Advances in Immunotherapy for Head and Neck Squamous Cell Carcinoma: Focus on PD-1/PD-L1 Blockade and Beyond

Abstract

Head and neck squamous cell carcinoma (HNSCC) ranks as the seventh most common cancer globally, with etiological subtypes—carcinogen-driven (human papillomavirus [HPV-negative]) and HPV-driven—shaping tumor immunogenicity and treatment responses. This review highlights immunotherapy’s evolution, focusing on PD-1/PD-L1 blockade. HPV-positive tumors feature a “hot” microenvironment with dense tumor-infiltrating lymphocytes (TILs) and PD-L1 upregulation, yielding better immune checkpoint inhibitor (ICI) outcomes. In contrast, HPV-negative cases exhibit a “cold,” immunosuppressive profile with inferior ICI responses. Landmark trials like KEYNOTE-048 and CheckMate 141 established pembrolizumab and nivolumab as standards for recurrent/metastatic HNSCC, improving median OS (overall survival) by 2 to 4 months over the EXTREME regimen (cetuximab plus platinum-based chemotherapy), especially in patients with PD-L1 Combined Positive Score (CPS) ⩾ 1. Combination strategies enhance efficacy through multiple mechanisms: chemotherapy induces immunogenic cell death, radiotherapy elicits abscopal effects, and cetuximab provides additional antitumor activity. In locally advanced disease, the KEYNOTE-689 trial demonstrated superior event-free survival with perioperative pembrolizumab versus placebo (59.7 vs 29.6 months), supporting treatment de-escalation strategies. Management of immune-related adverse events follows established NCCN/SITC guidelines. Emerging therapies, including anti-LAG-3/TIM-3 and oncolytic viruses, target resistance. Future efforts emphasize multiomic biomarkers and equitable access to optimize outcomes in this heterogeneous malignancy.

Introduction: The Evolving Landscape of Head and Neck Squamous Cell Carcinoma

Head and neck squamous cell carcinoma (HNSCC) is a global tumor disease burden, ranking as the seventh most diagnosed cancer worldwide.^1,2 Global cancer statistics (GLOBOCAN) estimate that HNSCC accounts for about 4.5% (900 000 new diagnoses and 450 000 deaths each year) of all cancer cases globally. ³ HNSCC incidence and mortality show geographic and socioeconomic gaps, hitting hardest in developing countries—especially South and Southeast Asia—thanks to widespread substance use, including smoking, tobacco chewing, and betel quid. ⁴ In India, for example, HNSCC is associated with elevated prevalence, incidence, and mortality rates, with lip and oral cavity cancers being the predominant subtype. By 2050, incident cases are anticipated to rise markedly, with the greatest proportional increases projected for oropharyngeal (103.9%), laryngeal (103.8%), and hypopharyngeal (98.8%) cancers. ⁵ These trends showed the epidemiological profile influenced by regional etiological reasons. Global data demonstrate a dichotomy in HNSCC patterns: in low- and middle-income countries, carcinogen-associated disease remains predominant, while in high-income countries, human papillomavirus (HPV)-associated oropharyngeal cancers have begun to exceed tobacco-attributable cases. ⁶ This disparity extends beyond epidemiology: carcinogen-driven and HPV-driven HNSCC constitute 2 biologically distinct entities with divergent tumor immunogenicity and therapeutic responses to immunotherapy.

Dueling Etiologies: Carcinogen-Driven Versus HPV-Driven HNSCC

Head and neck squamous cell carcinoma is not a monolithic disease but rather a collection of malignancies defined by 2 primary and distinct etiological pathways: chronic exposure to carcinogens and persistent infection with high-risk HPV.^7,8

Carcinogen-Driven (HPV-Negative) HNSCC is predominantly caused by exposure to tobacco and excessive alcohol consumption. ⁹ These 2 risk factors act synergistically, with heavy use of both increasing the risk of developing HNSCC by as much as 40-fold. Together, tobacco and alcohol are implicated in at least 75% of all HNSCC cases, particularly those arising in the oral cavity, larynx, and hypopharynx. Other significant risk factors, especially prevalent in certain geographic regions, include the chewing of betel quid and areca nut, as well as poor diet and specific occupational exposures. These tumors are characterized by a high burden of somatic mutations accumulated over years of carcinogen exposure, with frequent alterations in key tumor suppressor genes such as TP53.

Human papillomavirus–driven HNSCC is caused by persistent infection of high-risk HPV strains (most notably HPV-16 ¹⁰ and, less frequently, HPV-18). ¹¹ This etiology is associated with squamous cell carcinomas arising in the oropharynx, mainly the tonsils and the base of the tongue. In many developed countries, including the United States, HPV-positive oropharyngeal cancer is now the fastest-growing subtype of HNSCC. The molecular pathogenesis of HPV-positive tumors is fundamentally different from their HPV-negative counterparts. Carcinogenesis is driven by the expression of 2 viral oncoproteins, E6 and E7. The E6 protein targets the tumor suppressor gene p53 for degradation, while the E7 protein inactivates the retinoblastoma protein (pRb), leading to uncontrolled cell cycle progression and genomic instability.

These distinct etiologies give rise to 2 separate clinical entities. Patients with HPV-positive HNSCC are often younger, may have no history of tobacco or alcohol use, and present with a disease that has a markedly better prognosis. Large cohort studies, including data from the Surveillance, Epidemiology, and End Results (SEER) database, have consistently demonstrated superior survival outcomes for this group. For example, patients with HPV-positive HNSCC exhibit a 5-year overall survival (OS) rate of about 75%, in contrast to 48% among those with HPV-negative disease. This survival advantage reflects the different immunobiological features of the tumor rather than mere chance. Sustained presentation of viral antigens E6 and E7 confers greater inherent immunogenicity to these tumors, as their foreign nature provokes a heightened host antitumor immune response—albeit one frequently dampened by the tumor itself—that creates an opportune setting for immunotherapeutic strategies. This biological principle explains why HPV status has become a critical stratification factor in HNSCC clinical trials and provides a powerful rationale for the transformative impact of immunotherapy in this disease. ¹²

The Preimmunotherapy Era: Foundational Treatment Modalities

Prior to the advent of effective immunotherapy, the standard of care for HNSCC was a grueling, multimodality regimen centered on surgery, radiotherapy (RT), and platinum-based chemotherapy.^13-15 For patients with resectable locally advanced disease, treatment typically involved surgical resection followed by risk-adapted adjuvant RT, often with concurrent high-dose cisplatin for high-risk pathological features. In cases of unresectable disease, or when organ preservation was a primary goal (eg, laryngeal cancer), definitive chemoradiotherapy (CRT) with concurrent cisplatin was the established standard. ¹⁶

In patients with recurrent or metastatic HNSCC (R/M HNSCC), the prognosis remains dismal, marked by a median OS of just 7 to 10 months. The established first-line therapy in this context is the EXTREME regimen, comprising cetuximab—an estimated glomerular filtration rate (EGFR)-directed monoclonal antibody—combined with a platinum compound and 5-fluorouracil (5-FU). Although this approach yields a limited extension in survival relative to chemotherapy alone, it also increases toxicity effects.

Even with such interventions, the 5-year survival rate in advanced HNSCC remains suboptimal, ranging from 40% to 50%. These therapies often induce substantial acute and chronic adverse effects, resulting in lasting deficits in speech, deglutition, and quality of life. This landscape of high unmet clinical need and substantial treatment-related morbidity underscored the urgency of developing novel therapeutic strategies with improved efficacy and a more favorable safety profile, setting the stage for the immunotherapy revolution,^17,18 as illustrated in the timeline Figure 1.

