A CD81-centered macrophage network links efferocytosis to immunosuppression in head and neck squamous cell carcinoma

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Tumor-associated macrophages (TAMs) critically shape the immunosuppressive tumor microenvironment of head and neck squamous cell carcinoma (HNSCC), yet the identity and functional drivers of tumor-promoting TAM subtypes remain poorly defined. Efferocytosis-driven macrophage reprogramming, ligand–receptor communication, and metabolic remodeling have been implicated in tumor progression, but their integration within a unified TAM regulatory network has not been elucidated. We performed single-cell RNA sequencing on multi-stage HNSCC specimens, combined with spatial transcriptomics, cell–cell communication modeling, and multi-level in vitro and in vivo functional assays to define TAM heterogeneity and dissect mechanistic pathways underlying TAM–tumor interactions. We identified a previously unrecognized CD81 + TAM subtype enriched within the tumor and characterized by potent efferocytosis activity, lipid metabolic reprogramming, and immunosuppressive features. CD81 + TAMs preferentially communicated with tumor cells through the SPP1 –integrin β1 axis, promoting tumor migration, stemness, and immune-evasive programming. Reciprocal GAS6 – MERTK signaling from tumor cells reinforced the immunoregulatory state of CD81 + TAMs. Mechanistically, CD81 activated an integrin β1–TGF-β–p62– CREM transcriptional cascade, driving the expression of MERTK , AXL , and GAS6 , which in turn induced phagocytic mimicry, AXL – GAS6 –Beclin1 activation, and PD-L1/TGF-β up-regulation in tumor cells. Functional inhibition of integrin β1 disrupted this TAM–tumor feedback loop in vivo experiments. Our data reveal a CD81 -centered signaling cascade in which SPP1 –integrin β1 activates TGF-β, engages p62-mediated signal integration, and subsequently induces CREM -dependent up-regulation of MERTK , AXL , and GAS6 , thereby reinforcing efferocytosis and immunosuppression in HNSCC. Targeting CD81 + TAMs or their downstream pathways offers a promising strategy to remodel the immunosuppressive tumor microenvironment and improve therapeutic responses in HNSCC.