The centerpiece of current clinical success is the immune checkpoint inhibitor class, particularly antibodies that block the programmed cell death protein 1 (PD-1) receptor and its ligand PD-L1. Under normal conditions, the PD-1 pathway acts as a molecular brake on T cells, preventing autoimmune damage; tumors exploit this brake by expressing PD-L1 to disable attacking lymphocytes. Landmark trials such as KEYNOTE-048 demonstrated that pembrolizumab, alone or with chemotherapy, could outperform the cetuximab-based EXTREME regimen as first-line treatment for recurrent or metastatic head and neck squamous cell carcinoma, while nivolumab showed survival benefits in the platinum-refractory setting. For oral squamous cell carcinoma (OSCC), the most common malignancy of the oral cavity, these agents have translated into meaningful survival extensions, and the review highlights that anti-PD-1 therapy is now firmly embedded in standard practice for recurrent and metastatic disease.

Perhaps the most consequential shift described in the review is the migration of immunotherapy from the late-stage setting into the perioperative arena. In locally advanced disease, where surgery and radiation remain the backbone of care, neoadjuvant checkpoint blockade given before surgery has produced remarkable pathological responses. A phase 2 randomized trial by Schoenfeld and colleagues showed that nivolumab, alone or combined with ipilimumab, could be safely administered to untreated oral cavity squamous cell carcinoma patients before resection. More recently, the KEYNOTE-689 trial of perioperative pembrolizumab in locally advanced head and neck cancer and the GORTEC 2018-01 NIVOPOST-OP phase 3 trial, which tested postoperative nivolumab added to cisplatin chemoradiotherapy in high-risk patients, have begun to define how checkpoint inhibition can be woven into curative-intent treatment. A randomized phase 2 trial from China further showed that neoadjuvant immunotherapy with or without chemotherapy improved outcomes in locally advanced OSCC, suggesting that earlier immune intervention may prevent micrometastatic seeding and reduce relapse.

Yet the biology of the tumor microenvironment (TME) imposes hard limits on these gains. The review devotes substantial attention to the immunosuppressive ecosystem that OSCC builds around itself. Regulatory T cells, which express CD25 and the transcription factor FoxP3, accumulate in the blood and tumors of OSCC patients and actively suppress antitumor immunity. Myeloid-derived suppressor cells, identified by markers such as CD11b, contribute to malignant progression and correlate with poor prognosis. Tumor-associated macrophages, particularly the CD163-positive M2-like subset, are associated with lymphangiogenesis, lymph node metastasis, and cancer stem cell maintenance. Each of these cell populations represents both a mechanism of immune evasion and a potential therapeutic target.

Cancer-associated fibroblasts (CAFs) add another layer of resistance. These stromal cells remodel the extracellular matrix into a dense, often hypoxic scaffold that physically excludes cytotoxic T cells from tumor nests, a phenomenon the review describes as immune exclusion. Hypoxia, driven in part by hypoxia-inducible factors HIF-1α and HIF-2α, further promotes angiogenesis, metabolic reprogramming, and chemo-resistance, and meta-analyses have linked HIF-1α overexpression to worse survival in OSCC. Altered extracellular matrix composition has been shown to correlate with an immunosuppressive microenvironment and disease progression, particularly in younger patients. The practical consequence is that even when checkpoint inhibitors release the brakes on T cells, those cells may never reach their targets in sufficient numbers, explaining why response rates in unselected OSCC populations remain modest.

Beyond checkpoint blockade, the review catalogs a wave of emerging modalities now under active investigation. Near-infrared photoimmunotherapy (NIR-PIT) conjugates an antibody, typically against EGFR, to a photoabsorbing dye; when activated by near-infrared light, the conjugate induces rapid and selective necrosis of targeted tumor cells while sparing adjacent normal tissue. Phase 1 and 2 studies of RM-1929 photoimmunotherapy in recurrent head and neck squamous cell carcinoma have demonstrated encouraging local control. Bispecific antibodies (BsAbs), engineered molecules that simultaneously bind a tumor antigen and an immune cell receptor, are another fast-moving area. Petosemtamab, an IgG1 bispecific targeting EGFR and LGR5, has shown clinical activity in advanced head and neck cancer, and cadonilimab, a PD-1/CTLA-4 bispecific, is being tested with neoadjuvant chemotherapy in locally advanced disease. Oncolytic viruses, which infect and lyse tumor cells while releasing antigens that prime systemic immunity, have been combined with pembrolizumab in the MASTERKEY-232 study using talimogene laherparepvec.

