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

ABSTRACT 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.