Dysregulated heme metabolism in cancer progression: Pathways, biomarkers, and therapeutic challenges

Heme, a vital inorganic compound consisting of a tetrapyrrole protoporphyrin ring (protoporphyrin IX) with an iron ion at its core, is essential for several metabolic processes, including the electron transport chain, oxidative phosphorylation, glycolysis, and the tricarboxylic acid cycle. As a critical cofactor for enzymes such as hemoglobin, myoglobin, cytochrome P450, and peroxidase, heme is fundamental to normal cell function at physiological concentrations, and above these concentrations, it can also act as a driver of oncogenesis. Dysregulated heme metabolism profoundly impacts cancer biology, affecting tumor growth, progression, and resistance to currently available treatments. Disruptions in heme homeostasis alter redox balance, modulate immune responses, and increase metabolic flexibility within the tumor microenvironment (TME). Elevated levels of heme oxygenase, a key enzyme responsible for heme degradation, and other enzymes of the heme biosynthetic pathway—including transporter and trafficking proteins—are associated with enhanced cancer cell survival, therapeutic resistance, and immune evasion. Moreover, the buildup of porphyrins (porphyrin overdrive) within the TME has potential utility as a biomarker for early cancer detection and monitoring. This review synthesizes the literature on tumor-derived heme and its role in multiple cancers, emphasizing the significance of considering heme as a major factor in oncogenesis, including tumor initiation, progression, and resistance to current treatment options.