SPON2 (spondin 2) is a matricellular extracellular matrix protein with dual roles in immune regulation and cancer progression. As a pattern-recognition molecule, SPON2 promotes macrophage recruitment and innate immune responses 1. However, SPON2 functions exhibit context-dependent effects in different cancers. In hepatocellular carcinoma (HCC), SPON2 promotes M1-like macrophage infiltration via integrin-Rho GTPase signaling and inhibits tumor metastasis, correlating with improved patient prognosis 1. Conversely, in colorectal cancer (CRC), tumor cell-derived SPON2 promotes M2-polarized macrophage infiltration through the integrin β1/PYK2 axis, enhancing tumor progression and poor prognosis 2. SPON2 is a transcriptional target of MACC1 and drives CRC metastasis; high SPON2 expression predicts shorter metastasis-free survival 3. In lung adenocarcinoma, SPON2 activates NF-κB signaling to promote bone metastasis via MMP2/MMP9 upregulation 4. Pan-cancer analysis confirms SPON2 as a biomarker with diagnostic and prognostic value across multiple tumor types 5. Recent spatial immune scoring demonstrates SPON2 enhances NK cell infiltration and IFNγ secretion, with potential utility in predicting HCC recurrence 6. Additionally, SPON2 expression correlates with NK cell-mediated atherosclerotic homeostasis in coronary artery disease 7, and differential SPON2 methylation is associated with autoinflammatory disease 8.