Adoptive cell therapies represent the most technologically ambitious frontier. Tumor-infiltrating lymphocyte (TIL) therapy, which involves harvesting, expanding, and reinfusing a patient’s own tumor-reactive T cells, has already earned accelerated FDA approval for melanoma as lifileucel, and a 2025 report in the Journal for ImmunoTherapy of Cancer described efficacy and safety of one-time autologous TIL therapy in recurrent or metastatic head and neck squamous cell carcinoma. Chimeric antigen receptor (CAR) T and CAR-NK cells, genetically engineered to recognize surface antigens such as ErbB family receptors, MUC1, and CD276, have shown preclinical activity against oral tongue squamous cell carcinoma, and an intratumoral pan-ErbB targeted CAR-T study (T4 immunotherapy) has reported interim results in head and neck cancer. T cell receptor (TCR)-engineered T cells targeting viral antigens such as HPV-16 E6 and E7 have produced complete tumor regressions in metastatic HPV-associated epithelial cancers, while neoantigen-specific and cancer-testis antigen targets like MAGE-C2 are being explored for HPV-negative tumors, which dominate the oral cavity.

The obstacles, however, are formidable. The review identifies tumor heterogeneity, inadequate immune cell trafficking, antigen escape, and manufacturing complexity as the principal barriers to durable responses. Solid tumors like OSCC present a hostile terrain for engineered cells, and antigen loss following CAR-T therapy can render treated tumors invisible to the infused product. The lack of reliable predictive biomarkers remains perhaps the most clinically frustrating gap: PD-L1 expression, tumor-infiltrating lymphocyte density, and HPV status all provide hints, but none reliably forecasts which patient will benefit. Notably, HPV-positive tumors tend to harbor inflamed immune microenvironments and respond better to anti-PD-1 therapy, whereas most oral cavity cancers are HPV-negative and immunologically cold. Combination strategies, from checkpoint inhibitors paired with radiotherapy, which can release tumor antigens and inflame the microenvironment, to dual durvalumab and tremelimumab in the DUTRELASCO neoadjuvant study, are being pursued precisely to convert cold tumors into hot ones.

The authors conclude that future progress will depend on biomarker-guided patient selection, rational combination regimens, and engineered cellular therapies capable of overcoming microenvironment-mediated resistance. Cytokine-based approaches are also re-emerging: the IRX-2 natural cytokine biologic completed the INSPIRE trial as neoadjuvant therapy for resectable oral cavity carcinoma and is being combined with durvalumab in recurrent disease. As the field moves toward personalized, multimodal immunotherapy, the message of this comprehensive synthesis is clear: the immune system can be mobilized against oral cavity tumors, but doing so reliably will require dismantling the tumor’s protective ecosystem as systematically as the first generation of immunotherapy dismantled its molecular brakes. For patients with a disease whose five-year survival has barely budged in decades, that systematic dismantling may finally change the trajectory.

Subject of Research: Immunotherapy strategies and tumor microenvironment resistance mechanisms in oral squamous cell carcinoma

Article Title: Immunotherapy for oral cavity tumors: recent advances, key challenges, and future perspectives

Article References: Sharipova, G., Amonov, S., Kim, A., Kenjayev, S., Masharipova, N., Maxkamov, Z., Shaniyazov, S., & Alimova, Z. (2026). Immunotherapy for oral cavity tumors: recent advances, key challenges, and future perspectives. Molecular Biology Reports, 53(1), Article 1718. https://doi.org/10.1007/s11033-026-12906-4

Image Credits: AI Generated

DOI: 10.1007/s11033-026-12906-4

Keywords: oral squamous cell carcinoma, immunotherapy, immune checkpoint inhibitors, PD-1, tumor microenvironment, CAR-T cells, tumor-infiltrating lymphocytes, bispecific antibodies, oncolytic viruses, neoadjuvant immunotherapy, cancer-associated fibroblasts, hypoxia