FAP-targeted gold nanocluster-mediated radioligand therapy in combination with TGF-βRI inhibition for tumor therapy.

Targeted radioligand therapy (TRT) is an emerging treatment modality that selectively delivers radioisotopes to tumors while sparing healthy tissues. However, optimizing TRT radiopharmaceuticals to concurrently achieve sustained tumor retention and rapid systemic clearance remains a fundamental challenge. Gold nanoclusters with favorable pharmacokinetic properties and tunable blood half-life are advantageous in addressing this issue. Here, we develop a renally clearable GN-based TRT agent (GNFAPI) that efficiently chelates diagnostic 68Ga or therapeutic 177Lu isotopes, conferring precise targeting of fibroblast activation protein (FAP)-enriched and cancer-associated fibroblast (CAF)-dominated tumor stroma for integrated tumor theranostics. PET imaging demonstrates high tumor-specific uptake and renal clearance of 68Ga-GNFAPI in multiple models, with minimal retention in the liver and spleen. For treatment, we propose the Radio-Hook based Crosstalk Cut (RHCC) strategy, synergizing 177Lu-GNFAPI with a TGF-βRI inhibitor. This strategy utilizes β-radiation from 177Lu-GNFAPI like a powerful "hook" to disrupt the stroma and tumor cells, while the inhibitor blocks tumor-stromal crosstalk, thus abrogating the TGF-β-CAF-tumor feedback loop to suppress residual CAF reactivation, inhibit metastasis, and enhance antitumor immunity. Moreover, species-specific transcriptomics in patient-derived xenograft (PDX) models further elucidates the underlying mechanisms. Validation across various tumor models, achieving complete responses in some instances, supports its clinical translational promise.