Oral squamous cell carcinoma (OSCC) is part of the heterogeneous group of head and neck cancers, with more than 389,000 new cases reported annually worldwide. According to GLOBOCAN estimates, the incidence is expected to increase by approximately 65 % by 2050 (Bray et al., 2024). For OSCC patients, key predictors of poor clinical outcomes include locoregional recurrence and the development of regional or distant metastases (Liao et al., 2011). Reliable molecular or immunological markers could improve early detection, risk stratification, and prognosis assessment for OSCC patients, helping to identify individuals at highest risk for relapse or progression (Liu et al., 2025). However, despite advances in cancer biology, the role of biomarkers in OSCC and head and neck squamous cell carcinoma (HNSCC) remains insufficiently defined. Most existing candidates lack specificity, reproducibility, or clinical validation, and none are routinely implemented in practice (Liu et al., 2025) (Wenjie et al., 2024).Our study seeks to address these challenges by exploring novel biomarkers that could improve OSCC diagnosis and prognosis.

The programmed cell death protein 1 (PD-1) and its ligands, PD-L1 and PD-L2, are vital components of immune checkpoint regulation (Pardoll, 2012). In many cancers, PD-L1 inhibits T-cell activity by binding to PD-1 on T-cells, thereby promoting immune evasion and tumor growth (Jiao and Zhang, 2023; Konishi et al., 2004). Blocking the PD-1/PD-L1 pathway with anti-PD-L1 antibodies can prevent immune evasion, enabling the immune system to target cancer cells (Bellucci et al., 2015) (Paderno et al., 2024). While PD-L1 expression often correlates with poor outcomes across various cancers, some studies suggest it may be associated with better prognosis in cancers like colorectal cancer and melanoma (Lin et al., 2015). However, the relationship between PD-L1 expression and clinical outcomes in OSCC remains complex, with approximately 80 % of advanced OSCC patients showing limited responses to anti-PD-1 therapies (Zhao et al., 2021). Similarly, while PD-L2 has been proposed as a marker of response to immune checkpoint inhibitors, its prognostic utility in OSCC requires further investigation (Corti et al., 2023; Pai et al., 2016).

Chronic infection and inflammation significantly contribute to malignancy, influencing cancer initiation, progression, and metastasis (Huang et al., 2017). Inflammasome activation, particularly the NLRP3 inflammasome, has emerged as a critical factor in cancer related inflammation (Wang et al., 2021). The NLRP3 inflammasome, a multiprotein complex consisting of nucleotide-binding oligomerization domain-like receptor (NLR) protein 3, the adapter protein ASC, and caspase-1, functions as a major sensor of cellular stress and infection (Swanson et al., 2019). Upon activation, the NLRP3 inflammasome can promote tumor growth, metastasis, and immunosuppression, or it can enhance antitumor immune responses and sensitivity to chemotherapy (Shadab et al., 2023; Wu et al., 2020). Recent evidence suggests that NLRP3 expression may also vary based on tumor localization, potentially influenced by the tumor microenvironment(Scuderi et al., 2021). This complexity makes the NLRP3 inflammasome a compelling target for therapeutic intervention.

In this study we evaluated the expression levels of PD-L1, PD-L2, NLRP3, ASC, and caspase-1 across 151 patients with distinct oral and head and neck pathologies, including squamous cell carcinoma (SCC), cervical metastases, premalignant lesions such as leukoplakia, and benign lesions like papillomas and fibromas. Using immunohistochemical analysis and statistical comparisons, this study provides the first large-scale combined analysis of immune checkpoint and inflammasome markers in OSCC and related pathologies. While these biomarkers play critical roles in immune regulation and inflammation-driven tumorigenesis, their prognostic utility in OSCC remains limited. Our findings aim to offer valuable insights into their roles across malignant, premalignant, and benign lesions, with the goal of identifying novel diagnostic and therapeutic strategies.