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. 2026 Oct 5;34(10):1056. doi: 10.1007/s00520-026-11115-w

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

Vincenzo Zurlo 1, Arianna Piccirillo 2,✉, Maria Luisa Marciano 2, Monica Pontone 2, Fabiana Raffaella Rampetta 2, Erica Perri 3, Francesco Perri 2
PMCID: PMC13638751  PMID: 42832090

Abstract

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.

Supplementary information

The online version contains supplementary material available at https://doi.org/10.1007/s00520-026-11115-w.

Keywords: Head and neck squamous cell carcinoma, Cancer-related malnutrition, Sarcopenia, Tumor metabolism, Immunonutrition

Cancer-related malnutrition in HNSCC: Beyond reduced intake

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 [1, 2].

According to the Global Leadership Initiative on Malnutrition (GLIM), the diagnosis of malnutrition is based on the presence of at least one phenotypic criterion (such as weight loss, low body mass index, or reduced muscle mass) together with one etiologic criterion, including reduced food intake or disease-related inflammation. This internationally accepted framework recognizes inflammation as a key pathogenic driver of cancer-related malnutrition, supporting the concept that nutritional impairment in oncology extends beyond inadequate caloric intake alone [3].

Traditionally, nutritional impairment in this population has been attributed to mechanical obstruction, dysphagia, mucositis, pain, and treatment-related toxicities leading to reduced oral intake [4]. While these factors undoubtedly contribute, they fail to fully explain the early and progressive loss of body weight and skeletal muscle mass observed in many patients, even before the initiation of anticancer therapy.

In parallel, the updated Hallmarks of Cancer framework identifies metabolic reprogramming and the ability to shape the immune and inflammatory microenvironment as fundamental characteristics of malignant disease. These concepts provide a strong biological rationale for considering cancer-related malnutrition in HNSCC as a systemic tumor-driven immune-metabolic syndrome rather than merely a consequence of local mechanical impairment or treatment-related toxicity [5].

Growing evidence indicates that malnutrition in HNSCC is largely driven by tumor-induced metabolic and inflammatory alterations rather than by insufficient caloric intake alone [6]. Tumor cells actively reprogram host metabolism, inducing a hypercatabolic state characterized by increased energy expenditure, systemic inflammation, and impaired anabolic signaling [6]. This metabolic stress precedes overt cachexia and may manifest clinically as early sarcopenia, nutritional risk, and functional decline.

Therefore, cancer-related malnutrition should be considered a dynamic, tumor-driven process rather than a purely nutritional deficit. This paradigm shift has important clinical implications, suggesting that early nutritional intervention must aim not only to increase caloric intake but also to counteract the metabolic and inflammatory mechanisms underlying tissue wasting and immune dysfunction.

Unlike previous reviews that have separately addressed inflammation, cachexia, or nutritional support, the present review proposes an integrated immune-metabolic framework linking tumor metabolic burden (assessed by total lesion glycolysis (TLG)), systemic inflammation, and imaging-based skeletal muscle assessment (C3-derived skeletal muscle indices) as complementary determinants of cancer-related malnutrition in HNSCC. This integrated perspective may facilitate earlier risk stratification and support more personalized nutritional management.

Tumor metabolism and systemic energy wasting

HNSCC is characterized by profound metabolic reprogramming that extends beyond the tumor microenvironment and affects whole-body energy homeostasis. One of the central hallmarks of cancer metabolism is the preferential reliance on aerobic glycolysis, known as the Warburg effect, which allows tumor cells to sustain rapid proliferation despite inefficient ATP generation [7, 8]. This metabolic phenotype is associated with increased glucose uptake, lactate production, and continuous nutrient consumption.

Tumor-derived lactate enters the Cori cycle, stimulating hepatic gluconeogenesis and contributing to increased resting energy expenditure [9]. In parallel, inflammatory cytokines and tumor-derived factors such as parathyroid hormone–related protein (PTHrP) promote lipolysis and white adipose tissue browning, leading to thermogenic inefficiency and accelerated energy wasting [10, 11]. Importantly, these processes do not directly nourish the tumor but force the host to mobilize metabolic substrates in an attempt to maintain homeostasis.

Skeletal muscle plays a central role in this systemic metabolic adaptation. Cytokine-mediated activation of proteolytic pathways induces muscle protein breakdown and release of amino acids, including glutamine, which can be redirected toward tumor metabolism [12]. As a result, the tumor behaves as a metabolic sink, redistributing glucose, lipids, and amino acids from muscle, liver, and adipose tissue to sustain its growth at the expense of host tissues [13]. These mechanisms provide a biological explanation for the limited efficacy of caloric supplementation alone in preventing muscle loss and cachexia in HNSCC.

