The role of fumarate and itaconate in tumor microenvironment.

In recent years, the mechanisms of abnormal metabolite accumulation in tumor development have become an emerging research field. Cells within the tumor microenvironment (TME) sustain tumor proliferation via metaboalic reprogramming. Such metabolic remodeling triggers aberrant oncometabolite accumulation, which drives tumor progression, distant metastasis and therapeutic resistance through the modulation of tumor cell proliferation, angiogenesis and immune evasion. Notably, fumarate and itaconate, originating from different subcellular localizations, modulate protein function primarily covalent or non-covalent interactions. Functionally, the modified target proteins can be roughly divided into four categories that drive tumor progression: key metabolic enzymes, epigenetic regulators, immune-related molecules and resistance-associated proteins, which respectively modulate metabolic rewiring, epigenetic reprogramming, the immunosuppressive microenvironment and therapeutic resistance. Herein, we systematically summarize the oncogenic mechanisms of these two oncometabolites, propose viable strategies to address technical hurdles in studying non-enzymatic protein modifications and offer new directions for the clinical treatment of tumors through targeted inhibition of fumarate and itaconate.