Figure 1.

Timeline of Key Immunotherapy Milestones in Head and Neck Squamous Cell Carcinoma (HNSCC). This timeline depicts major milestones in the development and approval of immunotherapy for HNSCC from 2016 onward, highlighting pivotal trials, approvals, and ongoing research. Key events include: 2016—Initial FDA approvals of PD-1 inhibitors (eg, nivolumab based on CheckMate 141 ¹⁹ and pembrolizumab accelerated approval via KEYNOTE-012/040) for recurrent/metastatic (R/M) HNSCC; 2019—KEYNOTE-048 results establishing pembrolizumab (monotherapy for PD-L1 CPS ⩾ 1 or in combination with chemotherapy) as first-line standard for R/M HNSCC; 2023/2024—IMvoke010 trial reports negative results, showing no event-free survival (EFS) benefit with adjuvant atezolizumab after definitive local therapy in high-risk locally advanced (LA) HNSCC; 2025—KEYNOTE-689 demonstrates positive EFS (median 59.7 vs 29.6 months in PD-L1 CPS ⩾ 1) with neoadjuvant/adjuvant pembrolizumab plus standard-of-care, ²⁰ leading to FDA approval in June 2025 for resectable LA HNSCC; Ongoing trials include LiGeR-HN1 (NCT06525220), a phase 3 study evaluating petosemtamab (EGFR/LGR5 bispecific antibody) plus pembrolizumab versus pembrolizumab alone in first-line PD-L1-positive R/M HNSCC, following breakthrough therapy designation in February 2025 based on phase 2 data showing a 67% objective response rate. The gradient shading represents progression from historical to emerging developments.

This narrative review aims to provide a comprehensive and updated synthesis of the transformative role of immunotherapy in HNSCC, with a primary focus on PD-1/PD-L1 blockade while extending to combination strategies and emerging approaches. The rationale for this review stems from the rapid evolution of the field, marked by landmark clinical trials, mechanistic insights into the tumor immune microenvironment (TIME), and the extension of immunotherapy to curative setting, coupled with persistent challenges in overcoming resistance and achieving equitable outcomes in this etiologically heterogeneous malignancy.

The article is structured as follows to guide the reader through this landscape: we begin with an overview of HNSCC epidemiology, etiological dichotomy, and the preimmunotherapy treatment era (section “Introduction: The Evolving Landscape of Head and Neck Squamous Cell Carcinoma”), followed by a detailed examination of the TIME and the immunological contrast between HPV-positive and HPV-negative disease (section “The Immunological Battlefield: HNSCC and Its Microenvironment”). Subsequent sections delineate the mechanism of PD-1/PD-L1 blockade and evidence from pivotal clinical trials (section “PD-1/PD-L1 Blockade in HNSCC: Clinical Evidence and Key Trials”), combination strategies with chemotherapy, RT, and targeted agents (section “Combination Strategies to Enhance Efficacy”), extension to neoadjuvant and adjuvant paradigms (section “Moving Immunotherapy to Earlier Lines of Treatment”), management of immune-related adverse events (section “Clinical Considerations: Management of Immune-Related Adverse Events (irAEs)”), and promising emerging therapies (section “The Next Wave: Emerging Agents and Future Therapeutic Targets”). The review concludes with a discussion of ongoing challenges (section “Discussion”), overall conclusions (section “Conclusions”), and forward-looking directions to optimize personalized immunotherapy in HNSCC (section “Future Directions”).

The Immunological Battlefield: HNSCC and Its Microenvironment

Head and neck squamous cell carcinoma progression relies on the malignant cells and the TIME. This milieu consists of varied components, including tumor cells, stromal elements such as cancer-associated fibroblasts (CAFs), vasculature, extracellular matrix, and numerous infiltrating immune populations, all of which can promote tumor expansion, dissemination, and therapeutic resistance.

A hallmark of the HNSCC TIME is its immunosuppressive profile. ²¹ Malignant cells actively modulate this setting to sustain their viability and elude immune clearance, primarily by enlisting and engaging multiple immunosuppressive cell types that synergistically suppress antitumor immunity:

• Regulatory T-cells (Tregs): These specialized CD4+ T-cells are potent suppressors of effector T-cell function. They are actively recruited into the HNSCC TIME by chemokines secreted by tumor cells and macrophages. A high density of tumor-infiltrating Tregs is a well-established negative prognostic factor in HNSCC.

• Tumor-associated macrophages (TAMs): Macrophages that infiltrate the tumor are often skewed toward an M2-polarized, pro-tumor phenotype. ²² These M2 TAMs contribute to immune suppression by producing antiinflammatory cytokines like IL-10, promoting angiogenesis, and remodeling the extracellular matrix to facilitate invasion. They are also a significant source of PD-L1 expression within the TIME and are associated with resistance to both conventional therapies and immunotherapy.

• Myeloid-derived suppressor cells (MDSCs): This heterogeneous population of immature myeloid cells expands in cancer patients and is a powerful inhibitor of T-cell activation and proliferation. High levels of MDSCs in the HNSCC TIME are correlated with tumor progression and poor clinical outcomes.

Beyond this cellular immunosuppressive network, HNSCC cells increase immune evasion by upregulating immune checkpoint molecules on their surface. The most critical of these is Programmed Death-Ligand 1 (PD-L1). ²³ By engaging with its cognate receptor, Programmed Death-1 (PD-1), on the surface of activated T-cells, PD-L1 delivers an inhibitory signal that leads to a state of T-cell dysfunction known as “exhaustion,” ultimately allowing the tumor to escape immune-mediated destruction.

The Immunological Dichotomy of HPV-Positive and HPV-Negative Disease

The primary influence on the HNSCC TIME stems from the tumor’s etiologic origin. HPV-positive and HPV-negative HNSCC display a stark immunologic contrast, commonly described as an “inflamed” or “hot” TIME in the HPV-positive subtype versus a “non-inflamed” or “cold” TIME in the HPV-negative counterpart.^18,24 HPV-Positive HNSCC (“Hot” TIME): The persistent expression of viral E6 and E7 oncoproteins provides a strong source of non-self antigens, making these tumors highly immunogenic. ²⁵ This inherent antigenicity leads to the development of a “hot” or T-cell-inflamed microenvironment characterized by the following:

• High immune infiltration: HPV-positive tumors have higher density of infiltrating immune cells, particularly in total tumor-infiltrating lymphocytes (TILs), cytotoxic CD8+ T-cells, and CD4+ T-helper cells. ²⁶

• Activated immune pathways: Gene expression analyses showed activation of immune-related signaling pathways, such as antigen processing, and interferon-gamma (IFN-γ) signaling.

• Upregulated checkpoints: This active immune response drives a mechanism of adaptive immune resistance. The IFN-γ secreted by activated T-cells induces the upregulation of PD-L1 on both tumor cells and immune cells within the TIME. Consequently, HPV-positive tumors have higher levels of PD-1 expression on T-cells and higher PD-L1 expression overall, creating a scenario of a potent but actively suppressed antitumor response.

• Distinct spatial architecture: The immune cells in HPV-positive tumors are not just present in higher numbers; they are also organized for an active, albeit stalled, immune attack. Spatial analyses show closer proximity between cytotoxic T-cells and tumor cells, as well as between PD-1-expressing T-cells and PD-L1-expressing cells, indicative of an engaged but inhibited immune synapse.

