**Background:** Head and neck cancers, of which head and neck squamous cell carcinoma (HNSCC) constitutes approximately 90%, represent a significant global health burden. According to GLOBOCAN 2020, an estimated 830,000 new cases of tumors arising in the lip, oral cavity (377,713), larynx (184,615), nasopharynx (133,354), hypopharynx (84,254), and salivary glands (53,583) occur annually, accounting for 4.4% of all new global cancer cases. HNSCC is responsible for an estimated 420,000 deaths globally, representing 3.4% of all cancer-related deaths. Early diagnosis is critical for effective treatment, yet current diagnostic approaches—including clinical examination, biopsy, and radiologic imaging—have limitations. Human beta-defensins (hBDs) are cationic antimicrobial peptides expressed in epithelial tissues including the oral cavity, gingiva, tongue, and salivary glands. They possess multifunctional properties including antimicrobial activity, immune regulation, and potential roles in tumor biology. This narrative review aims to summarize current evidence on the possible use of hBDs as biomarkers for head and neck cancers.
**Methods:** This is a narrative review that synthesizes findings from clinical studies evaluating hBD levels in head and neck cancer patients. The authors reviewed studies identified through literature search, focusing on studies that used immunohistochemistry (IHC), reverse transcription polymerase chain reaction (RT-PCR), quantitative real-time PCR (qRT-PCR), and mRNA sequencing to assess hBD-1, hBD-2, and hBD-3 expression in cancer tissues compared to healthy controls or premalignant lesions. Key studies summarized include those by Han et al. (2014; 30 OSCC, 17 oral leukoplakia, 15 controls), Wang et al. (2014; 60 OSCC, 30 oral leukoplakia, 15 controls), Shuyi et al. (2011; 79 OSCC, 79 controls), Kesting et al. (2009; 45 OSCC, 16 controls), and others examining OSCC, salivary gland tumors, tonsillar carcinoma, esophageal SCC, and recurrent respiratory papillomatosis.
**Key Results:** The evidence reveals no generalized expression pattern of hBDs across all head and neck cancers. For hBD-1, multiple studies (Han et al. 2014, Wang et al. 2014, Pantelis et al. 2009, Kesting et al. 2012, Wenghoefer et al. 2008) demonstrated reduced expression in OSCC tissue samples. Han et al. (2014) showed that hBD-1 expression decreases progressively from oral precancerous lesions to OSCC, and higher hBD-1 expression was associated with better prognosis and absence of lymph node metastasis. For hBD-2, expression is generally reduced in OSCC, salivary gland tumors, and during malignant transformation of tonsillar carcinoma, though some studies (Chong et al. 2006, Hoppe et al. 2016) found elevated hBD-2 in cancerous tissues. A positive correlation between hBD-2 levels and tumor differentiation in OSCC was reported, and hBD-2 was associated with lymph node metastasis. For hBD-3, most studies found elevated levels in OSCC tissues (Shuyi et al. 2011, Kesting et al. 2009, Hussaini et al. 2006), though contradictory findings exist. hBD-3 has been shown to enhance cancer metastasis through EGFR or TLR4 pathways in SCC-25 cells and can protect HNSCC cells from cisplatin-mediated apoptosis via the PI3/Akt pathway. The authors note that hBD-1 and hBD-2 are downregulated while hBD-3 is increased in head and neck cancers, but this pattern is primarily documented in OSCC.
**Clinical Implications:** The significant shifts in hBD levels in head and neck cancers suggest they may serve as biomarker candidates for early diagnosis. However, the available evidence is highly limited, primarily restricted to OSCC, and almost exclusively based on tissue biopsies using immunohistochemistry. The authors emphasize that hBD expression profiles are cancer-type specific and that creating general principles about β-defensin behavior in cancer must be avoided. They identify a critical need for studies on salivary or serum levels of hBDs, as biopsy collection carries its own risks. The review concludes that defining expression profiles, cellular receptors, and biological roles of hBDs in head and neck cancers may allow researchers to propose their potential use as diagnostic, prognostic, or therapeutic agents, but current evidence is insufficient for clinical application.