Background <p>Oral squamous cell carcinoma (OSCC) is an aggressive head and neck malignancy with frequent lymphatic metastasis and poor clinical outcomes. IL-12p40, a shared subunit of IL-12 and IL-23, can engage IL-12Rβ1, but its role in OSCC tumor-cell responses remains unclear. This study investigated whether IL-12p40 promotes OSCC progression and explored the underlying IL-12Rβ1/STAT3/MMP pathway.</p> Methods <p>IL-12p40 expression was examined by immunohistochemistry in 90 OSCC tissues and 60 adjacent oral mucosa samples, and serum IL-12p40 was measured in 30 patients and 15 healthy controls. SCC9 and CAL33 cells were treated with recombinant IL-12p40, anti-IL-12p40 antibody, Stattic, or GM6001. Proliferation, wound healing, migration, invasion, and colony formation were assessed. RNA sequencing, quantitative real-time PCR, western blotting, IL-12Rβ1 silencing, and shRNA-mediated STAT3 knockdown were used for mechanistic validation. Subcutaneous xenograft, orthotopic tongue tumor, and lymphatic metastasis models were established. Statistical analyses included t tests, analysis of variance, chi-square or Fisher’s exact tests, Kaplan-Meier analysis, Cox regression, and receiver operating characteristic analysis.</p> Results <p>IL-12p40 was elevated in OSCC tissues and patient serum. High tissue IL-12p40 expression was associated with lymph-node metastasis and poorer overall survival. IL-12p40 enhanced OSCC cell proliferation, migration, invasion, and colony formation in vitro and promoted tumor growth and lymphatic dissemination in vivo. Mechanistically, IL-12p40 activated IL-12Rβ1/STAT3 signaling and increased MMP2/MMP9 expression. IL-12Rβ1 silencing, STAT3 inhibition, STAT3 knockdown, and GM6001-mediated MMP blockade attenuated these effects.</p> Conclusions <p>IL-12p40 promotes OSCC progression through an IL-12Rβ1/STAT3/MMP-related pathway, suggesting a candidate mechanism that warrants further therapeutic validation.</p>