ADAM12 is a metalloprotease with multifaceted roles spanning immune regulation, tissue regeneration, and disease pathology. Mechanistically, ADAM12 functions through proteolytic cleavage of membrane-bound substrates and extracellular matrix components. In reproduction, ADAM12S regulates trophoblast invasion during placentation 1, and processes epiregulin precursors to facilitate decidualization and embryo implantation 2. In skeletal tissues, ADAM12 variants associate with osteoarthritis susceptibility, particularly the rs1871054 polymorphism in Asian populations 3. ADAM12 expression marks functionally distinct cell populations in the tumor microenvironment: ADAM12+ fibroblasts promote pathological angiogenesis and immunosuppression 4, while ADAM12 expression in cancer-associated fibroblasts impedes anti-tumor immunity through TGF-β signaling 5. In glioblastoma, ADAM12 promotes temozolomide resistance by shedding TNF-α to activate NF-κB pathways and upregulate MGMT 6. ADAM12 emerges as a viable immunotherapeutic target: vaccination against ADAM12 reduces pancreatic cancer desmoplasia and depletes pro-tumoral fibroblasts 7. Conversely, in tendon repair, ADAM12+ fibroblasts contribute to fibrotic adhesion formation 8. These findings position ADAM12 as a therapeutic checkpoint amenable to targeted intervention across oncologic and regenerative contexts.