Recent advances in cancer biology indicate that metabolic reprogramming should not be viewed solely as an intrinsic property of malignant cells but rather as a dynamic process involving continuous metabolic crosstalk between the tumor and the host. Through competition for nutrients, inflammatory signaling, and remodeling of peripheral tissues, the tumor progressively reshapes whole-body energy homeostasis, affecting skeletal muscle, adipose tissue, and liver metabolism. This systemic perspective provides the biological rationale for considering cancer-related malnutrition as a manifestation of tumor–host metabolic interaction rather than simply the consequence of localized tumor growth or impaired oral intake [14, 15].

Cytokine-driven immune dysregulation and muscle wasting

Chronic systemic inflammation is a key driver of metabolic derangement and muscle wasting in HNSCC. Elevated circulating levels of pro-inflammatory cytokines, including IL-6, TNF-α, and IL-1β, are commonly observed and correlate with weight loss, sarcopenia, and poor clinical outcomes [16, 17]. These cytokines promote anorexia, insulin resistance, and activation of catabolic pathways, thereby linking immune activation with metabolic decline.

IL-6 has been strongly associated with loss of body mass and adipose tissue depletion, while TNF-α enhances ubiquitin–proteasome–mediated protein degradation and impairs glucose transport in peripheral tissues [18]. In skeletal muscle, activation of the myostatin/SMAD signaling pathway further suppresses protein synthesis and accelerates muscle atrophy [19–21]. Together, these mechanisms establish a self-perpetuating loop in which inflammation sustains catabolism and tissue wasting.

Beyond innate immune activation, recent clinical data suggest that nutritional strategies enriched with immunomodulatory substrates may influence adaptive immunity. Perioperative immunonutrition has been shown to improve CD4/CD8 T-cell balance and accelerate postoperative recovery in HNSCC patients, supporting the concept that nutrition can modulate immune competence rather than merely compensate for caloric deficits [22]. The abovementioned mechanisms are depicted in Fig. 1. These findings reinforce the emerging view of early nutritional intervention as an immune-metabolic strategy capable of attenuating inflammation, preserving lean body mass, and improving resilience to anticancer treatments.

Fig. 1.

Fig. 1

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Systemic redistribution of metabolic substrates driven by tumor glycolysis, inflammation, and tissue catabolism. Blue arrows indicate the redistribution of metabolic substrates between the tumor and host tissues, whereas gray arrows represent systemic inflammatory signaling mediated by circulating cytokines. The different gray shades used in the figure are intended only to improve graphical readability and do not indicate different biological categories or levels of evidence

Key tumor-driven mechanisms underlying cancer-related malnutrition are summarized in Table 1.

Table 1.

Tumor-driven biological mechanisms contributing to cancer-related malnutrition in HNSCC beyond reduced oral intake

Mechanism Key mediators/drivers Metabolic consequences Impact on body composition Clinical implications
Tumor glycolysis and hypermetabolism (Warburg effect) Increased glucose uptake, lactate production Elevated energy expenditure, hepatic gluconeogenesis (Cori cycle) Progressive weight loss despite preserved intake Caloric supplementation alone often insufficient; need early metabolic monitoring
Systemic inflammation IL-6, TNF-α, IL-1β Insulin resistance, anorexia, activation of catabolic pathways Loss of lean body mass and functional decline Supports early anti-inflammatory and immunonutrition strategies
Adipose tissue remodeling and browning PTHrP, inflammatory cytokines Lipolysis, thermogenic inefficiency, increased resting energy expenditure Reduction of fat mass and energy reserves Explains rapid nutritional deterioration even before therapy
Skeletal muscle proteolysis Myostatin/SMAD signaling, ubiquitin–proteasome activation Amino acid release (e.g., glutamine) toward tumor metabolism Sarcopenia independent of BMI Highlights need for body composition assessment rather than weight alone
Tumor–host metabolic competition (“metabolic sink”) Tumor nutrient demand, systemic cytokine signaling Redistribution of glucose, lipids and amino acids Combined muscle and adipose tissue wasting Justifies early multimodal nutritional intervention targeting metabolism and immunity
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Metabolic reprogramming, systemic inflammation, adipose tissue remodeling, and skeletal muscle catabolism interact to promote progressive loss of body mass and functional decline, supporting the need for early immune-metabolic nutritional strategies

Clinical translation: Skeletal muscle loss, metabolic imaging, and nutritional risk

Sarcopenia represents one of the most clinically relevant manifestations of cancer-related metabolic derangement in patients with HNSCC. According to the revised European Working Group on Sarcopenia in Older People (EWGSOP2), sarcopenia is a progressive skeletal muscle disease characterized by low muscle strength as the primary determinant, confirmed by reduced muscle quantity or quality, and considered severe when accompanied by impaired physical performance. Although originally developed for the geriatric population, these diagnostic principles have been widely adopted in oncology, where imaging-based assessment of muscle mass has become an essential component of nutritional and prognostic evaluation. In patients with HNSCC, cross-sectional muscle assessment at the third cervical vertebra (C3) has emerged as a practical surrogate for whole-body skeletal muscle mass, enabling early identification of sarcopenia in routine clinical practice [23].

