Purpose: Gastric cancer (GC), one of the most prevalent and deadliest tumors worldwide, is often diagnosed at an advanced stage with limited treatment options and poor prognosis. The development of a CLDN18.2-targeted radioimmunotherapy probe is a potential treatment option for GC.Methods: The CLDN18.2 antibody TST001 (provided by Transcenta) was conjugated with DOTA and radiolabeled with the radioactive nuclide Lu-177. The specificity and targeting ability were evaluated by cell uptake, imaging and biodistribution experiments. In BGC823(CLDN18.2)/AGS(CLDN18.2) mouse models, the efficacy of [Lu-177]Lu-TST001 against CLDN18.2-expressing tumors was demonstrated, and toxicity was evaluated by H&E staining and blood sample testing.Results: [Lu-177]Lu-TST001 was labeled with an 99.17%+/- 0.32 radiochemical purity, an 18.50 +/- 1.27 MBq/nmol specific activity and a stability of >= 94% after 7 days. It exhibited specific and high tumor uptake in CLDN18.2-positive xenografts of GC mouse models. Survival studies in BGC823(CLDN18.2) and AGS(CLDN18.2) tumor-bearing mouse models indicated that a low dose of 5.55 MBq and a high dose of 11.10 MBq [Lu-177]Lu-TST001 significantly inhibited tumor growth compared to the saline control group, with the 11.1 MBq group showing better therapeutic efficacy. Histological staining with hematoxylin and eosin (H&E) and Ki67 immunohistochemistry of residual tissues confirmed tumor tissue destruction and reduced tumor cell proliferation following treatment. H&E showed that there was no significant short-term toxicity observed in the heart, spleen, stomach or other important organs when treated with a high dose of [Lu-177]Lu-TST001, and no apparent hematotoxicity or liver toxicity was observed.Conclusion: In preclinical studies, [Lu-177]Lu-TST001 demonstrated significant antitumor efficacy with acceptable toxicity. It exhibits strong potential for clinical translation, providing a new promising treatment option for CLDN18.2-overexpressing tumors, including GC.