Inﬂammation as a master regulator of immunotherapy response in head and neck squamous cell carcinoma - from malignant transformation to ecology-aware precision combinations

Sep 22, 2026

In the immunotherapy era, head and neck squamous cell carcinoma shows clear benefits from immune-based treatment yet also exhibits variability in response. Robust, persistent inflammatory programs drive tumor initiation and progression while simultaneously creating therapeutic vulnerabilities and barriers by reshaping immune-cell states and the tumor immune microenvironment. This review explains how chronic inflammatory cues rewire immune signaling and tissue architecture, catalogues inflammation-linked pathways, biomarkers, and micro-niche interactions, and outlines ecology-aware precision combinations to improve outcomes.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages19

Reading Time48 min

AccessFree to download

Introduction

Inﬂammation, immunity, and tumor biology framework

Immune cell reprogramming under inflammatory pressure

Inﬂammation-linked pathways and biomarkers

Pathological interplay across tumor, stromal, and immune compartments

Translational directions for precision immunotherapy

TYPE Review PUBLISHED 17 July 2026 DOI 10.3389/fimmu.2026.1798938 OPEN ACCESS EDITED BY Shisong Jiang, University of Oxford, United Kingdom REVIEWED BY Chen Feng, Shandong University, China Roberto Rangel, University of Texas MD Anderson Cancer Center, United States *CORRESPONDENCE Jia Gu [gujia19840128@aliyun.com](gujia19840128@aliyun.com)[ ](gujia19840128@aliyun.com)Zhaozhe Liu [lzz_summer@126.com](lzz_summer@126.com)[ ](lzz_summer@126.com)Zhenguang Du [bone_tumor@sina.com](bone_tumor@sina.com)[ ](bone_tumor@sina.com)†These authors have contributed equally to this work and share ﬁrst authorship RECEIVED 29 January 2026 REVISED 05 June 2026 ACCEPTED 26 June 2026 PUBLISHED 17 July 2026 CITATION Han Y, Wu P, Song H, Yu R, Liu R, Du Z, Liu Z and Gu J (2026) Inﬂammation as a master regulator of immunotherapy response in head and neck squamous cell carcinoma: from malignant transformation to ecology-aware precision combinations. Front. Immunol. 17:1798938 . doi: 10.3389/fimmu.2026.1798938 COPYRIGHT © 2026 Han, Wu, Song, Yu, Liu, Du, Liu and Gu. 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. Inﬂammation as a master regulator of immunotherapy response in head and necksquamous cell carcinoma: from malignant transformation to ecology-aware precision combinations Yingchen Han 1†, Peihong Wu 1†, Haoran Song 1†, Ruoxi Yu 2, Ruotong Liu 3, Zhenguang Du 4*, Zhaozhe Liu 5* and Jia Gu 2* 1 Department of Medical Oncology, The First Afﬁliated Hospital of China Medical University, Shenyang, Liaoning, China, 2 Department of Otolaryngology, The First Afﬁliated Hospital of China Medical University, Shenyang, Liaoning, China, 3Shenyang Medical College, Shenyang, Liaoning, China, 4 Department of Interventional Medicine, Liaoning Provincial People’s Hospital, Shenyang, Liaoning, China, 5 Department of Oncology, General Hospital of the Northern Theater Command, Shenyang, Liaoning, China In the era of immunotherapy, head and neck squamous cell carcinoma (HNSCC) has demonstrated clear beneﬁts from immune-based treatments and is widely regarded as a tumor type with high immunotherapeutic potential. These tumors are characterized by robust and persistent inﬂammatory responses that actively drive tumor initiation and progression while concurrently shaping their sensitivity or resistance to therapy. Inﬂammation simultaneously creates therapeutic vulnerabilities and barriers by altering tumor behavior and reprogramming the immune microenvironment. This review examined HNSCC through a tripartite prism of inﬂammation, immunity, and tumor biology to demonstrate how chronic inﬂammatory cues rewire immune cells, reshape signaling circuits, and remodel tissue architecture, ultimately altering responses to immunotherapy. We ﬁrst examined how immune cell reprogramming occurs under inﬂammatory pressure. Macrophages, regulatory T cells, exhausted CD8+ T cells, and specialized dendritic cell subsets can switch roles—from tumor-clearing sentinels to promoters of tumor growth, stemness, and invasion. This plasticity—sometimes transient, sometimes entrenched—determines whether the immune ecosystem favors elimination or tolerance, and consequently whether immune checkpoint blockade succeeds or fails. Next, we catalogued the inﬂammation-linked pathways and readouts that capture these state changes. Signaling hubs such as NF-kB/STAT3, IL-6/TNFa, TGF-b, HA-CD44, and PI3K-4EBP1-SOX2 orchestrate the trade-offs between proliferation and invasion and govern cancer stem cell dynamics. Corresponding biomarkers—PD-L1, C

FAQs

Why does inflammation strongly influence immunotherapy response in HNSCC?

Inflammation is robust and persistent in HNSCC, driving tumor initiation and progression while also altering immune-cell behavior and the immune microenvironment. This can create both therapeutic vulnerabilities and resistance barriers.

Which immune cells and dendritic cell subsets are highlighted as plastic under inflammatory pressure?

Macrophages, regulatory T cells, exhausted CD8+ T cells, and specialized dendritic cell subsets can switch roles between tumor-clearing functions and promoters of tumor growth, stemness, and invasion.

How does the review connect specific signaling pathways and biomarkers to immune-state changes?

It links pathways such as NF-kB/STAT3, IL-6/TNFa, TGF-b, HA-CD44, and PI3K-4EBP1-SOX2 to trade-offs governing proliferation, invasion, and cancer stem cell dynamics. Corresponding biomarkers (e.g., PD-L1 and myeloid-related ratios) become more informative when resolved at single-cell and spatial scales for patient stratification.

Sep 22, 2026

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