BACKGROUND: Considering that trophoblast cell-surface antigen 2 (Trop2) is overexpressed in a wide range of human epithelial cancers, it presents an attractive target for diagnosis and treatment of multiple types of cancer. Herein, we have developed a Trop2-specific radiotracer, ⁶⁸ Ga-MY6349, and present a prospective, investigator-initiated trial to explore the clinical value of ⁶⁸ Ga-MY6349 PET/CT. METHODS: In this translational study, 90 patients with 15 types of cancer who underwent ⁶⁸ Ga-MY6349 PET/CT were enrolled prospectively. Among them, 78 patients underwent paired ⁶⁸ Ga-MY6349 and ¹⁸ F-FDG PET/CT, and 12 patients with prostate cancer underwent paired ⁶⁸ Ga-MY6349 and ⁶⁸ Ga-PSMA-11 PET/CT. RESULTS: Among the 90 patients across 15 types of cancer, ⁶⁸ Ga-MY6349 uptake in tumors was generally high but heterogeneous, varying among lesions, patients, and cancer types. Trop2 expression level determined by immunohistochemistry was highly correlated with ⁶⁸ Ga-MY6349 uptake at primary and metastatic tumor sites. ⁶⁸ Ga-MY6349 PET/CT showed higher tumor uptake (quantified by maximum standardized uptake value) than ¹⁸ F-FDG PET/CT in certain types of cancer, including breast (7.2 vs. 5.4, P < 0.001), prostate (9.2 vs. 3.0, P < 0.001), and thyroid cancers (8.5 vs. 3.7, P < 0.001). Compared with ⁶⁸ Ga-PSMA-11, ⁶⁸ Ga-MY6349 PET/CT exhibited comparable lesion uptake (12.2 vs. 12.5, P = 0.223) but a better tumor-to-background contrast (15.8 vs. 12.2, P < 0.001) for primary and metastatic prostate cancer, allowing visualization of more metastatic lesions. CONCLUSION: ⁶⁸ Ga-MY6349 PET/CT is a noninvasive method for comprehensively assessing Trop2 expression in tumors, which can improve diagnosis and staging for cancer patients and aid in decision making for Trop2-targeted therapies and advancing of personalized treatment. TRIAL REGISTRATION: ClinicalTrials.gov NCT06188468. FUNDING: National Natural Science Foundation of China, National Key R&D Program of China, Nuclear Energy R&D project, Fujian Research and Training Grants for Young and Middle-aged Leaders in Healthcare, Key Scientific Research Program for Young Scholars in Fujian, and Fujian Natural Science Foundation for Distinguished Young Scholars.

Cancer is the leading cause of mortality worldwide. The proliferation and viability of cancer cells are intricately related to the complex tumor microenvironment in which they reside. Cancer-associated fibroblasts (CAFs) play a pivotal role in multiple stages of tumorigenesis, including tumor growth, invasion, metastasis, and resistance to treatment, through intricate crosstalk with tumor and immune cells. Targeted radionuclide therapy involves the systemic administration of small molecule drugs labeled with β-emitting or α-emitting radioisotopes, allowing precise targeting of tumor sites and delivering radiation directly to the tumor. Prostate-specific membrane antigen-targeted radioligand therapy (RLT) and somatostatin receptor-targeted peptide receptor radionuclide therapy (PRRT) have demonstrated favorable safety profiles and significant antitumor efficacy, leading to their approval by the Food and Drug Administration. Recently, the utilization of theranostic approaches that target overexpressed fibroblast activation proteins (FAPs) within the CAFs of the tumor stroma has demonstrated encouraging preliminary outcomes. This review aims to provide a concise summary of current clinical research outcomes and the applications of RLT based on FAP inhibitors in the context of solid tumors.