Radical nephroureterectomy (RNU) is the standard treatment for locally advanced upper tract urothelial carcinoma (UTUC); however, disease recurrence and progression following surgery remain common, emphasizing the need for reliable prognostic markers. Tumor-associated macrophages (TAMs), particularly CD163+ TAMs, are important immune cells within the tumor microenvironment and have been linked to tumor progression across various cancers. GATA3, a transcription factor involved in cell differentiation and immune response, has also emerged as a potential prognostic marker in UTUC. This study investigates the relationship between CD163+ TAM infiltration and GATA3 expression in advanced UTUC (≥ pT3) and assesses their impact on disease progression after RNU.

This retrospective, single-center study obtained ethical committee approval from Institutional Review Board. Clinicopathological data and tumor samples were collected from 136 patients with locally advanced UTUC treated with RNU from 2017 to 2021 at National Cheng Kung University hospital. Immunohistochemical (IHC) analysis was conducted on UTUC tissue samples using anti-CD163 and anti-GATA3 antibodies to measure TAM density and GATA3 expression. CD163+ TAMs were quantified by averaging macrophage density (count/mm⊃2;) in ten intra-tumoral hotspots at 400× magnification. GATA3 expression was assessed with an H-score, combining staining intensity (0–3) and the percentage of positive cells. Kaplan-Meier and multivariate Cox regression analyses were used to evaluate the effects of CD163+ TAM density and GATA3 expression on metastasis-free survival (MFS) and cancer-specific survival (CSS) after RNU.

High CD163+ TAM density was inversely associated with GATA3 expression. Patients with both low GATA3 expression and high CD163+ TAM density had significantly worse MFS and CSS compared to those with either low GATA3 or high TAM density alone (P < 0.001). Both factors independently predicted poor survival outcomes in multivariate Cox regression analyses.

The combination of high CD163+ TAM infiltration with low GATA3 expression identifies UTUC patients at increased risk of post-surgical progression, underscoring their value as prognostic markers. These biomarkers can assist in risk stratification and support targeted therapies for high-risk UTUC patients.