Metabolic Reprogramming in Cancer: Implications for Tumor Progression, Metastasis, Immune Evasion and Therapy Resistance

Dear Colleagues,

Metabolic reprogramming is widely recognized as a defining hallmark of cancer that enables tumor cells to adapt to dynamic and often hostile microenvironmental conditions such as nutrient deprivation, hypoxia, and therapeutic stress. One of the earliest observations of altered cancer metabolism was described by Otto Warburg, who reported that cancer cells preferentially utilize glycolysis even in the presence of oxygen. Since this initial discovery, it has become increasingly clear that tumor cells undergo extensive metabolic remodeling that extends far beyond the classical Warburg effect.

Accumulating evidence indicates that cancer cells reconfigure multiple metabolic pathways to sustain proliferation, survival, immune evasion, and resistance to cell death. These alterations include increased glutamine utilization, mitochondrial anaplerosis, metabolic flexibility during nutrient limitation, lipid droplet mobilization, redox homeostasis, and dynamic metabolic interactions with stromal and immune cells within the tumor microenvironment. Signaling pathways such as AMPK and other metabolic sensors play critical roles in coordinating these adaptations and maintaining cellular energy balance.

Recent studies further suggest that metabolites themselves can function as signaling molecules that directly influence oncogenic pathways and cellular fate decisions. In response to metabolic stress, cancer cells often display remarkable metabolic plasticity, allowing them to switch between distinct nutrient sources and bioenergetic programs. For example, tumor cells may rely on glutamine metabolism when glucose availability is limited and revert to glucose-dependent pathways under glutamine deprivation. Emerging findings also indicate that certain metabolites can directly regulate signaling pathways involved in innate immunity and tumor–immune interactions, thereby contributing to immune evasion and resistance to immunotherapy.

Metabolic adaptations are also closely associated with metastatic progression. Circulating tumor cells and metastatic colonies frequently exhibit distinct metabolic signatures that reflect the changing energetic and biosynthetic demands encountered during dissemination and colonization of distant organs. Understanding how metabolic programs evolve during these stages of cancer progression may reveal new vulnerabilities that can be therapeutically exploited.

This Special Issue aims to provide an updated perspective on the molecular mechanisms and biological consequences of metabolic reprogramming in cancer progression, metastasis, immune evasion, and therapy resistance. We particularly encourage submissions that investigate metabolic signaling networks, mitochondrial metabolism, metabolic plasticity under stress conditions, and the identification of druggable metabolic targets. Studies exploring the relationship between metabolic rewiring and resistance to conventional therapies or immunotherapies are also highly welcome. By bringing together insights from molecular biology, metabolism, and translational oncology, this Special Issue highlights emerging strategies to target metabolic vulnerabilities in cancer and improve therapeutic outcomes.

Dr. Vasudevarao Penugurti
Dr. Bramanandam Manavathi
Guest Editors

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

• cancer and mitochondrial metabolism
• metabolic reprogramming
• glutamine metabolism
• tumor microenvironment
• metabolic plasticity
• oxidative phosphorylation
• drug resistance
• immune evasion
• cancer metastasis
• therapeutic metabolic targeting