Loss of skeletal muscle mass is frequently observed at diagnosis and may progress rapidly during treatment, independent of body weight changes [24, 25]. Importantly, sarcopenia has been consistently associated with poorer overall survival, increased treatment-related toxicity, and reduced quality of life, highlighting its role as a robust prognostic biomarker rather than a mere consequence of treatment intolerance [26–28].

In recent years, imaging-based assessment of body composition has emerged as a reliable and reproducible tool to quantify skeletal muscle depletion in HNSCC. Due to the lack of routine abdominal imaging in this population, cross-sectional muscle area at the level of the third cervical vertebra (C3) has been validated as a surrogate for whole-body skeletal muscle mass [29]. The C3 skeletal muscle index (SMI) allows identification of skeletal muscle depletion and provides clinically meaningful information beyond conventional nutritional parameters such as body mass index.

Parallel to body composition analysis, functional imaging has offered new insights into tumor-driven metabolic burden. 18F-FDG PET-derived parameters, particularly total lesion glycolysis (TLG), integrate both tumor volume and metabolic activity, reflecting the overall glycolytic demand of the tumor [30]. High TLG values have been associated with aggressive tumor biology, increased inflammatory burden, and adverse oncologic outcomes, suggesting that tumor metabolism may act as a key upstream driver of systemic metabolic stress.

Recent clinical evidence suggests a significant association between tumor metabolic activity, skeletal muscle depletion, and nutritional risk. In a prospective cohort of patients with locally advanced HNSCC, increased tumor metabolic activity measured by TLG was significantly associated with reduced skeletal muscle mass at the level of C3, higher inflammatory markers, and impaired nutritional status at the start of treatment [31]. These findings provide clinical validation of the biological model in which tumor-driven hypermetabolism and inflammation translate into measurable deterioration of body composition and nutritional reserve.

In parallel with what has been said, several clinical studies have highlighted the close interaction between nutritional impairment and systemic inflammation in HNSCC, further underlining the concept that in cancer patients, malnutrition, hypercatabolism, and systemic inflammation often go hand in hand [32–37]. Despite these encouraging findings, several limitations should be acknowledged.

Current evidence linking PET-derived metabolic parameters, particularly TLG, with nutritional impairment is based on a limited number of observational studies, and external validation in larger prospective HNSCC cohorts is still needed. Furthermore, methodological heterogeneity in PET acquisition protocols, lesion segmentation strategies, and TLG cutoff values currently limits direct comparison across studies. Similarly, although C3-derived skeletal muscle assessment has emerged as a practical surrogate for whole-body muscle mass in patients with HNSCC, standardized imaging protocols and universally accepted diagnostic thresholds have not yet been fully established. Therefore, metabolic imaging biomarkers should currently be considered complementary tools to conventional nutritional and body composition assessment rather than stand-alone markers of cancer-related malnutrition.

From a translational perspective, these data reinforce the concept that nutritional risk in HNSCC is not solely determined by oral intake but reflects the interaction between tumor metabolism, systemic inflammation, and host tissue catabolism. Integrating metabolic imaging (TLG), body composition assessment (C3 SMI), and inflammatory biomarkers into routine evaluation may allow earlier identification of patients at high risk of sarcopenia and nutritional decline. This approach creates the rationale for timely, personalized nutritional, and immune-metabolic interventions aimed at modifying the disease trajectory rather than reacting to late-stage cachexia.

A summary of currently available clinical and imaging tools for early nutritional risk stratification is provided in Table 2. Key clinical studies supporting the interaction between nutritional status, inflammation, and tumor metabolic burden are summarized in Table 3.

Table 2.

