeneity, driven by intrinsic and extrinsic factors, contributes to the distinct metabolic characteristics and vulnerabilities of tumor subtypes, which can be exploited to develop anticancer strategies. In this review, we summarize the fundamental roles and regulation of GSH and H2S in normal physiological systems and in the genesis and progression of cancer, their effects on the tumor microenvironment (TME), and their contribution to drug resistance. We also discuss the influences of diet and the gut microbiome on GSH and H2S production, and how cancer cells reprogram their metabolism to grow and survive in a stressful environment by overproducing GSH and H2S.
Keywords: Persulfide; ferroptosis; gut microbiome; immunotherapy; lipid peroxidation; methionine restriction; oxidative stress; targeted therapy.