A groundbreaking study published in BMC Cancer unveils the intricate relationship between lactate metabolism and immune dynamics in head and neck squamous cell carcinoma (HNSCC), offering new hope for improved prognostic tools and targeted therapies. By harnessing integrated multi-omics approaches, researchers have identified specific gene signatures linked to lactate metabolism that not only predict patient outcomes but also shed light on the tumor microenvironment’s immunological landscape. This comprehensive investigation underscores the pivotal role of the gene PYGL, highlighting its potential both as a biomarker and a therapeutic target in combating this challenging cancer type.
HNSCC remains a formidable clinical challenge due to its aggressive nature and limited response to traditional treatments. The metabolic rewiring of cancer cells—particularly the aberrant accumulation and utilization of lactate—has been recognized as a hallmark of various malignancies, influencing tumor progression and immune evasion. Lactate, once considered a mere metabolic byproduct, is now understood to shape the tumor microenvironment (TME) profoundly, orchestrating immune cell behavior and facilitating immune suppression. Despite these insights, the prognostic relevance of lactate metabolism-related genes (LMRGs) in HNSCC and their interplay with immune components remained poorly characterized until now.
The authors embarked on an ambitious effort to construct a robust prognostic model based on the expression patterns of LMRGs. By analyzing extensive patient datasets through integrative genomic and transcriptomic profiling, they developed a multigene signature capable of stratifying patients into discrete risk categories with significantly different overall survival (OS) and progression-free survival (PFS) outcomes. This signature provides clinicians with a powerful tool to identify high-risk patients who may benefit from intensified or tailored therapeutic interventions.
Delving deeper, the study evaluated how this lactate-centric signature correlates with the immune milieu within tumors. The low-risk group, characterized by diminished lactate metabolism, demonstrated notably higher infiltration of CD8+ T cells, potent effectors of anti-tumor immunity. This immunologically "hot" phenotype aligns with a more favorable prognosis and suggests that metabolic modulation could potentiate immune responses. Conversely, tumors in the high-risk category exhibited metabolic profiles conducive to immune suppression, denoting a "cold" microenvironment less amenable to immune clearance.
To unravel cellular heterogeneity within the TME, the researchers employed state-of-the-art single-cell sequencing technologies. This approach revealed remarkable insights: tumor cells displayed the highest lactate metabolic activity among all cell types in the microenvironment, indicating their metabolic dominance and potential contribution to immune suppression. Such granular data emphasize that targeting tumor-specific metabolic pathways holds substantial promise for altering TME dynamics.
Central to the study’s findings is the identification of PYGL, a gene encoding glycogen phosphorylase, liver form, as the most critical prognostic factor within the LMRG signature. Fascinatingly, PYGL was predominantly expressed not only in tumor cells but also in tumor-associated macrophages (TAMs), a key immune subset implicated in cancer progression. The functional role of PYGL in TAMs appears to involve the suppression of M1 macrophage polarization—the phenotype typically associated with inflammatory and tumoricidal functions—thereby skewing the immune microenvironment toward a more tumor-permissive state.
Experimental knockdown of PYGL in vitro yielded compelling evidence of its functional importance: reduced PYGL levels led to decreased lactate production, supporting the gene’s direct involvement in metabolic regulation. Moreover, PYGL expression inversely correlated with CD8+ T cell presence in tumors, reinforcing its role in shaping immune exclusion. These findings illuminate a novel mechanism by which tumor metabolism intersects with immune cell function to influence cancer progression.
Intriguingly, the study also implicated PYGL in copper-dependent cell death pathways, a less explored avenue of cancer biology. This connection suggests that PYGL’s involvement in cell viability extends beyond metabolism, potentially linking to metal-ion homeostasis and programmed cell death mechanisms. The dual role of PYGL may thus represent an Achilles’ heel exploitable for therapeutic gain.
In pursuit of translational impact, the researchers utilized in silico drug screening methods to identify compounds targeting PYGL. Elesclomol, a copper ionophore known for inducing oxidative stress and cell death, emerged as a promising candidate. Treatment with elesclomol demonstrated enhanced efficacy in PYGL-knockdown cells, underscoring the potential for combinatorial strategies that disrupt metabolic and cell death pathways simultaneously.
This comprehensive study advances our understanding of how lactate metabolism influences tumor biology and immune interactions in HNSCC. The prognostic gene signature offers a novel biomarker panel with immediate clinical applicability, guiding personalized medicine efforts. Simultaneously, the elucidation of PYGL’s multifaceted role unlocks new therapeutic avenues, potentially enhancing the efficacy of existing immunotherapies by overcoming metabolic barriers.
Beyond its immediate findings, this research exemplifies the power of integrating multi-omics data and single-cell analyses to decode complex cancer ecosystems. As precision oncology continues to evolve, such integrative approaches will be vital in uncovering hidden vulnerabilities within tumors, tailoring treatments to individual patient profiles, and ultimately improving survival outcomes.
Given the immunosuppressive effects of lactate accumulation within the TME, strategies aiming to inhibit PYGL or modulate lactate pathways could revitalize anti-tumor immunity. This approach aligns with broader efforts to counteract metabolic checkpoints that tumors exploit to escape immune surveillance. By normalizing metabolic imbalances, therapy may shift the TME towards an environment conducive to robust immune activation.
The discovery that PYGL suppression enhances sensitivity to elesclomol also opens the door for repurposing existing drugs or developing novel agents focused on metabolic regulation. Clinical trials designed to test such combinations in HNSCC patients, particularly those identified by the prognostic signature as high-risk, could transform treatment paradigms.
Moreover, the link between PYGL and copper-dependent cell death introduces a fresh perspective on metabolic vulnerabilities. Targeting metal ion homeostasis within tumors could complement immunotherapeutic strategies, fostering an integrated attack on cancer cells. This multifactorial approach underscores the complexity of tumor biology and the necessity for multi-pronged interventions.
In conclusion, the integration of multi-omics data has unearthed critical insights into how lactate metabolism governs immune landscapes and influences the clinical trajectory of HNSCC. PYGL stands out as a linchpin in this network, simultaneously mediating metabolic fluxes, immune modulation, and cell death pathways. These findings herald a new era of targeted therapies designed to disrupt metabolic crosstalk within tumors and enhance immunotherapy effectiveness, promising improved outcomes for patients battling head and neck cancers.
Subject of Research: Head and neck squamous cell carcinoma (HNSCC) lactate metabolism and immune microenvironment.
Article Title: Integrated multi-omics reveal lactate metabolism-related gene signatures and PYGL in predicting HNSCC prognosis and immunotherapy efficacy.
Article References:
Chen, X., Jiang, Z., Pan, J. et al. Integrated multi-omics reveal lactate metabolism-related gene signatures and PYGL in predicting HNSCC prognosis and immunotherapy efficacy. BMC Cancer 25, 773 (2025). https://doi.org/10.1186/s12885-025-13982-8
Image Credits: Scienmag.com
