Fibroblast Activation Protein (FAP)

Class

FAP-targeted radioligand therapy (177Lu-labeled small-molecule/peptidomimetic ligand)

Pathway

Cancer-associated fibroblast stromal marker overexpressed in tumor stroma of most epithelial malignancies

Fibroblast Activation Protein (FAP) is a cell-surface serine protease that is largely absent from normal adult tissues but becomes highly expressed on cancer-associated fibroblasts, the supporting stromal cells that surround tumor cells in most solid, epithelial-derived cancers. Because this stromal compartment is present across a wide range of tumor types and is relatively consistent in its FAP expression, it offers a broad, tumor-selective handle that does not depend on the genetic makeup of the cancer cells themselves. Radioligand therapies exploit this by attaching a small molecule or peptide-like ligand that binds FAP to a radioactive isotope, in this case lutetium-177, a beta-particle emitter. Once the ligand localizes to FAP-rich stroma, the emitted radiation damages nearby cells, including tumor cells adjacent to the stroma, through direct and crossfire effects. This strategy is being explored broadly across epithelial malignancies precisely because tumor stroma, rather than a specific oncogenic mutation, is the shared feature being targeted. The approach reflects a general principle in oncology: rather than attacking the tumor cell directly, therapy can be directed at the supportive microenvironment that tumors depend on for growth, invasion, and immune evasion, offering a mechanism applicable across otherwise molecularly distinct cancers.