• HPV-negative HNSCC (“Cold” TIME): Lacking the strong viral antigens, these tumors are generally less immunogenic. Their microenvironment is often described as “cold” or immune-excluded, featuring:

• Lower immune infiltration: HPV-negative tumors typically have a lower density of TILs, particularly CD8+ T-cells.

• Immunosuppressive Milieu: The TIME is often dominated by other cell types, such as neutrophils, and a high density of M2-polarized (CD163+) macrophages is associated with a particularly poor prognosis in this subgroup. This less inflamed microenvironment contributes to their more aggressive clinical behavior and historically poorer response to immunotherapy.

The “hot” nature of the HPV-positive TIME represents a biological double-edged sword, supported by robust translational evidence. Preclinical models using HPV-positive cell lines and syngeneic tumors demonstrate that persistent E6/E7 oncoprotein expression drives strong neoantigen presentation, leading to dense CD8+ T-cell infiltration and IFN-γ signaling—components essential for a potent antitumor immune response that underlies the superior prognosis of these patients. ²⁷ However, this inflammatory cascade triggers a countermeasure: IFN-γ-induced PD-L1 upregulation on tumor and immune cells, representing a classic adaptive resistance mechanism in which the host immune assault prompts its own inhibition. Clinically, this translates to enhanced susceptibility to PD-1/PD-L1 blockade, as evidenced by subgroup analyses in landmark trials such as KEYNOTE-048 and CheckMate 141, where HPV-positive tumors derived greater OS benefit (eg, HR 0.55 for nivolumab in PD-L1 ⩾ 1% subgroups) compared with HPV-negative disease. ²⁸ Far from incidental, this targeted resistance pathway underpins the rationale for immune checkpoint inhibitors (ICIs), which excel not by initiating de novo immunity but by reinvigorating and alleviating suppression of a preexisting antitumor response. Accordingly, this mechanism directly bridges the viral origins of HPV-associated tumors to their heightened therapeutic vulnerability to PD-1/PD-L1 antagonists.

PD-1/PD-L1 Blockade in HNSCC: Clinical Evidence and Key Trials

Mechanism of Action: Restoring T-Cell Mediated Antitumor Immunity

The PD-1/PD-L1 axis serves as a regulatory checkpoint that maintains immune homeostasis and prevents autoimmunity. ²⁹ The PD-1 receptor, a member of the CD28 superfamily, is expressed on the surface of activated T-cells, B-cells, and natural killer (NK) cells, where it functions as an inhibitory “brake” to temper the duration and amplitude of an immune response. Many tumor types, including HNSCC, co-opt this physiological mechanism to evade immune destruction. They achieve this by overexpressing PD-L1 on the surface of tumor cells and other cells within the TIME.

When PD-L1 on a tumor cell binds to the PD-1 receptor on an activated, tumor-specific T-cell, it transduces a potent inhibitory signal into the T-cell. ³⁰ This signal, mediated by the recruitment of phosphatases like SHP-2 to the PD-1 cytoplasmic tail, dephosphorylates key components of the T-cell receptor signaling cascade. This results the downregulation of T-cell function, leading to a state of anergy or “exhaustion,” characterized by decreased proliferation, reduced cytokine production (eg, IFN-γ and IL-2), and ultimately, apoptosis.

Immune checkpoint inhibitors are monoclonal antibodies designed to physically obstruct this immunosuppressive interaction. Anti-PD-1 antibodies (eg, pembrolizumab and nivolumab) bind to the PD-1 receptor on T-cells (mechanism of PD-1/PD-L1 blockade is illustrated in Figure 2), while anti-PD-L1 antibodies (eg, avelumab and durvalumab) bind to the PD-L1 ligand on tumor cells. ³¹ In either case, the blockade prevents the PD-1/PD-L1 engagement, thereby “releasing the brakes” on the T-cell. This restores the ability of preexisting, tumor-specific T-cells to recognize their targets and execute their cytotoxic functions, leading to tumor cell killing and, in some patients, durable, long-lasting antitumor responses. While the primary site of action is thought to be the reinvigoration of exhausted T-cells within the TIME, emerging evidence also suggests that checkpoint blockade can enhance the initial priming and activation of new antitumor T-cell responses in tumor-draining lymph nodes.

Figure 2.

Mechanism of PD-1/PD-L1 Blockade and Restoration of T-Cell Antitumor Activity. This schematic illustrates the inhibitory role of the PD-1/PD-L1 axis in tumor immune evasion and the therapeutic effect of PD-1 blockade. Left panel: A tumor cell expressing PD-L1 engages with PD-1 on an activated T-cell, delivering an inhibitory signal that suppresses T-cell function (exhaustion), preventing effective antitumor response despite MHC-TCR antigen recognition. Middle panel: Introduction of an anti-PD-1 antibody blocks the PD-1/PD-L1 interaction, preventing the inhibitory signal. Right panel: Blockade restores T-cell activation, leading to cytotoxic activity and tumor cell death. MHC indicates major histocompatibility complex; TCR: T-cell receptor. (Parvez et al. ³² Licensed under Open Access license CC BY 4.0, with modification.)

Landmark Clinical Trials: Establishing a New Standard of Care

The clinical efficacy of PD-1/PD-L1 blockade in HNSCC was definitively established through a series of landmark phase III clinical trials that have reshaped the treatment paradigm for patients with R/M disease (Table 1).

Table 1.

Key Phase III Clinical Trials of PD-1/PD-L1 Inhibitors in R/M HNSCC.

Trial (NCT ID)	Agent(s)	Setting	Comparator	Patient Population	Median OS (mos) (HR)	Median PFS (mos) (HR)	ORR (%)	HPV Status
KEYNOTE-048 (NCT02358031) 28	Pembrolizumab	1 L R/M	EXTREME	Total Population	11.5 (HR 0.81)	2.3 (HR 1.11)	16.9	Mixed
				PD-L1 CPS ⩾ 1	12.3 (HR 0.74 a )	2.6 (HR 1.09)	19.1	Mixed
				PD-L1 CPS ⩾ 20	14.8 (HR 0.61 a )	3.4 (HR 0.99)	23.3 a	Mixed
	Pembrolizumab + Chemo	1 L R/M	EXTREME	Total Population	13.0 (HR 0.71 a )	5.0 (HR 0.82 a )	36.4 a	Mixed
				PD-L1 CPS ⩾ 1	13.6 (HR 0.64 a )	5.1 (HR 0.77 a )	36.9 a	Mixed
				PD-L1 CPS ⩾ 20	14.7 (HR 0.62 a )	5.1 (HR 0.78 a )	42.9 a	Mixed
CheckMate 141 (NCT02105636)33,34	Nivolumab	Platinum-Refractory	Investigator’s Choice	Total Population	7.5 (HR 0.70 a )	2.0 (HR 0.89)	13.3 a	Mixed
				PD-L1 ⩾ 1%	7.7 (HR 0.55 a )	2.1	17 a	Mixed
				PD-L1 < 1%	5.7 (HR 0.89)	1.9	10.1	Mixed

a

Statistically significant improvement versus comparator.

OS, overall survival; PFS, progression-free survival; HR, hazard ratio; ORR, objective response rate.