Overview of imaging-based, metabolic, and clinical tools that may support early identification of nutritional risk in patients with HNSCC

Tool/parameter Biological domain assessed Strengths Limitations Clinical relevance
Body mass index (BMI) and weight loss Global nutritional status Easy to obtain, widely used in clinical practice Poor sensitivity for early sarcopenia or metabolic alterations Useful for screening but insufficient alone for risk stratification
C3 skeletal muscle index (SMI) from CT imaging Body composition/muscle mass Reproducible, available from routine head and neck imaging Requires image analysis expertise and standardized cutoffs Early detection of sarcopenia and treatment-related risk
18F-FDG PET-derived total lesion glycolysis (TLG) Tumor metabolic burden Integrates tumor volume and glycolytic activity Not yet standardized for nutritional assessment Potential biomarker linking tumor metabolism with systemic catabolism
Systemic inflammatory markers (e.g., CRP, IL-6) Immune-metabolic status Reflects inflammatory burden and prognosis Non-specific and influenced by comorbidities May complement imaging in identifying high-risk patients
Functional and clinical nutritional assessment Nutritional risk and performance status Integrates clinical judgment and patient-reported outcomes Subjective variability Supports early, personalized nutritional intervention strategies
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Integrating body composition analysis (C3 SMI), tumor metabolic activity (TLG), and inflammatory markers may improve risk stratification beyond traditional measures such as BMI or weight loss alone

Table 3.

Overview of clinical studies evaluating the interaction between nutritional status, systemic inflammation, and tumor-related metabolic burden in patients with HNSCC

Study Population/setting Nutritional parameters Inflammatory markers Main findings Primary clinical application
Rey et al. [32] HNSCC at diagnosis NRI, C3 SMI, oral intake CRP, NLR, mGPS Higher tumor metabolic activity associated with reduced muscle mass, increased inflammation, and nutritional risk Nutritional risk stratification integrating metabolic imaging and body composition
Briuxola et al. [33] Locally advanced HNSCC Prognostic Nutritional Index (PNI) NLR/dNLR Low PNI combined with high inflammation predicts poorer outcomes Prognostic assessment
Yamahara et al. [34] HNSCC pre-treatment Nutritional risk factors Inflammatory markers Combined nutritional and inflammatory impairment associated with worse prognosis Combined prognostic and nutritional assessment
Ling et al. [35] Locally advanced HNC treated with CCRT PNI Platelet-to-lymphocyte ratio (PLR) Low PNI and elevated PLR identify high-risk patients Prognostic assessment
Tomasoni et al. [36] LA-HNC undergoing CCRT PNI SII/SIRI/RLR Poor immunonutritional status linked to adverse outcomes Prognostic assessment based on immunonutritional status
CONUT-based studies/reviews Mixed HNC cohorts CONUT score SII/SIRI/NLR Integrated immune-nutritional scores reflect systemic inflammation and malnutrition Nutritional risk assessment and prognostic stratification
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These findings support the concept that malnutrition and inflammatory activation represent interconnected clinical manifestations of tumor-driven hypermetabolism

From a practical perspective, no single biomarker is currently sufficient to identify tumor-driven malnutrition in routine clinical practice. Instead, a multimodal assessment combining clinical nutritional evaluation, body composition analysis (C3-derived skeletal muscle assessment when available), routinely accessible inflammatory biomarkers (e.g., CRP and NLR), and metabolic imaging parameters such as TLG in patients undergoing 18F-FDG PET/CT may provide a more comprehensive evaluation of nutritional risk. While IL-6 and other cytokines remain mainly research tools, CRP and NLR are inexpensive and widely available, and may support clinical decision-making when interpreted together with imaging and nutritional assessment rather than as standalone biomarkers.

Early immune-metabolic nutritional strategies in HNSCC

Beyond risk stratification and metabolic characterization, the recognition of cancer-related malnutrition as an immune-metabolic syndrome has important therapeutic implications. In patients with HNSCC undergoing radiotherapy or chemoradiotherapy, early nutritional intervention should not be interpreted solely as caloric supplementation but as a strategy aimed at modulating systemic inflammation and preserving functional body composition [38]. Current evidence, including the European Society for Clinical Nutrition and Metabolism (ESPEN) guidelines and available systematic reviews, supports early nutritional intervention as a cornerstone of multidisciplinary care in patients with HNSCC. Although immunonutrition enriched with arginine, omega-3 fatty acids, and nucleotides has shown promising effects on selected perioperative and treatment-related outcomes, the overall evidence remains heterogeneous with respect to patient selection, treatment setting, and nutritional formulations. Accordingly, while immunonutrition represents a promising adjunctive strategy, further adequately powered randomized studies are warranted before its routine use can be recommended beyond current guideline indications [39–41]. From a translational perspective, this approach aligns with the concept that nutritional support in HNSCC should target the immune-metabolic axis rather than focusing exclusively on oral intake.

