The Landscape of SPP1 ⁺ Macrophages Across Tissues and Diseases: A Comprehensive Review

Macrophages play a critical role in shaping the immune landscape of various diseases, with secreted phosphoprotein 1 (SPP1)-expressing macrophages emerging as a distinct subset implicated in both cancerous and non-cancerous conditions. Leveraging recent advances in single-cell RNA sequencing, numerous studies have identified SPP1⁺ macrophages across diverse pathological contexts, shedding light on their functional heterogeneity. In cancer, SPP1⁺ tumour-associated macrophages contribute to tumour growth, angiogenesis, and immune evasion, often interacting with T cells and stromal components to sustain an immunosuppressive microenvironment. Conversely, in non-cancerous diseases, these macrophages exhibit both profibrotic and disease-promoting properties, depending on the tissue context. This review provides a comprehensive synthesis of the latest findings on SPP1⁺ macrophages, highlighting their roles in tumour progression, immune suppression, tissue remodelling, and fibrosis. By comparing their shared traits and tissue-specific differences, we explore how SPP1⁺ macrophages adapt to distinct microenvironments and influence disease progression. Understanding their conserved and context-dependent functions may open new avenues for therapeutic targeting.