Bridging the gaps in fibroblast activation protein targeted radionuclide therapy: a translational perspective

Fibroblast activation protein-targeted radionuclide therapy (FAP-TRT) has emerged as a novel strategy for modulating the tumour microenvironment (TME) by selectively eradicating FAP-expressing cancer-associated fibroblasts (CAFs). Although preclinical studies have demonstrated promising results across various tumour models using diverse radiolabelled FAP inhibitors, clinical translation remains limited by modest efficacy, short tumour retention, and highly heterogeneous responses. This review aims to provide an overview of recent advances in radiopharmaceutical design to enhance tumour targeting and prolong retention. Furthermore, we summarise early clinical findings and ongoing trials, while emphasising the potential translational challenges of FAP-TRT. Special emphasis is placed on the radiobiological underpinnings of FAP-TRT, including the impact of CAFs heterogeneity, potential pro-tumorigenic effects of sublethal irradiation, and the uncertain contribution of bystander and abscopal effects. We further highlight the need for the development of translationally relevant tumour models, optimised dosimetry, predictive biomarkers, and refined patient selection criteria. Finally, we propose future directions such as combination therapy with immune checkpoint inhibitors (ICIs). Together, these insights aim to bridge the gap between promising preclinical efficacy and limited clinical outcomes in FAP-TRT.