Preclinical studies of fibroblast activation protein (FAP)-2286 showed improved tumor-targeting specificity and prolonged intratumoral retention. However, clinical trials on the safety and efficacy of 177Lu-FAP-2286 for gastrointestinal tumors are limited. This study aims to evaluate its safety and efficacy in patients with FAP-positive gastrointestinal tumors.A prospective, single-center, single-arm clinical trial was conducted at the Affiliated Hospital of Southwest Medical University from December 2020 to December 2024. After confirming FAP expression in tumor lesions using 68Ga-FAP-2286, 177Lu-FAP-2286 targeted radiotherapy was performed. Tumor response was assessed using RECIST 1.1 and PERCIST 1.0 criteria. Adverse events were graded according to the CTCAE 5.0.Fourteen participants (mean age, 62.1 ± 7.6 years) completed 30 treatment cycles. Four participants (28.6 %) achieved stable disease, and ten (71.4 %) exhibited progressive disease. The disease control rate was 28.6 %. No significant correlations were found between clinical efficacy and imaging parameters. No grade III or IV adverse events occurred, but transient nausea, vomiting, and diarrhea were observed.177Lu-FAP-2286 demonstrated good feasibility and safety in treating FAP-positive gastrointestinal tumors, resulting in disease stabilization in a subset of patients.Copyright © 2025. Published by Elsevier B.V.