FAP-Targeted Radionuclide Therapy: Mechanisms, Clinical Applications, and Combination Strategies

The fibroblast activation protein (FAP) has emerged as a compelling theranostic target because it is highly expressed in the tumour microenvironment of many solid malignancies, predominantly on cancer-associated fibroblasts and, in selected tumour types, also on tumour cells. Following the rapid clinical expansion of FAP-targeted PET imaging, FAP-targeted radionuclide therapy (FAP-TRT) is now being explored as a predominantly stromal-directed therapeutic strategy across a broad range of solid malignancies. However, unlike established theranostic paradigms, such as prostate-specific membrane antigen- and somatostatin receptor-directed radioligand therapies, FAP-TRT faces distinct biological and translational challenges, including stromal heterogeneity, variable patterns of FAP expression, and limited tumour retention of many early radioligands. This review outlines the biological rationale, mechanistic basis, radiopharmaceutical development, and emerging clinical evidence for FAP-TRT. We highlight the recent ligand-engineering strategies aimed to improve tumour residence time and absorbed dose, and to summarise the current clinical data with particular focus on dosimetry, safety, and early efficacy signals. We also discuss key future directions, including disease-focused clinical development and rational combination strategies with immune checkpoint inhibitors, DNA damage response inhibitors, and chemotherapy. Overall, the available data support the feasibility of FAP-TRT but also underscore the need for improved ligand design and biologically informed clinical development to define its role within the evolving theranostic landscape.