SPP1-mediated M2 macrophage polarization shapes the tumor microenvironment and enhances prognosis and immunotherapy guidance in nasopharyngeal carcinoma

Secreted phosphoprotein 1 (SPP1) shows carcinogenic potential in multiple cancers, yet its role in nasopharyngeal carcinoma (NPC) remains elusive. Leveraging transcriptomic data sourced from an NPC cohort at Fujian Cancer Hospital, alongside datasets from the Gene Expression Omnibus cohort and a single-cell RNA sequencing dataset, this investigation explored the role of SPP1 in tumor progression and the tumor microenvironment of NPC. A co-culture system involving tumor cells and macrophages was established to elucidate the relationship between SPP1 and tumor-associated macrophages in NPC. Subsequently, we established an SPP1-driven M2 macrophage signature using a machine-learning-based framework to predict patient prognosis. The results of our analysis indicated that SPP1 is associated with an elevated risk of disease progression and poor prognosis in NPC. Single-cell analysis demonstrated that SPP1 is a pivotal gene in the polarization of M2 macrophages within the tumor microenvironment. In vitro experiments demonstrated that NPC-derived SPP1 has the potential to activate the CD44/JAK2/STAT3 signaling pathway, promoting macrophage recruitment and polarization of the M2 subtype. Furthermore, we established a comprehensive SPP1-related M2 macrophage signature that can predict the prognosis and immune characteristics of patients with NPC. Our findings offer new insights into the role of SPP1 in the tumor microenvironment of NPC, and provide a novel SPP1-driven M2 macrophage signature with the potential to serve as a valuable tool for prognosis prediction and personalized therapy in NPC.