Gallium 68 fibroblast-activation protein inhibitor PET/CT had a higher tracer uptake and was superior to fluorine 18 fluorodeoxyglucose PET/CT in the detection of primary and metastatic lesions in ... Background Accurate clinical staging is crucial to managing gastrointestinal cancer, but fluorine 18 (18F) fluorodeoxyglucose (FDG) PET/CT has limitations. Targeting fibroblast-activation protein i...

In recent years, quinoline-based fibroblast activation protein (FAP) inhibitors (FAPI) have shown promising results in the diagnosis of cancer and several other diseases, making them the hotspot of much productive research. This review summarizes the literature for the state-of-the-art FAPI-PET imaging for cancer diagnosis compared with fluorodeoxyglucose (FDG)-PET. We also summarize the use of FAPI-PET for therapeutic regimen improvement and fibroblast activation protein (FAP)-targeted molecule modification strategies, as well as preliminary clinical studies regarding FAP-targeted radionuclide therapy. Our qualitative summary of the literature to date can inform future research directions, medical guidelines, and optimal clinical decision-making.

Radiotherapy combined with immune checkpoint blockade holds great promise for synergistic antitumor efficacy. Targeted radionuclide therapy delivers radiation directly to tumor sites. LNC1004 is a fibroblast activation protein (FAP)-targeting radiopharmaceutical, conjugated with the albumin binder Evans Blue, which has demonstrated enhanced tumor uptake and retention in previous preclinical and clinical studies. Herein, we demonstrate that ⁶⁸Ga/¹⁷⁷Lu-labeled LNC1004 exhibits increased uptake and prolonged retention in MC38/NIH3T3-FAP and CT26/NIH3T3-FAP tumor xenografts. Radionuclide therapy with ¹⁷⁷Lu-LNC1004 induced a transient upregulation of PD-L1 expression in tumor cells. The combination of ¹⁷⁷Lu-LNC1004 and anti-PD-L1 immunotherapy led to complete eradication of all tumors in MC38/NIH3T3-FAP tumor-bearing mice, with mice showing 100% tumor rejection upon rechallenge. Immunohistochemistry, single-cell RNA sequencing (scRNA-seq), and TCR sequencing revealed that combination therapy reprogrammed the tumor microenvironment in mice to foster antitumor immunity by suppressing malignant progression and increasing cell-to-cell communication, CD8⁺ T-cell activation and expansion, M1 macrophage counts, antitumor activity of neutrophils, and T-cell receptor diversity. A preliminary clinical study demonstrated that ¹⁷⁷Lu-LNC1004 was well-tolerated and effective in patients with refractory cancers. Further, scRNA-seq of peripheral blood mononuclear cells underscored the importance of addressing immune evasion through immune checkpoint blockade treatment. This was emphasized by the observed increase in antigen processing and presentation juxtaposed with T cell inactivation. In conclusion, our data supported the efficacy of immunotherapy combined with ¹⁷⁷Lu-LNC1004 for cancer patients with FAP-positive tumors.