Importantly, early intervention appears to be most effective when implemented during the pre-cachectic or early cachectic phases, when metabolic alterations remain potentially reversible [42]. Integration of nutritional therapy with oncologic treatment, pain control, and multidisciplinary supportive care may therefore represent a cornerstone of modern head and neck oncology, shifting the paradigm from reactive nutritional rescue to proactive metabolic management [43].

Patients with locally advanced HNSCC, high tumor metabolic burden, marked systemic inflammation, and early skeletal muscle depletion are particularly prone to developing tumor-driven immune-metabolic alterations. Additional clinical factors, including advanced age, poor performance status, HPV-negative disease, extensive smoking history, dysphagia, and multimodal treatments such as concurrent chemoradiotherapy, may further increase nutritional vulnerability by combining reduced oral intake with hypercatabolic metabolism. Early recognition of these high-risk features may facilitate timely nutritional assessment and personalized multimodal interventions.

From a clinical perspective, patients exhibiting tumor-driven metabolic and immune dysregulation should undergo early and individualized nutritional assessment to ensure adequate energy and protein provision. Although current ESPEN guidelines remain the reference for nutritional prescriptions, these patients often present with hypermetabolism, systemic inflammation, and accelerated skeletal muscle catabolism, suggesting that nutritional management should prioritize preservation of lean body mass rather than weight maintenance alone. Adequate protein intake, combined with sufficient energy provision and integrated multimodal supportive care, may help attenuate muscle loss, improve treatment tolerance, and support functional recovery, although nutritional support alone is unlikely to fully reverse the underlying immune-metabolic alterations.

Conclusions

Cancer-related malnutrition in HNSCC should no longer be interpreted solely as the consequence of reduced oral intake or treatment-related toxicity. Converging biological and clinical evidence supports a tumor-driven immune-metabolic model in which enhanced glycolysis, chronic inflammation, and systemic hypermetabolism progressively impair host tissue integrity. This immune-metabolic model is also consistent with the updated Hallmarks of Cancer framework, which recognizes metabolic reprogramming and the dynamic interplay between tumor cells and the host immune-inflammatory environment as key features of cancer progression. Framing cancer-related malnutrition within this broader biological context may facilitate the development of integrated metabolic and nutritional strategies capable of improving patient outcomes. Within this framework, metabolic substrate redistribution represents a measurable and clinically relevant manifestation of tumor–host interaction.

By integrating tumor metabolism, systemic inflammation, and imaging-based body composition assessment into a single conceptual framework, this review provides a translational perspective for earlier identification and management of cancer-related malnutrition in HNSCC.

Take-home messages

  • Cancer-related malnutrition in HNSCC is primarily driven by tumor-induced metabolic and inflammatory alterations rather than reduced intake alone.

  • The tumor behaves as a metabolic sink, promoting systemic substrate redistribution and energy wasting.

  • Sarcopenia reflects tumor-host biology and represents a robust prognostic biomarker beyond body weight.

  • Integration of tumor metabolic activity (e.g., TLG), C3-based muscle assessment, and inflammatory markers enables earlier risk stratification.

  • Early immune-metabolic nutritional intervention should be considered part of integrated oncologic care, not merely supportive supplementation.

Supplementary information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 21 kb) (21.2KB, docx)

Acknowledgements

The authors would like to thank the INT IRCCS Foundation G Pascale and the Ministry of Health for providing the funds (coming from PNRR) with which this manuscript was published and TRIAL Group.

Author contributions

A.P. contributed to writing the paper and revised the final version of the manuscript; V.Z. contributed to writing the paper and revised the final version of the manuscript and conceived the work; M.L.M. contributed to writing the paper and revised the final version of the manuscript; F.R.R. contributed to writing the paper and revised the final version of the manuscript; M.P. contributed to writing the paper and revised the final version of the manuscript; E.P. contributed to writing the paper and revised the final version of the manuscript; F.P. wrote the main manuscript text, conceived the work and revised the final version of the manuscript.

Funding

This work was funded by the European Union – NextGenerationEU under the National Recovery and Resilience Plan (NRRP), Mission 6 – Health, Component 2, Investment 2.1 “Strengthening and enhancement of NHS biomedical research”, Project Code PNRR-TR1-2023-12377022, CUP Master B13C24001080006, CUP Istituto Nazionale Tumori IRCCS Fondazione G. Pascale H63C24000410006. Inline graphic

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval

Not applicable because this study is based exclusively on published literature.

Competing interests

The authors declare no competing interests.

Footnotes

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplementary file1 (DOCX 21 kb) (21.2KB, docx)

Data Availability Statement

No datasets were generated or analysed during the current study.

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