Beyond reduced intake: tumor metabolism and immune dysregulation drive cancer-related malnutrition in head and neck squamous cell carcinoma (HNSCC)

Cancer-related malnutrition is highly prevalent in patients with head and neck squamous cell carcinoma (HNSCC) and represents a major determinant of treatment tolerance, quality of life, and survival. Although traditionally attributed to reduced oral intake caused by dysphagia, mucositis, and treatment-related toxicity, increasing evidence indicates that malnutrition in HNSCC is largely driven by tumor-induced metabolic and inflammatory alterations. Enhanced aerobic glycolysis, systemic inflammation, and tumor-derived factors promote hypermetabolism, substrate redistribution, and progressive skeletal muscle depletion. Within this immune-metabolic framework, the tumor behaves as a metabolic sink, redirecting glucose, lipids, and amino acids from host tissues to sustain its growth, thereby contributing to energy wasting and sarcopenia independently of caloric intake. Recent clinical data support the translational relevance of this model. Imaging-based assessment of body composition at the third cervical vertebra (C3) and metabolic imaging parameters such as total lesion glycolysis (TLG) provide measurable indicators of tumor metabolic burden and its association with skeletal muscle loss and nutritional risk. Integrating metabolic imaging, inflammatory biomarkers, and body composition analysis may enable earlier identification of patients at high risk of malnutrition and treatment-related toxicity. This review integrates these complementary biological and imaging domains into a unified immune-metabolic framework for nutritional risk stratification in HNSCC. Recognizing cancer-related malnutrition in HNSCC as a tumor-driven immune-metabolic syndrome has important therapeutic implications. Early immune-metabolic nutritional strategies, rather than reactive caloric supplementation alone, may represent a key component of integrated oncologic care aimed at preserving lean body mass and improving clinical outcomes.