Immunotherapeutic strategies in head and neck cancer: challenges and opportunities
Xia Liu, … , Sidharth V. Puram, Guangyong Peng
Xia Liu, … , Sidharth V. Puram, Guangyong Peng
Published April 15, 2025
Citation Information: J Clin Invest. 2025;135(8):e188128. https://doi.org/10.1172/JCI188128.
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Review

Immunotherapeutic strategies in head and neck cancer: challenges and opportunities

Abstract

HNSCC remains a substantial health issue, with treatment options including surgery, radiation, and platinum-based chemotherapy. Unfortunately, despite progress in research, only modest gains have been made in disease control, with existing treatments resulting in significant functional and quality-of-life issues. The introduction of immunotherapy in the treatment of HNSCC has resulted in some improvements in outlook for patients and is now standard of care for populations with both recurrent and metastatic disease. However, despite the early successes, responses to immune checkpoint inhibition (ICI) remain modest to low, approaching 14%–22% objective response rates. Challenges to the effectiveness of ICI and other immunotherapies are complex, including the diverse and dynamic molecular plasticity and heterogeneity of HNSCCs; lack of immunogenic antigens; accumulated suppressive immune populations such as myeloid cells and dysfunctional T cells; nutrient depletion; and metabolic dysregulation in the HNSCC tumor microenvironment. In this Review, we explore the mechanisms responsible for immunotherapy resistance, dissect these challenges, and discuss potential opportunities for overcoming hurdles to the development of successful immunotherapy for HNSCC.

Authors

Xia Liu, R. Alex Harbison, Mark A. Varvares, Sidharth V. Puram, Guangyong Peng

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Figure 1

Mechanisms driving resistance to immune checkpoint blockade therapy in HNSCC.

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Mechanisms driving resistance to immune checkpoint blockade therapy in H...
The potential mechanisms driving resistance to antitumor immune responses are illustrated. Overcoming immune-suppressive populations including Tregs, Bregs, tumor-associated macrophages (TAMs), tumor-associated neutrophils (TANs), myeloid-derived suppressor cells (MDSCs), and cancer-associated fibroblasts (CAFs), as well as immune plasticity, will be critical for enhancing the response to immunotherapy and antitumor immunity. Defining cell-intrinsic features of HPV-related and carcinogen-driven (e.g., smoking) HNSCC will also be fundamental for reducing their tumor-intrinsic immune-suppressive capacity and immune escape mechanisms. Dysfunctional T cells generated by chronic antigen stimulation or T cell senescence induced by the tumor metabolome, proteome, and chemokine/cytokine milieu also impair the effectiveness of the immune response in HNSCC. Inadequate T cell costimulation drives T cell anergy, further impairing this response. Less-well-understood mechanisms driven by metabolic dysregulation impact the antitumor immune response in the tumor microenvironment, for which further work is warranted.