Precision Immuno-Oncology in Oral Cancer: Biomarkers, Novel Drug Development, and Nanoparticle Platforms
Key Insights
Oral squamous cell carcinoma (search) accounts for over 370,000 new cases annually with 5-year survival rates of 50%–60%, driven by tobacco, alcohol, and rising HPV-linked cases.
PD-1 inhibitors nivolumab and pembrolizumab have demonstrated survival benefits in landmark trials including CheckMate-141 and KEYNOTE-048, particularly in PD-L1 (search) CPS-positive patients.
Next-generation checkpoint targets such as LAG-3 (search), TIGIT (search), and OX40 (search) are being evaluated in early-phase trials, with eftilagimod alpha plus pembrolizumab showing a ~30% ORR in HNSCC.
Oral squamous cell carcinoma (search) (OSCC) constitutes more than 90% of malignancies arising in the oral cavity and represents a major global health challenge. According to recent global cancer statistics, oral cancer accounts for over 370,000 new cases and nearly 180,000 deaths annually, with 5-year overall survival rates remaining approximately 50%–60% despite advances in surgery, radiotherapy, and systemic treatment. The epidemiological profile of the disease is shifting, with a rising incidence of cases linked to human papillomavirus, particularly in younger, non-smoking populations. These persistent unmet clinical needs underscore the urgency for biologically driven, less toxic, and more effective therapeutic strategies.
The Tumour and Immune Microenvironment in OSCC
The tumour and immune microenvironment (TIME) of OSCC plays a decisive role in disease progression, immune escape, and therapeutic response. OSCC is characterized by a highly dynamic and heterogeneous microenvironment in which malignant cells interact with stromal and immune components. Key cellular components include predominantly M2-polarized tumour-associated macrophages (TAMs) that promote tumour growth, angiogenesis, and immune suppression; myeloid-derived suppressor cells (MDSCs) that secrete IL-10 and TGF-β to inhibit T-cell activation; reduced cytotoxic CD8+ T cells with enrichment of CD4+ regulatory T cells; and cancer-associated fibroblasts that remodel extracellular matrix and secrete pro-angiogenic factors such as VEGF and FGF.
OSCC employs multiple immune escape mechanisms, including PD-L1 (search) upregulation, expansion of regulatory T cells, polarization of TAMs toward immunosuppressive phenotypes, and metabolic inhibition of effector T cells. TAMs frequently acquire an M2-like phenotype that suppresses cytotoxic T-cell and natural killer cell activity through secretion of anti-inflammatory cytokines such as interleukin-10 (IL-10) and TGF-β. Additionally, tumour cells may evade immune recognition by downregulating major histocompatibility complex expression, impairing effective antigen presentation to cytotoxic T lymphocytes.
Biomarkers for Patient Selection and Response Prediction
PD-L1 (search) expression is currently the most clinically established biomarker for predicting response to PD-1/PD-L1 immune checkpoint inhibitors (ICIs) in OSCC. Two principal scoring systems are widely used: the tumour proportion score (TPS) and the combined positive score (CPS). CPS incorporates PD-L1 staining in both tumour cells and tumour-associated immune cells and has become the preferred scoring method in clinical trials.
In the pivotal KEYNOTE-048 phase III trial, pembrolizumab monotherapy significantly improved overall survival compared with cetuximab-based chemotherapy in patients with recurrent or metastatic HNSCC whose tumours exhibited PD-L1 (search) CPS ≥20. Similarly, the CheckMate-141 study evaluating nivolumab in platinum-refractory HNSCC demonstrated improved survival compared with standard chemotherapy, with exploratory analyses suggesting greater clinical benefit among patients with higher PD-L1 expression.
Tumour mutational burden (TMB) has emerged as an important genomic biomarker. Comprehensive genomic characterization by The Cancer Genome Atlas Research Network identified frequent somatic alterations in HNSCC, providing early evidence that these tumours harbor substantial neoantigen potential. In a pan-tumour analysis, higher TMB levels were associated with significantly improved objective response rates across multiple cancer types, including head and neck malignancies.
Beyond single biomarkers, immune-related gene expression signatures have emerged as powerful tools. The IFN-γ–related gene expression signature reflects the presence of a T-cell–inflamed TIME. A seminal transcriptomic study demonstrated that tumours with high IFN-γ signature scores exhibited enhanced immune activation and were significantly more likely to respond to pembrolizumab therapy. The cytolytic activity score, which quantifies expression of effector molecules such as granzyme A (GZMA) and perforin (PRF1), reflects the cytotoxic capacity of infiltrating T lymphocytes and natural killer cells.
Peripheral blood–based biomarkers are gaining attention as minimally invasive tools. Circulating tumour DNA (ctDNA) profiling has demonstrated high concordance with tumour genomic alterations and allowed detection of minimal residual disease after treatment. Flow cytometry-based studies have shown that responders often exhibit higher baseline frequencies of activated CD8+ T cells and effector memory T-cell subsets, while elevated levels of immunosuppressive cell populations have been associated with poorer clinical outcomes.
Immune Checkpoint Inhibitors: Landmark Trials and Real-World Evidence
The treatment landscape for recurrent and metastatic OSCC has been fundamentally changed by immune checkpoint inhibition. KEYNOTE-048 established pembrolizumab as first-line standard of care, either alone or in conjunction with platinum-based chemotherapy, significantly improving overall survival compared to the EXTREME regimen. CheckMate-141 demonstrated that nivolumab significantly improved OS compared with investigator's choice in platinum-refractory recurrent/metastatic HNSCC.
