SPP1 macrophages across diseases: A call for reclassification?

SPP1+ macrophages, characterized by elevated expression of the osteopontin gene (secreted phosphoprotein 1, SPP1), have emerged as key players in various pathological contexts, including aging, chronic inflammatory diseases, and cancer. While frequently classified as a subclass of tumor-associated macrophages in oncological settings, their presence in noncancer conditions, such as aging-related disorders and muscular diseases, suggests a broader role beyond tumors. These macrophages share conserved traits, including fibrosis promotion, extracellular matrix remodeling, and immune modulation, often linked to poor clinical outcomes. This perspective explores the multifaceted roles of SPP1+ macrophages across diseases and advocates for their reclassification as a distinct macrophage subtype associated with chronic or prolonged inflammation. Recognizing their cross-disease relevance could reshape macrophage biology and inform targeted therapeutic strategies.