Tenascin-C (TNC) is a hexameric, multimodular extracellular matrix glycoprotein with diverse roles in development and pathology 1. During embryonic development, TNC guides neuronal migration and axon outgrowth and promotes synaptic plasticity and neuronal regeneration through integrin binding (α8β1, α9β1, αVβ3, αVβ6) 2. In adults, TNC expression is restricted but becomes aberrantly upregulated during wound healing, chr9 inflammation, and cancer 1. In ankylosing spondylitis, inflammation-induced TNC secretion by fibroblasts suppresses extracellular matrix adhesion forces and activates Hippo signaling to promote entheseal new bone formation 3. TNC similarly promotes kidney fibrosis through Twist1-mediated fibroblast activation via the Prrx1/TNC axis, with Twist1 inhibition reducing fibrotic pathology 4. In cancer, TNC is strongly overexpressed in tumor stroma and represents a promising therapeutic target; multiple TNC-targeting delivery vectors and conjugate agents including antibody-drug conjugates and radionuclide conjugates are under clinical investigation 5. TNC also plays dual pro- and anti-atherosclerotic roles depending on location, with isoform TNC-C being a promising atherosclerosis-targeted drug delivery vector 6. Overall, pathological TNC overexpression across multiple disease contexts makes it an attractive biomarker and therapeutic target 2.