The KEYNOTE-048 Study: Pembrolizumab in the First-Line Setting

The phase III KEYNOTE-048 trial was a practice-defining study that evaluated pembrolizumab, either as a monotherapy or in combination with standard platinum/5-FU chemotherapy, against the EXTREME regimen for the first-line treatment of R/M HNSCC. ²⁸ The trial’s results led to a new standard of care.

For pembrolizumab monotherapy, the study demonstrated a significant OS benefit compared with EXTREME in patients whose tumors expressed PD-L1. In the Combined Positive Score (CPS) ⩾ 20 population, median OS was 14.8 months with pembrolizumab versus 10.7 months with EXTREME. A similar benefit was seen in the CPS ⩾ 1 population (12.3 vs 10.3 months). Crucially, this survival benefit was achieved with a substantially more favorable safety profile than chemotherapy.

For pembrolizumab combined with chemotherapy, the trial showed a superior OS benefit over EXTREME across all tested populations, regardless of PD-L1 expression status. In the total patient population, the combination yielded a median OS of 13.0 months compared with 10.7 months for EXTREME. This established the chemo-immunotherapy combination as a new standard first-line option for all patients with R/M HNSCC.

The CheckMate 141 Study: Nivolumab for Platinum-Refractory Disease

The phase III CheckMate 141 trial established the role of immunotherapy in the second-line setting for patients with R/M HNSCC whose disease had progressed on or after platinum-based chemotherapy.^29,30 The study compared nivolumab to the investigator’s choice of single-agent therapy (methotrexate, docetaxel, or cetuximab).

Nivolumab demonstrated a better OS result, with a median OS of 7.5 versus 5.1 months for the control arm. This benefit was durable; with longer follow-up, the 18 month OS rate was nearly tripled in the nivolumab arm compared with the standard therapy arm (21.5% vs 8.3%). The survival benefit was particularly pronounced in patients with PD-L1 expression of 1% or greater (HR 0.55) and in the subgroup of patients with HPV-positive tumors (median OS 9.1 vs 4.4 months). In addition to superior efficacy, nivolumab was associated with a lower incidence of high-grade treatment-related adverse events and led to better preservation of patient-reported quality of life compared with standard chemotherapy.

PD-L1 CPS: A Clinically Relevant but Imperfect Biomarker

The results of these landmark trials have established PD-L1 expression, as measured by the CPS, as the primary predictive biomarker for guiding immunotherapy decisions in HNSCC. The CPS is calculated by taking the number of PD-L1-staining cells (which includes tumor cells, lymphocytes, and macrophages) and dividing it by the total number of viable tumor cells, then multiplying by 100.

The clinical utility of CPS is most clearly demonstrated by the KEYNOTE-048 data, which allows for a stratified approach to first-line therapy. The benefit of pembrolizumab monotherapy is directly proportional to the CPS level, with the greatest benefit seen in patients with a CPS of 20 or higher. However, CPS is a reliable biomarker. Its expression can be heterogeneous within a single tumor and can change over time in response to therapy, making it a dynamic rather than a static marker. Furthermore, patients with low or even negative CPS can still derive a benefit from immunotherapy, particularly when it is combined with chemotherapy, as shown in the total population analysis of the pembrolizumab-chemotherapy arm of KEYNOTE-048.

The nuanced results from KEYNOTE-048 provide a framework for clinical decision-making that balances efficacy with toxicity. For a patient with a high PD-L1 expression (CPS ⩾ 20), pembrolizumab monotherapy offers a survival benefit comparable to that of chemo-immunotherapy but with a significantly lower toxicity burden, making it a preferred option. For a patient with low-positive PD-L1 expression (CPS 1-19), the chemo-immunotherapy combination is demonstrably more effective than monotherapy and is the best choice. For the immunologically “cold” tumors with PD-L1 CPS < 1, neither pembrolizumab monotherapy nor the chemo-immunotherapy combination showed survival benefit over the EXTREME regimen, highlighting a critical unmet need and underscoring the necessity for novel therapeutic strategies and biomarkers. ³⁵ This demonstrates that CPS is not a simple binary test but a continuous variable that can be used to tailor therapy along a spectrum of immune reactivity.

Combination Strategies to Enhance Efficacy

While PD-1/PD-L1 inhibitor monotherapy has proven effective for a subset of patients, particularly those with high PD-L1 expression, most patients do not respond. This has driven intensive research into combination strategies designed to broaden the applicability and deepen the efficacy of immunotherapy by modulating the tumor microenvironment and overcoming resistance mechanisms.

Synergy With Chemotherapy

The combination of immunotherapy with conventional chemotherapy has emerged as one of the most successful strategies in HNSCC. ²⁸ The rationale for this synergy extends beyond the simple additive effects of 2 active treatments. Chemotherapy can promote a more robust antitumor immune response through several different mechanisms. Certain chemotherapeutic agents, including platinum compounds and 5-FU, can induce a form of cancer cell death known as immunogenic cell death (ICD). During ICD, dying tumor cells release a host of molecular signals, including tumor antigens and damage-associated molecular patterns (DAMPs), which act as “danger signals” to alert and activate the innate immune system. This process enhances the uptake of tumor antigens by antigen-presenting cells (APCs), leading to more effective priming of tumor-specific T-cells. In addition, chemotherapy can increase the expression of MHC class I molecules on the surface of surviving tumor cells, making them more visible to cytotoxic T-lymphocytes. Finally, some chemotherapy agents can selectively deplete immunosuppressive cell populations within the TIME, such as Tregs and MDSCs, further tilting the immunological balance in favor of an antitumor response. ³⁶ Translational studies provide strong mechanistic support: preclinical models demonstrate that platinum agents and 5-FU trigger calreticulin exposure, HMGB1 release, and ATP secretion (canonical hallmarks of ICD) resulting in dendritic cell maturation and enhanced cross-priming of T-cells. In essence, chemotherapy can help convert an immunologically “cold” or non-inflamed tumor into a “hot” one, thereby sensitizing it to the effects of checkpoint blockade.

Clinically, this concept has translated successfully, most notably in the phase III KEYNOTE-048 trial, where pembrolizumab combined with platinum/5-FU chemotherapy significantly improved OS over the EXTREME regimen across all PD-L1 CPS subgroups, including PD-L1-low or negative (“cold”) tumors that derive minimal benefit from ICI monotherapy. ²⁸ Subsequent studies exploring other combinations, such as PD-1 inhibitors with paclitaxel and cisplatin, have also reported high objective response rates (ORR) of up to 56% in cohorts of patients with R/M HNSCC, further cementing the role of chemo-immunotherapy as a cornerstone of treatment.

The Abscopal Effect and Beyond: Combining With Radiotherapy

The combination of immunotherapy with RT is another strategy with a compelling preclinical rationale. RT, a mainstay of HNSCC treatment, has profound and complex immunomodulatory effects. Similar to chemotherapy, RT can induce ICD, leading to the release of tumor antigens and DAMPs that stimulate an immune response. ³⁷ RT can also increase the expression of MHC class I on tumor cells and promote the infiltration of T-cells into the irradiated tumor. Intriguingly, RT upregulates PD-L1 expression on tumor cells, which is a mechanism of acquired radioresistance but also creates a specific vulnerability that can be exploited by concurrent PD-1/PD-L1 blockade. The local immune activation triggered by RT can, in some cases, lead to a systemic antitumor immune response capable of causing the regression of distant, non-irradiated metastatic lesions—a phenomenon known as the “abscopal effect.”

