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REVIEW ARTICLE

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

Ankit Kumar Yadav1 ,  Pooja Singh1 ,  Roopak Murali1 ,  Ganesh Venkatraman2 ,  Rajesh Kumar Gandhirajan1*
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1 Department of Human Genetics, Faculty of Biomedical Sciences Technology and Research, Sri Ramachandra Institute of Higher Education and Research, Chennai, Tamil Nadu, India
2 Department of Bio-Medical Sciences, School of Biosciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, India
Tumor Discovery, 025080015 https://doi.org/10.36922/TD025080015
Received: 23 February 2025 | Revised: 19 June 2025 | Accepted: 3 July 2025 | Published online: 29 August 2025
© 2025 by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution 4.0 International License ( https://creativecommons.org/licenses/by/4.0/ )
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Abstract

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.

Keywords
Heme
Porphyrin overdrive
Tumor microenvironment
Metabolism
Therapy resistance
Funding
Part of this work was funded by the Department of Biotechnology, India (Grant No: BT/PR44553/ MED/30/2391/2021).
Conflict of interest
The authors declare that they have no competing interests.
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Tumor Discovery, Electronic ISSN: 2810-9775 Print ISSN: 3060-8597, Published by AccScience Publishing
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