Targeting metabolic reprogramming to overcome immune suppression in head and neck cancer

Head and neck cancer remains a major global health challenge, ranking among the six most common cancers worldwide and claiming hundreds of thousands of lives each year. A growing body of evidence now points to an intricate connection between energy metabolism and immune regulation as a driving force behind the onset, progression, and treatment resistance of these cancers. The latest comprehensive review on this topic underscores the potential of targeting these intertwined processes to unlock more effective therapies.

Tumor cells in head and neck cancer exhibit profound metabolic reprogramming, altering the way they process glucose, lipids, and amino acids. This reprogramming fuels rapid growth, supports invasion into surrounding tissues, and fortifies tumors against hostile conditions. Changes in glucose transporters and key enzymes accelerate glycolysis, creating a microenvironment rich in lactate that fosters tumor progression and suppresses immune activity. Altered lipid metabolism not only sustains cell membrane production and energy storage but also promotes immune evasion by influencing macrophage polarization and dampening anti-tumor responses. Similarly, restructured amino acid metabolism, particularly in glutamine and arginine pathways, plays a critical role in both tumor growth and the regulation of immune cell activity.

The immune system, a natural line of defense, is often undermined in head and neck cancer. Tumor-driven metabolic shifts deprive CD8⁺ T cells and other immune cells of essential nutrients, weakening their ability to attack malignant cells. At the same time, immune checkpoints such as PD-L1 are upregulated, blocking immune activation. Dysregulation of antigen presentation pathways, altered cytokine signaling, and the recruitment of suppressive immune cells further deepen the immunosuppressive environment.

Importantly, the review highlights that this metabolism–immunity interplay is not just a byproduct of disease-it is a potential therapeutic target. Modulating glucose metabolism through transporter and enzyme inhibitors, interfering with lipid synthesis and cholesterol regulation, or restricting tumor access to key amino acids may tip the balance back in favor of the immune system. Moreover, combining metabolic interventions with immunotherapy could counteract immune suppression and improve patient outcomes, especially in cases resistant to standard treatments.