Promoting Toxic Metabolites in Cancer Therapy

Metabolic reprogramming supports cancer behaviors including proliferation, survival, and therapeutic resistance. Compared to our understanding of these processes, little is known about the detoxification liabilities that are introduced as a byproduct of this reprogramming. Here, we review recent findings that collectively support the notion that the metabolic reprogramming of cancer cells is accompanied by increased production of potentially toxic metabolites. As a result, these cells are critically dependent on enzymatic processing or export of these metabolites. When such processes are blocked, endogenously produced metabolites can accumulate in distinct subcellular compartments to exert a variety of cytotoxic mechanisms in cancer cells such as DNA damage and ferroptosis. Toxic metabolite overloading is discussed as an emerging therapeutic strategy that carries potential advantages such as allowing tuning of toxicity via dietary control of metabolite production and exerting microenvironmental toxic effects to enhance overall efficacy in the heterogenous tumor.