Dear Editor, Professor Lee Peng Karen-Ng,
I read with great interest the recently published review by Qin et al. titled “Immune-metabolic crosstalk in HNSCC: mechanisms and therapeutic opportunities” in Frontiers in Oncology (). I would like to commend the authors for their comprehensive and insightful synthesis of current knowledge on the complex interplay between metabolic reprogramming and immune regulation in HNSCC (Head and neck squamous cell carcinoma).
This review effectively highlighted the metabolic adaptations within the tumor microenvironment—such as glycolysis, fatty acid oxidation, amino acid metabolism, and adenosine signaling—and their roles in shaping immunosuppressive landscapes. The authors also underscored the relevance of key signaling pathways (PI3K/Akt/mTOR, NF-κB, PD-1/PD-L1) that linked metabolic and immune modulation, offering a compelling rationale for combinatorial therapeutic strategies.
Importantly, the review identified several potential therapeutic targets and ongoing clinical trials, reflecting the translational potential of immunometabolic interventions in HNSCC. This focused on actionable targets, such as glycolysis inhibitors, adenosine pathway antagonists, and mTOR inhibitors, was particularly timely given the challenges of resistance to current ICB (Immune checkpoint blockade) therapies.
While the review was thorough, I would like to offer a few additional suggestions:
Though the introduction of ICB therapies (e.g., anti PD-1/PD-L1 agent) to oncology can transform the management of various malignancies, including HNSCC, the application of anti PD-1/PD-L1 agent alone cannot achieve favorable survival rate of patients with targeted cancer (). As authors say, amino acid plays a vital role in immune regulation in HNSCC. Arginase-1 is a cytosolic enzyme originally isolated from the liver and found in the TME of most solid tumors, including HNSCC (). It not only has direct effects on tumor growth, but also further fosters tumorigenesis by inducing immune suppression (). OATD-02, a new boronic acid derivative, is the only dual inhibitor, which can address the benefits of pharmacological inhibition of arginase 1 and 2 in cancer (). Whether OATD-02 can enhance the anti-cancer effect of ICB therapies on HNSCC through immune-metabolic crosstalk signal should considered in the future. First, three group OATD-02+ICB, ICB, and control will be set for cell apoptosis, proliferation, and drug resistance trials in HNSCC cells. Next, co-cultivation of T-cell and tumor cell can be conducted to examine the bioactivity of immune cells. In addition, PI3K-AKT-mTOR signaling should be implemented to test for activation. Finally, bare mouse tumor formation test can be conducted in vivo.
Overall, authors have produced a highly valuable reference for clinicians and researchers aiming to develop new strategies to overcome immunotherapy resistance in HNSCC.
Statements
Author contributions
JC: Validation, Formal analysis, Methodology, Writing – review & editing, Data curation, Supervision, Project administration, Conceptualization, Software, Investigation, Writing – original draft, Resources, Visualization, Funding acquisition.
Funding
The author(s) declare that no financial support was received for the research and/or publication of this article.
Conflict of interest
The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Generative AI statement
The author(s) declare that Generative AI was used in the creation of this manuscript. The author would like to thank ChatGPT for its assistance in the preparation of this letter.
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Correction note
A correction has been made to this article. Details can be found at: 10.3389/fonc.2026.1806068.
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All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
References
1
QinXWuHPanJKangKShiYBuS. Immune-metabolic crosstalk in HNSCC: mechanisms and therapeutic opportunities. Front Oncol. (2025) 15:1553284. doi: 10.3389/fonc.2025.1553284
2
GoetzJWRabinowitsGKalmanNVillaA. A review of immunotherapy for head and neck cancer. J Dent Res. (2024) 103:1185–96. doi: 10.1177/00220345241271992
3
Süer GökmenSYörükYCakirEYorulmazFGülenS. Arginase and ornithine, as markers in human non-small cell lung carcinoma. Cancer Biochem Biophys. (1999) 17:125–31.
4
SinghRPervinSKarimiACederbaumSChaudhuriG. Arginase activity in human breast cancer cell lines: N(omega)-hydroxy-L-arginine selectively inhibits cell proliferation and induces apoptosis in MDA-MB-468 cells. Cancer Res. (2000) 60:3305–12.
5
GrzybowskiMMStańczakPSPomperPBłaszczykRBorekBGzikAet al. OATD-02 validates the benefits of pharmacological inhibition of arginase 1 and 2 in cancer. Cancers (Basel). (2022) 14:3967.
Summary
Keywords
HNSCC, TME, ICB, metabolic reprogramming, crosstalk
Citation
Chen J (2025) General Commentary: Immune-metabolic crosstalk in HNSCC: mechanisms and therapeutic opportunities. Front. Oncol. 15:1662713. doi: 10.3389/fonc.2025.1662713
Received
16 July 2025
Accepted
03 September 2025
Published
12 September 2025
Corrected
17 February 2026
Volume
15 - 2025
Edited by
Alberto Rodriguez-Archilla, University of Granada, Spain
Reviewed by
Jesús Jareb Benito-Lopez, National Institute of Respiratory Diseases-Mexico (INER), Mexico
Updates
Copyright
© 2025 Chen.
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Jiayi Chen, cjy13912736738@163.com
Disclaimer
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.