Tissue analyses further confirmed PFDN2 downregulation and CD64 upregulation in HNSC, correlating with advanced tumor grade and stage.<h4>Conclusions</h4>Our findings establish PFDN2 as a protective plasma protein that restrains HNSC progression by suppressing CD64 on monocyte-mediated inflammatory immune microenvironments, highlighting the PFDN2-CD64 axis as a potential prognostic biomarker and therapeutic target. The gene discussed is FCGR1A; the disease is neoplasm.