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Tumor-associated macrophages (TAMs) constitute the major innate immune population in the TIME where they facilitate crucial regulatory processes that participate in malignant tumor progression. SPP1\u2009+\u2009macrophages (SPP1\u2009+\u2009Macs) are found in many cancers, but their effects on HNSCC remain unknown. This study aimed to identify and validate the role and function of SPP1\u2009+\u2009Macs in the malignant progression of HNSCC.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>In this study, we applied single-cell RNA sequencing (scRNA-seq) analyses of paired tumor and normal tissues from 5 HNSCC patients to identify tumor-specific SPP1\u2009+\u2009Macs. RT-qPCR and multiplex immunohistochemical and multiplex immunofluorescence staining were used to verify the presence of SPP1\u2009+\u2009Macs in the clinical samples. Gene set variation analysis suggested that SPP1\u2009+\u2009Macs were actively involved in cytokine production. Thus, we constructed SPP1-OE macrophages and SPP1-KD macrophages (both differentiated from THP-1 cells), performed a Luminex liquid suspension chip detection assay to detect differential cytokines, and further assessed their biological functions and mechanisms in several HNSCC cell lines and adjacent macrophages. An in vivo experiment was used to verify the function of SPP1\u2009+\u2009Macs in HNSCC progression.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>The scRNA-seq results revealed that myeloid cells were heterogeneous and strongly correlated with tumor cells in the TIME in HNSCC and identified tumor-specific SPP1\u2009+\u2009Macs, which were positively correlated with poor prognosis of HNSCC patients. Gene set variation analysis (GSVA) suggested that SPP1\u2009+\u2009Macs were actively involved in cytokine production. Luminex liquid suspension chip detection assay indicated that SPP1\u2009+\u2009Mac-derived TNF-\u03b1 and IL-1\u03b2 played important roles. Both in vitro and in vivo experiments and the use of VGX-1027, an inhibitor of macrophage-derived TNF-\u03b1 and IL-1\u03b2, confirmed that SPP1\u2009+\u2009Mac-derived TNF-\u03b1 and IL-1\u03b2 promoted HNSCC progression by supporting tumor cell proliferation and migration. Mechanistically, we found that TNF-\u03b1 and IL-1\u03b2 were upregulated due to NF-kappa B signaling pathway activation in SPP1\u2009+\u2009Macs. Moreover, SPP1\u2009+\u2009Mac-derived TNF-\u03b1 and IL-1\u03b2 promoted the expression of OPN in both tumor cells and other adjacent macrophages through different signaling pathways.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>SPP1\u2009+\u2009Macs increase the secretion of TNF-\u03b1 and IL-1\u03b2 via the NF-kappa B pathway to promote HNSCC cell proliferation, and TNF-\u03b1 and IL-1\u03b2 in turn upregulate the expression of OPN in tumor cells and macrophages; thus, SPP1\u2009+\u2009Macs may be a candidate target through which antitumor efficacy can be enhanced.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s13046-024-03255-w","type":"journal-article","created":{"date-parts":[[2024,12,26]],"date-time":"2024-12-26T00:08:51Z","timestamp":1735171731000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":98,"title":["SPP1+\u2009macrophages promote head and neck squamous cell carcinoma progression by secreting TNF-\u03b1 and IL-1\u03b2"],"prefix":"10.1186","volume":"43","author":[{"given":"Chun","family":"Liu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kun","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chuwen","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhen","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peisong","family":"Zhai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haiyan","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianjun","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,12,26]]},"reference":[{"issue":"2","key":"3255_CR1","doi-asserted-by":"publisher","first-page":"161","DOI":"10.1158\/2326-6066.CIR-23-0221","volume":"12","author":"K Wu","year":"2024","unstructured":"Wu K, et al. 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