Despite this strong biological foundation, the translation of immunoradiotherapy into clinical practice has been challenging, with mixed results from clinical trials. While numerous early-phase studies have shown that combining ICIs with RT is generally safe and feasible, large, randomized phase III trials have thus far been disappointing. ³⁸ Major studies such as JAVELIN Head and Neck 100, which combined the anti-PD-L1 antibody avelumab with standard CRT, and KEYNOTE-412, which added pembrolizumab to CRT, both failed to demonstrate improvement in their primary survival endpoints in unselected patient populations. ³⁹

This discrepancy highlights important translational gaps. Negative outcomes in large trials likely stem from suboptimal integration of modalities, including the use of conventional RT fractionation schedules (which are less immunogenic than hypofractionated regimens), variable timing of ICI administration, and a lack of patient selection based on baseline TIME inflammation or PD-L1 status. The failure of these large trials does not necessarily invalidate the concept of immune RT but rather underscores the need for biologically informed trial designs that optimize critical variables, such as hypofractionated RT regimens, sequential versus concurrent scheduling, and biomarker-driven enrollment, to better capture the therapeutic “sweet spot” identified in preclinical and early clinical data. The future success of this strategy will depend on more sophisticated, biologically informed clinical trials that optimize key variables—such as RT fractionation, ICI sequencing, and biomarker-driven enrollment—to identify the therapeutic “sweet spot” that maximizes immune synergy.

Integrating With Targeted Agents: The Role of Cetuximab

Cetuximab, an EGFR-directed monoclonal antibody, has served as a therapeutic component in HNSCC management for an extended period. In addition to blocking EGFR-dependent tumor proliferation, its activity encompasses antibody-dependent cellular cytotoxicity (ADCC), an immune effector process. ¹⁹ During ADCC, the Fc portion of the cetuximab antibody (an IgG1 isotype) is recognized by Fc receptors on immune effector cells, such as NK cells, which then become activated and kill the tumor cell. This process can lead to the release of tumor antigens and the priming of a broader, T-cell-mediated antitumor immune response, providing a clear rationale for combining cetuximab with ICIs to achieve synergistic antitumor activity.

This hypothesis has been tested in the clinic with encouraging results. A multiinstitutional phase II trial evaluated the combination of cetuximab and nivolumab in 2 cohorts of patients with R/M HNSCC ⁴⁰ : those who had received prior therapy and those who were treatment-naïve. The combination proved to be highly effective, particularly in the first-line setting (cohort B), where it achieved a remarkable median OS of 20.2 months. The treatment was generally well-tolerated, with a manageable safety profile. These promising findings have spurred further investigation, and several other clinical trials are currently underway to further define the role of cetuximab-immunotherapy combinations in the treatment of HNSCC.

Moving Immunotherapy to Earlier Lines of Treatment

The transformative success of ICIs in the R/M setting has logically driven efforts to integrate these agents into the curative-intent treatment of earlier-stage, locally advanced HNSCC (LAHNSCC). The goal is to improve cure rates by leveraging the immune system before the development of widespread resistance and to potentially de-intensify toxic conventional therapies. This has led to the exploration of immunotherapy in the neoadjuvant, adjuvant, and combined perioperative settings (Table 2).

Table 2.

Selected Clinical Trials of Neoadjuvant and Adjuvant Immunotherapy in HNSCC.

Trial (NCT ID)	Setting	Intervention	Key population	HPV status	Primary endpoint(s)	Key findings/status
Meta-analysis (Pooled)	Neoadjuvant	ICI mono vs Chemo-ICI	LAHNSCC	Mixed	pCR, Safety	pCR: 1.4% (mono) vs 30.1% (combo). Safe, no surgical delays.
NCT03247712 (NIRT)	Neoadjuvant	Nivolumab + SBRT	p16 + LAHNSCC	Mixed	Safety, pCR	Safe, no surgical delays. pCR 67%.
NCT02641093	Neo + Adjuvant	Pembrolizumab + (chemo)RT	Resectable LAHNSCC	Primarily HPV-negative	1-yr DFS	PR associated with improved DFS. 1-yr DFS better in intermediate-risk group.
KEYNOTE-689 (NCT03765918)	Perioperative	Pembrolizumab + SOC	Resectable LAHNSCC	Mixed	EFS	Positive: Significant EFS benefit. New SOC.
IMvoke010 (NCT03452137)	Adjuvant	Atezolizumab	Post-definitive LAHNSCC	Primarily HPV-negative	DFS	Ongoing
KEYNOTE-412 (NCT03040999)	Adjuvant	Pembrolizumab + CRT	LAHNSCC	Mixed	EFS	Negative in unselected population.

HNSCC, head and neck squamous cell carcinoma; LA-HNSCC, locally advanced head and neck squamous cell carcinoma; ICI, immune checkpoint inhibitor; chemo, chemotherapy; RT, radiotherapy; SBRT, stereotactic body radiotherapy; SOC, standard of care; pCR, pathologic complete response; pRR, pathologic response rate; EFS, event-free survival; DFS, disease-free survival; PR, pathologic response; mono, monotherapy; combo, combination therapy; HPV, human papillomavirus; HPV+, HPV-positive; HPV−, HPV-negative.

The Neoadjuvant Approach: In Situ Vaccination and Pathological Response

Administering immunotherapy in the neoadjuvant setting—before definitive surgery—is based on a compelling immunological rationale. ²⁰ Treating a patient when their primary tumor and its draining lymph nodes are still intact is hypothesized to function as a form of “in situ vaccination.” The intact tumor provides a rich reservoir of tumor antigens, and the undisturbed lymphatic architecture allows for efficient antigen presentation and the subsequent priming and clonal expansion of a broad repertoire of tumor-specific T-cells. This approach aims to generate a robust, systemic antitumor immune response that can not only shrink the primary tumor but also target micrometastatic disease, potentially leading to better long-term disease control and immunological memory.

A primary concern with this approach was the potential for treatment-related toxicity to delay or prevent necessary surgery. However, numerous phase II trials have now consistently demonstrated that neoadjuvant immunotherapy, both as monotherapy and in combination with chemotherapy, is safe and well-tolerated, with no significant increase in surgical delays or postoperative complications.^41,42

A key endpoint in neoadjuvant trials is the degree of pathological response observed in the resected surgical specimen. While rates of pathological complete response (pCR; no residual viable tumor) are modest with ICI monotherapy, typically ranging from 1% to 5%, they are substantially higher when ICIs are combined with chemotherapy, reaching approximately 30% in some studies. Moreover, major pathologic response rates (MPR; ⩽10% viable tumor remaining) prove even more elevated. Notably, substantial pathologic regression following neoadjuvant treatment serves as a robust proxy for extended prognosis, as individuals attaining MPR or pathologic complete response (pCR) exhibit markedly superior disease-free survival (DFS).

The Adjuvant Setting: Preventing Recurrence in High-Risk Disease

The adjuvant setting represents another opportunity to improve cure rates in LAHNSCC. Following definitive local treatment with surgery and/or CRT, patients with high-risk pathological features remain at substantial risk of recurrence. Adjuvant immunotherapy is intended to eradicate any remaining micrometastatic disease and prevent relapse by reactivating the immune system during a period of minimal residual disease burden, when the ratio of effector immune cells to tumor cells is most favorable.

