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IL-12p40, a shared subunit of IL-12 and IL-23, can engage IL-12R\u03b21, but its role in OSCC tumor-cell responses remains unclear. This study investigated whether IL-12p40 promotes OSCC progression and explored the underlying IL-12R\u03b21\/STAT3\/MMP pathway.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats: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-12R\u03b21 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\u2019s exact tests, Kaplan-Meier analysis, Cox regression, and receiver operating characteristic analysis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats: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-12R\u03b21\/STAT3 signaling and increased MMP2\/MMP9 expression. IL-12R\u03b21 silencing, STAT3 inhibition, STAT3 knockdown, and GM6001-mediated MMP blockade attenuated these effects.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>IL-12p40 promotes OSCC progression through an IL-12R\u03b21\/STAT3\/MMP-related pathway, suggesting a candidate mechanism that warrants further therapeutic validation.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12935-026-04413-0","type":"journal-article","created":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T12:14:37Z","timestamp":1784204077000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["IL-12p40 drives oral squamous cell carcinoma progression via MMPs and IL-12R\u03b21\/STAT3 signaling"],"prefix":"10.1186","volume":"26","author":[{"given":"Dongxiao","family":"Tang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaoqin","family":"Tu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiting","family":"Shao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuxuan","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nan","family":"Wei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongkun","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Feng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zheng","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,7,16]]},"reference":[{"key":"4413_CR1","doi-asserted-by":"publisher","first-page":"209","DOI":"10.3322\/caac.21660","volume":"71","author":"H Sung","year":"2021","unstructured":"Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. 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