Neoadjuvant PD-1 inhibition has been investigated in early-phase trials. A phase II study of neoadjuvant nivolumab in patients with stage II–IVA OSCC exhibited an objective response rate of approximately 33% with favourable safety and no surgical delays. Furthermore, recent phase III trials KEYNOTE-689 and NIVOPOSTOP have added meaningful evidence supporting incorporation of immunotherapy into curative treatment of locally advanced HNSCC. In KEYNOTE-689, perioperative pembrolizumab led to clear improvement in event-free survival and pathological response.
Real-world clinical outcome studies complement randomized trial data. Retrospective analyses of patients with recurrent or metastatic HNSCC treated with pembrolizumab or nivolumab in routine practice report objective response rates of approximately 20–25% and median survival outcomes consistent with pivotal phase III results.
Next-Generation Checkpoints and Co-Stimulatory Targets
To overcome resistance to PD-1/PD-L1 (search) blockade, next-generation immune checkpoints are being actively explored. Lymphocyte activation gene-3 (LAG-3 (search)) is expressed on exhausted T cells and exerts inhibitory effects on antitumour T-cell responses. In the multicenter Phase II TACTI-002 study, the soluble LAG-3 protein agonist eftilagimod alpha (efti) plus pembrolizumab demonstrated an objective response rate of approximately 30% in patients with second-line recurrent/metastatic HNSCC. In the TACTI-003 Phase IIb trial evaluating first-line use in PD-L1–negative HNSCC, preliminary data showed a 26.9% ORR and a 57.7% disease control rate.
T-cell immunoreceptor with Ig and ITIM domains (TIGIT (search)) is an inhibitory immune checkpoint expressed on activated T cells and natural killer cells. Early-phase clinical evaluation of the anti-TIGIT monoclonal antibody tiragolumab, administered alone or in combination with atezolizumab, demonstrated acceptable safety and tolerability with evidence of sustained TIGIT receptor engagement and immune modulation.
Co-stimulatory agonists targeting OX40 (search) (CD134) aim to enhance T-cell activation and memory formation. In a Phase I study of the OX40 agonist MEDI0562, treatment was generally well tolerated with no dose-limiting toxicities, and pharmacodynamic analyses demonstrated increased activation and proliferation of peripheral T cells.
Personalized Cancer Vaccines and Adoptive Cell Therapies
Personalized cancer vaccines represent a transformative immunotherapeutic strategy targeting patient-specific neoantigens. Early landmark Phase I trials established feasibility, safety, and immunogenicity. The Phase IIb randomized KEYNOTE-942 trial evaluated the mRNA-4157/V940 personalized neoantigen vaccine in combination with pembrolizumab versus pembrolizumab alone in patients with resected high-risk melanoma, demonstrating significantly improved recurrence-free survival.
Adoptive cell therapies including tumour-infiltrating lymphocyte (TIL) therapy and chimeric antigen receptor (CAR) T-cell therapy remain at early developmental stages in OSCC. A landmark Phase II trial demonstrated feasibility of TIL therapy in heavily pretreated patients with metastatic HPV-associated epithelial cancers, including head and neck tumours. However, CAR T-cell therapy faces significant barriers in solid tumours including antigen heterogeneity, poor tumour infiltration, and an immunosuppressive microenvironment.
Nanoparticle-Based Therapeutic Platforms
Nanoparticle-based therapeutic platforms are increasingly being explored to address major therapeutic challenges in OSCC. Several classes of nanoparticles have been investigated, including liposomes, polymeric nanoparticles, inorganic nanoparticles, and bioinspired metal systems. Liposomal formulations such as liposomal cisplatin have demonstrated enhanced tumour accumulation, reduced nephrotoxicity, and improved cytotoxic efficacy compared with free cisplatin. PLGA nanoparticles loaded with docetaxel have shown sustained drug release and improved antitumour efficacy in OSCC xenograft models. Gold nanoparticles offer multifunctionality by combining drug delivery with photothermal and radiosensitizing properties.
Nanoparticle-based immunomodulatory platforms enable targeted delivery of tumour antigens, immune adjuvants, and immunomodulatory agents. Self-assembling peptide–TLR7/8 nanoparticle vaccines have demonstrated enhanced antigen presentation, dendritic cell maturation, and strong CD8+ T-cell responses. TLR7/8 agonist-loaded polymeric nanoparticles have induced TAM repolarization from M2 to pro-inflammatory M1 phenotype.
In a Phase II clinical study, albumin-bound paclitaxel (nab-paclitaxel) combined with carboplatin demonstrated encouraging response rates and manageable toxicity in patients with recurrent or metastatic HNSCC. However, clinical translation faces challenges including achieving effective biodistribution within oral tumours, overcoming mucosal barriers, and addressing manufacturing scalability and regulatory requirements.
Safety and Immune-Related Adverse Events
In the CheckMate-141 trial, nivolumab showed a favorable safety profile, with grade ≥3 immune-related adverse events (irAEs) in about 13% of patients. KEYNOTE-048 demonstrated acceptable safety of pembrolizumab, alone or with chemotherapy. Common irAEs include dermatologic, endocrine, gastrointestinal, and hepatic effects, with severe events occurring in approximately 10%–15% of patients. In OSCC specifically, toxicities such as mucositis, dysphagia, and fatigue may cause greater functional impairment. Management follows ASCO and ESMO guidelines, emphasizing early detection and corticosteroid therapy for moderate to severe events.
Future Directions
Future progress will depend on systematic biomarker validation in large prospective registries, scalable nanomedicine development, and integrative data-driven frameworks. Key priorities include assay standardization, reproducibility across laboratories, and clear regulatory validation pathways. Despite rapid progress in biomarker discovery, translating candidate biomarkers into routine clinical practice remains challenging. Continued collaboration among academic researchers, clinical laboratories, regulatory agencies, and industry partners will be necessary to translate biomarker discoveries into reliable tools for precision oncology in OSCC.