SPP1 (secreted phosphoprotein 1), also known as osteopontin, is a secreted glycoprotein that functions as a critical regulator of tumor microenvironment dynamics and immune responses across multiple cancer types. In colorectal cancer, SPP1+ macrophages interact with FAP+ fibroblasts to create immune-excluded environments that limit T cell infiltration and confer resistance to anti-PD-L1 immunotherapy 1. SPP1 drives colorectal cancer liver metastasis by stimulating CXCL12 production in cancer-associated fibroblasts through β-catenin/HIF1α signaling, which promotes epithelial-mesenchymal transition while suppressing CD8+ T cell infiltration 2. In head and neck squamous cell carcinoma, SPP1+ macrophages promote tumor progression by secreting TNF-α and IL-1β via NF-κB pathway activation 3. Beyond cancer, SPP1+ macrophages contribute to organ fibrosis in idiopathic pulmonary fibrosis through increased proliferation and myofibroblast activation 4, and drive atrial fibrillation through cross-talk with immune and stromal cells 5. In pancreatic cancer, SPP1 maintains mesenchymal cell fate by binding CD61 receptors and forming a regulatory loop with GREM1 6. These findings establish SPP1 as a key orchestrator of pathological tissue remodeling and immune evasion.