Unveiling the Tumor Microenvironment Through Fibroblast Activation Protein Targeting in Diagnostic Nuclear Medicine: A Didactic Review on Biological Rationales and Key Imaging Agents.

The tumor microenvironment (TME) is a dynamic and complex medium that plays a central role in cancer progression, metastasis, and treatment resistance. Among the key elements of the TME, cancer-associated fibroblasts (CAFs) are particularly important for their ability to remodel the extracellular matrix, promote angiogenesis, and suppress anti-tumor immune responses. Fibroblast activation protein (FAP), predominantly expressed by CAFs, has emerged as a promising target in both cancer diagnostics and therapeutics. In nuclear medicine, targeting FAP offers new opportunities for non-invasive imaging using radiolabeled fibroblast activation protein inhibitors (FAPIs). These FAP-specific radiotracers have demonstrated excellent tumor detection properties compared to traditional radiopharmaceuticals such as [F]FDG, especially in cancers with low metabolic activity, like liver and biliary tract tumors. The most recent FAPI derivatives not only enhance the accuracy of positron emission tomography (PET) imaging but also hold potential for theranostic applications by delivering targeted radionuclide therapies. This review examines the biological underpinnings of FAP in the TME, the design of FAPI-based imaging agents, and their evolving role in cancer diagnostics, highlighting the potential of FAP as a target for precision oncology.