This is an area of intense and ongoing clinical investigation. Several large, randomized phase III trials are currently evaluating the role of adjuvant immunotherapy. Studies like IMvoke010 (adjuvant atezolizumab after definitive therapy), EA3161 (adjuvant nivolumab after CRT in intermediate-risk HPV-positive disease), ⁴³ and NIVOPOSTOP (adjuvant nivolumab with CRT) are poised to define the future standard of care in this setting. ⁴⁴ While the final results of these trials are eagerly awaited, early-phase data suggest that the specific timing and sequence of administration—for example, giving immunotherapy concurrently with adjuvant CRT versus sequentially after its completion—may be a critical factor influencing outcomes.

The Perioperative Paradigm: Insights From KEYNOTE-689

The phase III KEYNOTE-689 trial evaluated a comprehensive perioperative immunotherapy strategy, integrating both neoadjuvant and adjuvant treatment. ²⁰ In this study, patients with resectable LAHNSCC were randomized to either standard of care (surgery followed by risk-adapted adjuvant therapy) or an experimental arm consisting of 2 cycles of neoadjuvant pembrolizumab, followed by surgery, and then adjuvant pembrolizumab administered concurrently with and following standard adjuvant (chemo)radiotherapy.

The trial met its primary endpoint, demonstrating a statistically significant and clinically meaningful improvement in event-free survival (EFS) for the perioperative pembrolizumab arm. Among patients with a PD-L1 CPS ⩾ 1, the median EFS was 59.7 months in the pembrolizumab group compared with just 29.6 months in the standard-of-care group. These landmark results are practice-changing, establishing the addition of both neoadjuvant and adjuvant pembrolizumab as a new standard of care for patients with resectable LAHNSCC.

While the immediate impact of KEYNOTE-689 is the establishment of a more intensive and effective standard of care, its most profound long-term implication may lie in paving the way for future treatment de-intensification. A key finding from the study was that patients who received neoadjuvant pembrolizumab not only had significant pathological responses but also were less likely to have high-risk pathological features (such as positive margins or extracapsular extension) in their surgical specimens that would mandate the addition of adjuvant chemotherapy. This observation, combined with the strong correlation between pathological response and excellent long-term survival, opens the door to a new paradigm of response-adapted therapy. It raises the possibility that pathological response to neoadjuvant immunotherapy could be used as a biomarker to identify a subset of “exceptional responders” who might be candidates for less aggressive adjuvant therapy (eg, RT alone instead of CRT) or perhaps even less extensive surgery. Such a strategy would represent a monumental step forward, shifting the focus of clinical research from simply improving survival to improving the quality of that survival by mitigating the devastating long-term toxicities that have long plagued HNSCC survivors.

Clinical Considerations: Management of Immune-Related Adverse Events (irAEs)

Spectrum and Grading of Common irAEs

The mechanism of action of ICIs—the amplification of the host immune response—is also the source of their unique toxicity profile. ⁴⁵ By removing the physiological brakes on the immune system, these agents can lead to a wide range of inflammatory side effects in any organ system, collectively known as immune-related adverse events (irAEs). ⁴⁶ In the HNSCC patient population, the overall incidence of irAEs of any grade ranges from 57% to 67%, with more severe grade 3-4 events occurring in 8% to 17% of patients.

The spectrum of irAEs is broad, but several organ systems are commonly affected:

• Dermatologic: Skin toxicities are among the most frequent irAEs, typically manifesting as maculopapular rash and pruritus. While usually low-grade and manageable, they can, in rare cases, progress to severe, life-threatening conditions such as Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN).

• Gastrointestinal: Diarrhea and colitis are common and result from immune-mediated inflammation of the intestinal lining. Immune-mediated hepatitis, characterized by elevated liver transaminases, is less frequent but can be severe.

• Endocrine: Endocrinopathies are a frequent and important class of irAEs. Immune-mediated inflammation of the thyroid gland (thyroiditis, leading to hypothyroidism or transient hyperthyroidism), pituitary gland (hypophysitis), and adrenal glands (adrenal insufficiency) can occur. These conditions often require long-term or lifelong hormone replacement therapy.

• Pulmonary: Immune-mediated pneumonitis is a less common but potentially fatal irAE that requires a high index of suspicion and prompt intervention.

• Oral: Particularly relevant to the HNSCC population, who often have preexisting oral morbidities, are oral irAEs. These can include severe dry mouth (xerostomia), altered taste (dysgeusia), and painful oral mucosal lesions that resemble lichen planus or mucous membrane pemphigoid, which can significantly impact nutrition and quality of life.

Guideline-Informed Management Principles

The successful use of ICIs in the clinic depends on the early recognition and appropriate management of irAEs. Comprehensive clinical practice guidelines have been developed by major oncology organizations, including the National Comprehensive Cancer Network (NCCN) and the Society for Immunotherapy of Cancer (SITC), to provide a standardized framework for toxicity management. ⁴⁶

The core principles of irAE management are rooted in prompt identification, accurate grading of severity using the Common Terminology Criteria for Adverse Events (CTCAE), and a grade-dependent therapeutic algorithm:

• Grade 1: These are typically mild, asymptomatic or mildly symptomatic events. Management is generally supportive and symptomatic (eg, topical emollients for rash), and ICI therapy can usually be continued with close monitoring.

• Grade 2: These are moderate events that interfere with some activities of daily living. Management often involves holding the next dose of ICI and initiating treatment, such as topical or low-dose systemic corticosteroids (eg, prednisone at a dose of 0.5-1 mg/kg/day). ICI can often be resumed once the toxicity improves to grade 1 or less.

• Grades 3-4: These are severe or life-threatening events. Management requires immediate holding or permanent discontinuation of ICI therapy and the administration of high-dose systemic corticosteroids (eg, prednisone at 1-2 mg/kg/day or its intravenous equivalent). For patients whose symptoms do not improve rapidly on high-dose steroids (steroid-refractory irAEs), the addition of a second-line immunosuppressive agent is necessary. The choice of agent depends on the organ system involved; for example, infliximab is often used for severe colitis, while mycophenolate mofetil may be used for hepatitis.

A critical component of safe immunotherapy administration is patient education. Patients must be thoroughly counseled on the potential signs and symptoms of irAEs and instructed to report them to their clinical team immediately. Early intervention is necessary to preventing the progression of mild toxicities to more severe, life-threatening events and is the key to successful management.

The Next Wave: Emerging Agents and Future Therapeutic Targets

While PD-1/PD-L1 blockade has transformed HNSCC care, a large proportion of patients either do not respond or develop resistance. This has fueled the development of a new wave of immunotherapeutic agents aimed at targeting alternative resistance pathways and further amplifying the antitumor immune response (Table 3). ⁴⁷

Table 3.

Emerging Immunotherapeutic Agents in HNSCC.

Agent class	Example agent(s)	Target(s)	Rationale/Mechanism of action	Key clinical trial(s)/status
Anti-LAG-3	Fianlimab, Relatlimab	LAG-3	Reverses T-cell exhaustion, synergistic with PD-1 blockade.	Phase 1 (NCT03005782): fianlimab + cemiplimab: ORR 33% in PD-1 naïve 48
Anti-TIM-3	Surzebiclimab, Cobolimab	TIM-3	Reverses T-cell exhaustion, targets another resistance pathway.	Phase 2 (NCT05909904): triple combo recruiting 49
Oncolytic Virus (HSV-1)	Talimogene laherparepvec (T-VEC)	Tumor Cells (direct lysis) + GM-CSF expression	Induces immunogenic cell death, converts “cold” tumors to “hot”.	MASTERKEY-232: No added benefit to pembrolizumab 50 .
Oncolytic Virus (Adenovirus)	Oncorine (H101) 51	p53-deficient Tumor Cells	Selective oncolysis, synergizes with chemotherapy.	Approved in China with chemo for NPC (Nasopharyngeal Carcinoma).

