ISLR (immunoglobulin superfamily containing leucine-rich repeat) is a secreted stromal protein with dual roles in tissue homeostasis and cancer progression. Primary function: ISLR functions as a cell adhesion molecule located in the extracellular region and platelet alpha granules 1. Mechanism: ISLR operates through multiple signaling pathways. In intestinal epithelium, stromal ISLR suppresses Hippo signaling and activates YAP to promote epithelial cell growth during regeneration 2. In cancer-associated fibroblasts (CAFs), ISLR promotes bone morphogenetic protein (BMP) signaling, contrasting with GREM1 which inhibits it 3. ISLR is regulated by BMP9/ALK1 signaling in cardiac progenitor cells and coordinates angiogenic responses 4. In gastric cancer, ISLR interacts with MGAT5 to promote malignant progression via epithelial-mesenchymal transition 5. Disease relevance: High ISLR expression correlates with poor survival in colorectal cancer but favorable survival when promoted in stromal cells 3. In triple-negative breast cancer, ISLR promotes immune evasion by stabilizing immunosuppressive niches via MIF/CD74 signaling 6. ISLR marks cancer-restraining CAFs in pancreatic cancer and maintains mesenchymal cell undifferentiation in adipose tissue 78. Clinical significance: ISLR represents a promising therapeutic target; AAV8-mediated ISLR delivery improved survival in hepatic metastasis models, while ISLR knockdown enhanced radiotherapy-induced anti-tumor immunity 36.