ObjectiveTo evaluate the efficacy and safety of 177Lu-FAP-2286 radioligand therapy (RLT) in advanced digestive system malignancies and explore its clinical potential as a novel targeted therapeutic approach. MethodsThis retrospective analysis examined clinical data from 19 patients with advanced digestive system tumors who received 177Lu-FAP-2286 treatment at the Affiliated Hospital of Southwest Medical University between June 2023 and December 2024. Treatment response was assessed using response evaluation criteria in solid tumor (RECIST) 1.1 criteria and modified PERCIST（PET response criteria in solid tumor, PERCIST） 1.0 guidelines. Adverse events (AEs) were graded according to CTCAE v5.0. ResultsAt the last follow-up, consistent therapeutic outcomes were observed between RECIST 1.1 and PERCIST 1.0 evaluations, we observed 2 cases of partial response / partial metabolic response, 4 cases of stable disease / stable metabolic disease, and 13 cases of progressive disease / progressive metabolic disease, demonstrating an objective response rate of 10.5% (2/19) and disease control rate of 31.6% (6/19). Post-treatment monitoring revealed 7 AEs of grade 2 and 1 AE of grade 1, with no occurrence of grade 3–4 haematological or hepatorenal toxicities. Common treatment-related symptoms, including nausea, decreased appetite, and fatigue, showed spontaneous resolution over time. ConclusionsPreliminary findings indicate that 177Lu-FAP-2286 exhibits favourable safety and tolerability in patients with advanced digestive system malignancies while demonstrating efficacy in controlling disease progression for a subset of patients. However, multicenter prospective studies with larger cohorts are warranted to further validate its long-term efficacy and identify clinical characteristics of digestive system malignancy patients who may benefit.