HNSCC, head and neck squamous cell carcinoma; LAG-3, lymphocyte-activation gene 3; PD-1, programmed cell death protein 1; TIM-3, T-cell immunoglobulin and mucin-domain containing-3; ORR, objective response rate; HSV-1, herpes simplex virus type 1; T-VEC, talimogene laherparepvec; GM-CSF, granulocyte-macrophage colony-stimulating factor; p53, tumor protein p53; NPC, nasopharyngeal carcinoma.

Targeting Novel Immune Checkpoints: Anti-LAG-3 and Anti-TIM-3 Antibodies

A key mechanism of resistance to PD-1 blockade is T-cell exhaustion, a state of cellular dysfunction defined by the co-expression of multiple inhibitory checkpoint receptors on the T-cell surface. This has provided a strong rationale for developing agents that can block these alternative checkpoints, with the goal of more completely reversing T-cell exhaustion, particularly in combination with PD-1 inhibitors.

Lymphocyte-Activation Gene 3 (LAG-3) is an inhibitory receptor that, like PD-1, is upregulated on exhausted T-cells. Its blockade has been shown to restore T-cell function. Preclinical syngeneic models confirm that dual PD-1/LAG-3 blockade synergistically enhances CD8+ T-cell effector function and tumor control beyond PD-1 inhibition alone. The clinical validity of this approach was established in advanced melanoma, where the combination of the anti-LAG-3 antibody relatlimab with nivolumab demonstrated better progression-free survival over nivolumab alone, leading to its FDA approval. This strategy is now being actively investigated in HNSCC. Early results from a phase I trial combining the anti-LAG-3 antibody fianlimab with the anti-PD-1 antibody cemiplimab have shown encouraging clinical activity in patients with R/M HNSCC, with an ORR of 33% in the anti-PD-1-naïve cohort. Several other trials of LAG-3 inhibitors are ongoing. ⁴⁸

T-cell immunoglobulin and mucin-domain containing-3 (TIM-3) is another critical inhibitory receptor expressed not only on exhausted T-cells but also on other key immune cells, including Tregs and macrophages, where it contributes to an immunosuppressive TIME. Preclinical models have demonstrated that co-expression of PD-1, LAG-3, and TIM-3 on exhausted T-cells in HNSCC limits the efficacy of single or dual blockade, whereas simultaneous inhibition of all 3 restores proliferative capacity and cytokine production, leading to superior antitumor activity. ⁴⁷ This hypothesis is now being tested in the clinic. A phase II trial is currently recruiting patients with first-line R/M HNSCC to evaluate a novel triple combination of tislelizumab (anti-PD-1), LBL-007 (anti-LAG-3), and surzebiclimab (anti-TIM-3) (NCT05909904), representing a direct translational effort to overcome multifaceted exhaustion observed in resistant tumors. ⁴⁹

Oncolytic Virotherapy: A Dual-Mechanism Approach

Oncolytic virotherapy (OVT) represents a fundamentally different immunotherapeutic strategy. Oncolytic viruses (OVs) are naturally occurring or genetically engineered viruses that are designed to selectively infect and replicate within cancer cells, which often have defective antiviral defense mechanisms. This selective replication leads to direct tumor cell lysis, a process known as oncolysis. This oncolytic process serves a dual purpose. First, it directly kills cancer cells. Second, and perhaps more importantly, it functions as a powerful in situ immunization. The bursting of tumor cells releases a flood of tumor antigens, DAMPs, and viral pathogen-associated molecular patterns (PAMPs), which trigger a potent innate and adaptive immune response. This can effectively convert an immunologically “cold,” non-inflamed tumor into a “hot” one, making it more susceptible to other forms of immunotherapy, particularly ICIs.

Preclinical models robustly support this dual mechanism, showing that oncolysis induces type I interferon signaling, dendritic cell activation, and increased T-cell infiltration, with synergistic tumor regression when combined with PD-1 blockade. The first and only OV to receive FDA approval is talimogene laherparepvec (T-VEC), a modified herpes simplex virus-1 engineered to express GM-CSF, for the treatment of advanced melanoma. In HNSCC, clinical development is ongoing. The MASTERKEY-232 trial, which combined T-VEC with pembrolizumab, did not show a significant additive benefit over pembrolizumab monotherapy, highlighting challenges with delivery and patient selection. ⁵⁰

Another agent, Oncorine (H101), a modified adenovirus, is approved in China for use in combination with chemotherapy for nasopharyngeal carcinoma, based on trials showing improved response rates. The field of OVT is evolving rapidly, with a multitude of novel viral platforms and combination strategies currently in early-phase clinical development; successful translation will likely require optimized delivery methods and biomarker-guided patient selection to overcome the gaps observed in prior trials, holding promise as a future component of HNSCC therapy. ⁵²

Discussion

The advent of PD-1/PD-L1 blockade has reshaped the therapeutic paradigm for HNSCC, transitioning from a reliance on cytotoxic and targeted therapies to a more immunologically driven approach. As evidenced by clinical trials such as KEYNOTE-048 and CheckMate 141, these agents have achieved ORRs ranging from 13% to 47% in R/M settings, with durable responses translating to median OS improvements of 2 to 4 months over prior standards like the EXTREME regimen. This efficacy is particularly obvious in HPV-positive subsets, where the “hot” TIME—characterized by high TIL density, IFN-γ signaling, and adaptive PD-L1 upregulation—facilitates a more robust unleashing of preexisting antitumor immunity. In contrast, HPV-negative tumors, often exhibiting a “cold” microenvironment dominated by suppressive elements like MDSCs and M2 TAMs, show modest responses, underscoring the etiological dichotomy’s influence on immunotherapy outcomes.

Combination strategies have emerged as a strategy to augment benefits and decrease resistance. ⁵³ The synergy of ICIs with platinum-based chemotherapy, as in KEYNOTE-048, not only enhances antigen release through ICD but also modulates the TIME by depleting immunosuppressive populations, yielding superior PFS and OS in PD-L1-high expressors. Similarly, dual checkpoint inhibition (eg, nivolumab plus ipilimumab in CheckMate 651) and ICI-RT combinations exploit radiation’s abscopal effects to prime systemic immunity, though challenges persist in optimizing dosing and sequencing to minimize overlapping toxicities. Neoadjuvant applications, exemplified by the significant EFS benefit observed in KEYNOTE-689, highlight immunotherapy’s potential to downstage tumors and inform response-adapted de-escalation. This approach may spare patients from overtreatment while preserving function—a particularly important consideration in HNSCC given the disease’s impact on vital structures.

