A mGluR1-targeted radiotheranostic strategy visualizes lesions and potentiates antitumor efficacy in melanoma and pancreatic cancer.

Targeting metabotropic glutamate receptor 1 (mGluR1), an oncoprotein involved in glutamine metabolism that is frequently overexpressed in most cancers, is a promising strategy for cancer treatment and management. Here, we engineered a radiotheranostic strategy to target mGluR1 by integrating positron emission tomography (PET)-guided targeted α-particle therapy (TAT) with a small-molecule pair, β-emitting C-IMTM and α-emitting At-AMTM, to identify and eradicate refractory cancers, including melanoma and pancreatic cancer. C-IMTM PET clearly visualized the primary and metastatic melanoma burden; α-particles from At-AMTM anchored to mGluR1 downregulated this oncoprotein, which was subsequently internalized to trigger cancer cell senescence via the p21/caveolin-1 pathway. In mice with localized and metastatic melanoma, a single dose of At-AMTM induced a >86% reduction in tumor volume and a 2-fold increase in survival. Moreover, 46.67% (7/15) of the tumor-bearing mice exhibited complete elimination of pancreatic cancer without significant toxicity. This mGluR1-targeted radiotheranostic strategy, C-IMTM PET-guided At-AMTM TAT, represents an effective approach for the diagnosis and treatment of melanoma and pancreatic cancer and provides unique insights into the clinical development and application of approaches targeting cancer-specific metabolic vulnerabilities.