Advances and challenges in immunotherapy in head and neck cancer

Abstract

Head and neck squamous cell carcinoma (HNSCC) remains a challenging malignancy with suboptimal survival outcomes despite advances in surgery, radiotherapy, and chemotherapy. Immunotherapy, particularly immune checkpoint inhibitors (ICIs) targeting programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1), has transformed treatment paradigms, yet its full potential in HNSCC is still being explored. This review evaluates the current landscape of immunotherapy in both locally advanced (LA) and recurrent/metastatic (R/M) HNSCC, discussing key clinical trials, emerging biomarkers, and novel therapeutic strategies. For LA HNSCC, phase III trials such as KEYNOTE-412 and JAVELIN Head and Neck 100 failed to demonstrate survival benefits with ICI-chemoradiotherapy combinations in unselected populations, though post hoc analyses suggest efficacy in PD-L1-positive tumors. Recent studies, including KEYNOTE-689 and NIVOPOSTOP GORTEC 2018-01, indicate potential benefits of perioperative ICIs in resectable disease. In R/M HNSCC, ICIs have redefined the standard of care. KEYNOTE-040 and CheckMate 141 led to Food and Drug Administration (FDA) approvals of pembrolizumab and nivolumab, while KEYNOTE-048 established pembrolizumab monotherapy for PD-L1 combined positive score (CPS) ≥1 and pembrolizumab plus chemotherapy as first-line treatment. However, dual checkpoint blockade trials (KESTREL, CheckMate 651) have yielded mixed results, highlighting the complexity of immune resistance. Beyond ICIs, emerging strategies include oncolytic virotherapy, chimeric antigen receptor-T cell therapy (CAR-T), and cancer vaccines, with promising preclinical and early-phase clinical results. Biomarkers such as PD-L1 expression, tumor mutational burden (TMB), and Human Papillomavirus (HPV) status play a critical role in treatment selection, but further validation is needed. Despite advancements, challenges persist, including heterogeneous response rates, immune-related toxicities, and optimal integration of immunotherapy in multimodal treatment regimens. Future research should focus on refining biomarker-driven treatment algorithms, developing rational immunotherapy combinations, and leveraging tumor microenvironment modifications to enhance therapeutic efficacy.

Keywords: chemoradiotherapy; head and neck squamous cell carcinoma; immune checkpoint inhibitors; immunotherapy; locally advanced; radiotherapy; recurrent/metastatic.

Figure 1

Composition of the tumor immune microenvironment. The tumor microenvironment (TME) consists of various immune cells, stromal cells, and cytokines. Immune cells within the TME may include neutrophils, CD8+ T cells, dendritic cells (DCs), and natural killer (NK) cells. The composition of the TME can influence biomarker expression and the efficacy of immune checkpoint inhibitors. A “cold” tumor microenvironment is characterized by low immune cell infiltration, often referred to as an immune desert or immunosuppressive environment. It may contain a higher proportion of immunosuppressive cells, such as tumor-associated macrophages (TAMs) and regulatory T (Treg) cells. The scarcity of T cell targets can reduce the effectiveness of immune checkpoint inhibitors, such as PD-1 inhibitors. A “hot” tumor microenvironment is enriched with immune cells, such as CD8+ T cells, increasing the availability of biomarkers like PD-1. In this setting, cytotoxic T cells can effectively recognize and eliminate cancer cells, enhancing antitumor immunity. Understanding the immune composition of the TME and its impact on therapeutic response is a critical aspect of oncology research. CAF, cancer-associated fibroblast; DC, dendritic cell; MHC, major histocompatibility complex; NK cell, natural killer cell; TAM, tumor-associated macrophage; TCR, T cell receptor; TME, tumor microenvironment; Treg cell, T regulatory cell. Created in BioRender. Thein, K. (2025) https://BioRender.com/t08e962.

Figure 2

PD-1 / PD-L1 expression and immune checkpoint inhibition. PD-1 is a key biomarker for targeting head and neck cancers. PD-1 receptors are expressed on T cells, while PD-L1 receptors are found on cancer cells. Effective T cell activation also requires the presence of the T cell receptor (TCR) and the major histocompatibility complex (MHC). In the absence of immune checkpoint inhibition (top panel), PD-1 binds to PD-L1, leading to T cell inactivation. This suppresses immune surveillance, allowing cancer cells to evade detection and proliferate. With immune checkpoint inhibitors (bottom panel), such as antibodies targeting PD-1 or PD-L1, T cell inactivation is blocked. As a result, more T cells remain active, enhancing tumor cell recognition and elimination. Created in BioRender. Thein, K. (2025) https://BioRender.com/t08e962.

Figure 3

mPFS/EFS of key clinical trials in LA HNSCC. The graph represents an overview of mPFS/EFS among 5 clinical trials, with comparison between experimental and control groups in patients with LA HNSCC. The data for median overall survival were not represented as results were not reached. mPFS (median progression-free survival), EFS (event-free survival), LA HNSCC (locally advanced head and neck squamous cell carcinoma). Created in BioRender. Thein, K. (2025) https://BioRender.com/l8wlnx3.

Figure 4

Data for clinical trials in R/M HNSCC. The figure represents key data for clinical trials in recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC). The top graph compares ORR across the different trials. The middle graph compares mPFS, and the bottom graph compares mOS. R/M HNSCC, recurrent/metastatic head and neck squamous cell carcinoma; ORR, objective response rate; mPFS, median progression-free survival; mOS, median overall survival; CPS, combined positive score; PD-L1, programmed cell death-ligand 1. Created in BioRender. Thein, K. (2025) https://BioRender.com/l8wlnx3.

Figure 5

Novel immunotherapy agents for head and neck cancers. Several novel immunotherapy options are being explored for head and neck cancers. The main categories of these agents include oncolytic virus therapies, cancer vaccines, adoptive cell therapy, and immunomodulators. Adoptive cell therapy encompasses approaches such as chimeric antigen receptor T (CAR-T) cell therapy, which enhances T cell recognition of tumor cells. Immunomodulators include checkpoint inhibitors, such as PD-1 and PD-L1 inhibitors, as well as cytokine modulators that regulate immune responses. These emerging therapies offer promising strategies to improve immune system activation against head and neck cancers. Created in BioRender. Thein, K. (2025) https://BioRender.com/t08e962.