Nonetheless, ongoing challenges temper progress in this domain. Intrinsic tumor features, such as limited neoantigen load, and extrinsic TIME elements, including hypoxia-mediated metabolic shifts, constrain sustained efficacy to approximately 20% to 30% of cases. Biomarker constraints hinder optimal patient stratification; although PD-L1 CPS ⩾ 1 identifies potential beneficiaries, its predictive accuracy (~40%-50%) calls for adjunctive multiomic metrics (eg, TMB, inflammatory GEP) to refine selection. Immune-related adverse events (irAEs), while typically controllable via NCCN/SITC protocols, carry heightened implications in HNSCC due to preexisting mucosal fragility, potentially worsening nutritional compromise and prolonging convalescence. Novel modalities, including anti-LAG-3/TIM-3 regimens and oncolytic virotherapies, show potential in countering T-cell exhaustion and immunizing immunologically inert tumors, yet preliminary findings (eg, 33% ORR with fianlimab plus cemiplimab) demand corroboration through expanded trials to substantiate incremental gains absent undue morbidity. Relative to melanoma and NSCLC, HNSCC immunotherapy echoes comparable advances but exhibits restricted generalizability owing to site-specific and causal diversity. For example, melanoma’s elevated TMB facilitates widespread ICI utility, whereas HNSCC’s heterogeneous mutational profile requires customized interventions, exemplified by HPV-directed vaccines under investigation. Key evidentiary limitations include retrospective biases in many combinatorial analyses, limited inclusion of extra-oropharyngeal subsites, and underrepresentation of diverse ethnic groups, in whom socioeconomic variables may influence TIME characteristics. These limitations highlight the need for prospective, biomarker-guided studies to clarify risk-benefit profiles and promote equitable implementation across populations.

In summary, PD-1/PD-L1 inhibition has transformed HNSCC from a consistently grave outlook to one affording cure in targeted subsets, yet maximal impact relies on surmounting refractoriness via cohesive, multifaceted regimens. This advancement extends beyond longevity to encompass functional integrity, thereby establishing a framework for targeted immuno-oncology in head and neck neoplasms (Table 4).

Table 4.

Key Foundational Literature and Salient Findings in HNSCC Immunotherapy.

Reference	Study/Trial or focus	Salient findings	Relevance to HNSCC immunotherapy
Burtness et al 28 (KEYNOTE-048)	Phase III randomized trial (pembrolizumab ± chemotherapy vs EXTREME in 1 L R/M HNSCC).	Pembrolizumab monotherapy improved OS in PD-L1 CPS ⩾ 1 (especially CPS ⩾ 20); combination with chemotherapy improved OS across all PD-L1 levels vs EXTREME.	Established PD-1 blockade (alone or with chemo) as new first-line standard for R/M HNSCC.
Ferris et al 34 (CheckMate 141)	Phase III randomized trial (nivolumab vs investigator’s choice in platinum-refractory R/M HNSCC).	Nivolumab improved median OS (7.5 vs 5.1 months) with durable responses; greater benefit in PD-L1 ⩾ 1% and HPV-positive subgroups.	First demonstration of survival benefit with ICI in second-line R/M HNSCC, leading to FDA approval.
Uppaluri et al 20 (KEYNOTE-689)	Phase III trial (neoadjuvant + adjuvant pembrolizumab vs placebo in resectable LA-HNSCC).	Perioperative pembrolizumab significantly improved EFS (median 59.7 vs 29.6 months in PD-L1 CPS ⩾ 1); enabled response-guided de-escalation.	Extended PD-1 blockade benefit to curative-intent locally advanced disease, supporting perioperative paradigms.
Mandal et al 21	Comprehensive immune profiling of HNSCC tumor microenvironment.	Identified immunosuppressive cells (Tregs, M2 TAMs, MDSCs) and PD-L1 upregulation; HPV-positive tumors showed inflamed (“hot”) phenotype vs “cold” HPV-negative.	Provided foundational understanding of TIME dichotomy driving differential ICI responses.
Galon and Bruni 36	Review of strategies for hot, altered, and cold tumors.	Chemotherapy/radiotherapy induce immunogenic cell death and convert “cold” to “hot” tumors; rationale for combinations with ICI.	Mechanistic basis for successful chemo-ICI and radio-ICI synergies observed clinically.
Qin et al 47	Review of novel immune checkpoints beyond PD-1/CTLA-4.	LAG-3 and TIM-3 co-expressed on exhausted T-cells; preclinical synergy with dual/triple blockade.	Rationale for emerging multicheckpoint inhibitors to overcome resistance in HNSCC.

Conclusions

Immunotherapy has fundamentally transformed the management of HNSCC, with PD-1/PD-L1 inhibitors establishing a new frontline standard in both R/M and locally advanced settings. Key trials demonstrate clinically meaningful improvements in ORR, PFS, and OS, particularly when combined with chemotherapy or RT, leveraging the immunogenic potential of HPV-positive disease while addressing the immunosuppressive barriers in HPV-negative tumors. Neoadjuvant and adjuvant applications further extend these benefits, enabling pathological response-guided de-escalation and potentially reducing long-term morbidity. Management of irAEs through guideline-based interventions ensures safety, while emerging therapies like multicheckpoint inhibitors and oncolytic viruses hold promise for refractory cases.

Despite these advances, challenges such as resistance, biomarker imprecision, and toxicity underscore that immunotherapy is not a panacea but a cornerstone requiring integration with existing modalities. ⁵⁴ By synthesizing mechanistic insights from the TIME with clinical evidence, this review affirms immunotherapy’s role in prolonging survival and enhancing quality of life, paving the way for personalized regimens that maximize therapeutic index in this heterogeneous malignancy.

Future Directions

The trajectory of HNSCC immunotherapy demands a multifaceted approach to surmount current limitations and harness untapped potential. First, advancing biomarker discovery is paramount; integrating PD-L1 CPS with composite scores incorporating TMB, TIL signatures, and ctDNA dynamics could refine patient stratification, as explored in trials like NCT05909904. Prospective validation of these multiomic panels in diverse cohorts will be essential to mitigate biases and enhance generalizability across subsites and ethnicities.

Second, rational combination regimens should prioritize biological synergy over empiricism. For instance, triplet checkpoint blockade (eg, PD-1/LAG-3/TIM-3) may fully reverse exhaustion in “hot” tumors, while OVT-ICI pairings could inflame “cold” microenvironments, with adaptive trials (eg, platform designs) accelerating optimization. Incorporating HPV-specific therapies, such as E6/E7-targeted vaccines or TCR-engineered T-cells, holds particular promise for oropharyngeal HNSCC, potentially eliciting durable, antigen-specific responses.

Third, perioperative immunotherapy warrants expanded investigation. Building on KEYNOTE-689, response-adapted paradigms—where major pathological response (MPR > 90%) guides adjuvant de-intensification—could minimize toxicity without compromising efficacy, as piloted in ongoing studies like IMvoke010. Long-term follow-up will clarify impacts on recurrence-free survival and functional outcomes, informing guidelines for organ preservation.

Finally, addressing disparities through global collaboration is critical. Real-world registries and AI-driven analyses of electronic health records could elucidate socioeconomic modulators of response, while affordable biosimilars expand access in low-resource settings. Ultimately, these directions converge on a precision framework, where immunotherapy evolves from broad application to tailored, TIME-informed strategies, optimizing outcomes for all HNSCC patients.

The detailed methodology for this narrative review is provided in Supplementary File S1.

Supplemental Material

sj-docx-1-onc-10.1177_11795549261446733 – Supplemental material for Advances in Immunotherapy for Head and Neck Squamous Cell Carcinoma: Focus on PD-1/PD-L1 Blockade and Beyond

Supplemental material, sj-docx-1-onc-10.1177_11795549261446733 for Advances in Immunotherapy for Head and Neck Squamous Cell Carcinoma: Focus on PD-1/PD-L1 Blockade and Beyond by Fei Le, Youfang Jiang, Yaoyao Chen, Xianming Huang, Qian Ouyang and Saiping Lü in Clinical Medicine Insights: Oncology