BACKGROUND: The incidence of gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) has been rising. However, current prognostic evaluation systems have certain limitations. As a key component of the tumor microenvironment, the prognostic value of tumor-infiltrating lymphocytes (TILs) in GEP-NENs remains controversial. This study aims to systematically evaluate the prognostic impact of common TILs subsets, including CD3+, CD4+, CD8+, and FoxP3 + cells, in patients with GEP-NENs to provide evidence-based support. METHODS: Following the PRISMA guidelines, we systematically searched PubMed, EMBASE, the Cochrane Library, and Web of Science for studies published up to February 2026. Two researchers independently completed the literature screening, data extraction, and quality assessment using the Newcastle-Ottawa Scale (NOS). Meta-analysis was performed using Stata 17.0 software to calculate pooled hazard ratios (HR) with 95% confidence intervals (CI). Heterogeneity testing, subgroup analysis, sensitivity analysis, and GRADE certainty of evidence assessment were also conducted. RESULTS: A total of 8 studies involving 915 patients were included after corrected literature screening. The meta-analysis demonstrated that a high density of FoxP3+ TILs was significantly associated with worse overall survival (OS) in patients with GEP-NENs (HR = 2.18, 95% CI: 1.36-3.49, P = 0.001). In contrast, infiltration of CD3+, CD4+, and CD8+ TILs showed no significant correlation with OS. The analysis of total TILs was not meta-analyzed as only one study reported this data; qualitatively, it showed a significant association with OS (HR = 1.37, 95% CI: 1.13-1.65). Exploratory subgroup analyses indicated that the prognostic value might be influenced by tumor location and the site of TILs detection. Sensitivity analysis confirmed the stability of the results, and publication bias could not be reliably assessed due to the small number of studies. GRADE assessment showed low-to-moderate certainty of evidence for all pooled estimates. CONCLUSION: High infiltration of FoxP3+ TILs can serve as a potential prognostic biomarker for poor prognosis in patients with GEP-NENs. The prognostic value of CD3+, CD4+, and CD8+ TILs remains unclear. The evaluation of TILs subsets is influenced by tumor characteristics and may help guide prognostic stratification and immunotherapeutic strategies. However, further validation through multicenter prospective studies and standardized protocols is needed.
Zheng et al. (Mon,) studied this question.