Secreted phosphoprotein 1 (SPP1)

Secreted phosphoprotein 1 (Spp1), also known as osteopontin (OPN), is a multifunctional, secreted glycoprotein that plays critical roles in immune regulation, cell adhesion, and extracellular matrix remodeling. As a phosphorylated protein containing integrin-binding and cell adhesion motifs, Spp1 serves as a key immunomodulatory factor in diverse pathophysiological contexts, including cancer, atherosclerosis, and inflammatory diseases. In the tumor microenvironment, Spp1 is predominantly expressed by tumor-associated macrophages (TAMs) and functions as a major driver of immunosuppression by promoting the infiltration and activation of regulatory T cells (Tregs) while simultaneously inhibiting CD8+ cytotoxic T cell function. Beyond its role as a soluble factor, Spp1 mediates cell-cell interactions and is regulated by multiple upstream signaling pathways including interferon signaling, STAT proteins, and receptor tyrosine kinase cascades, making it a focal point for understanding how tumors evade immune surveillance and develop resistance to immunotherapies.

Spp1 has emerged as a key molecular target in understanding tumor immune evasion mechanisms and therapy resistance. Recent studies have demonstrated that elevated Spp1 expression in macrophages and stromal compartments is strongly associated with poor prognosis and reduced response to checkpoint inhibitors and other anticancer therapies, highlighting its therapeutic potential as both a prognostic biomarker and intervention target.