Clinically, a prognostic model based on TREM2<sup>+</sup> TAM signature genes was trained to independently predict HNSCC outcomes.<h4>Conclusions</h4>This study delineates the mechanism that TREM2<sup>+</sup> TAMs promote LN metastasis in HNSCC by facilitating CD8<sup>+</sup> T cells exhaustion via SPP1-CD44-BHLHE40 axis, proposing TREM2<sup>+</sup> TAMs as potential therapeutic target for HNSCC. This evidence concerns the gene SPP1 and head and neck squamous cell carcinoma.