image: Image Caption: Roles of glucose metabolism in head and neck cancer. Glucose enters the cell via glucose transporter protein type 1 (GLUT1), a process regulated by several non-coding RNAs. Image link: https://ars.els-cdn.com/content/image/1-s2.0-S2352304225000960-gr1_lrg.jpg
Credit: Genes & Diseases
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.
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Reference
Haofan Li, Qiu Peng, Linda Oyang, Wenjuan Yang, Shizhen Li, Yaqian Han, Mingjing Peng, Shiming Tan, Longzheng Xia, Jinguan Lin, Xuemeng Xu, Nayiyuan Wu, Yanyan Tang, Xia Luo, Xianjie Jiang, Qianjin Liao, Yujuan Zhou, The regulatory role and mechanism of energy metabolism and immune response in head and neck cancer, Genes & Diseases, Volume 12, Issue 6, 2025, 101607, https://doi.org/10.1016/j.gendis.2025.101607
Funding Information:
National Natural Science Foundation of China 82302987
National Natural Science Foundation of China 82303534
National Natural Science Foundation of China 82203233
National Natural Science Foundation of China 82202966
National Natural Science Foundation of China 82173142
Natural Science Foundation of Hunan Province, China 2023JJ60469
Natural Science Foundation of Hunan Province, China 2023JJ40413
Natural Science Foundation of Hunan Province, China 2023JJ30372
Natural Science Foundation of Hunan Province, China 2023JJ30375
Natural Science Foundation of Hunan Province, China 2023JJ40417
Natural Science Foundation of Hunan Province, China 2020JJ5336
Research Project of Health Commission of Hunan Province, China Z2023086
Research Project of Health Commission of Hunan Province, China R2023093
Research Project of Health Commission of Hunan Province, China R2023040
Research Project of Health Commission of Hunan Province, China 202203034978
Research Project of Health Commission of Hunan Province, China 202202055318
Research Project of Health Commission of Hunan Province, China 202203231032
Research Project of Health Commission of Hunan Province, China 202109031837
Research Project of Health Commission of Hunan Province, China 202109032010
Research Project of Health Commission of Hunan Province, China 20201020
Science and Technology Innovation Program of Hunan Province, China 2023ZJ1122
Science and Technology Innovation Program of Hunan Province, China 2023RC3199
Science and Technology Innovation Program of Hunan Province, China 2023SK4034
Science and Technology Innovation Program of Hunan Province, China 2023RC1073
Science and Technology Innovation Program of Hunan Province, China 2022SK2051
Hunan Provincial Science and Technology Department of China 2020TP1018
Changsha Science and Technology Board of China kh2201054
Ascend Foundation of National Cancer Center (China) NCC201909B06
Hunan Cancer Hospital Climb Plan (China) ZX2020001-3
Hunan Cancer Hospital Climb Plan (China) YF2020002