Abstract
BACKGROUND: CCR5 is a chemokine receptor involved in immune regulation and tumor progression. Its role in predicting therapy response in breast cancer remains unclear. METHODS: We evaluated CCR5 protein expression in a clinical cohort of 66 breast cancer patients treated with NAC, assessing its association with pathological complete response (pCR). Prognostic relevance was validated in the Kaplan-Meier Plotter database. We further investigated CCR5's predictive value in a cohort receiving chemo-immunotherapy (GSE173839). Immune-related transcriptional features were assessed via GSEA and deconvolution analysis. The structural impact of the V131I CCR5 variant was explored using AlphaFold modeling, molecular dynamics simulations, and AI-based protein stability prediction. RESULTS: High CCR5 expression was associated with reduced pCR rates in the NAC cohort (OR = 0.06, P = 0.012) and with poorer RFS, particularly in HER2-negative subtypes (P = 0.009). In contrast, CCR5-high tumors in the chemo-immunotherapy cohort exhibited significantly higher pCR rates (OR = 2.5, P = 0.046), suggesting a suppressed yet immune-infiltrated microenvironment potentially responsive to immune reactivation. GSEA analysis and immune cell infiltration profiling indicate a coexistence of immune activation and immunosuppression. Structural modeling of the V131I variant suggested increased conformational flexibility and reduced stability of CCR5, implying a potential sensitivity to subtle structural perturbations. CONCLUSION: Our study supports a dual regulatory hypothesis, in which CCR5 expression may influence immune dynamics and therapeutic response, while its structural stability may serve as a potential modulatory factor. This hypothesis-generating observation suggests that CCR5 could represent a potential prognostic and predictive biomarker, particularly in NAC-refractory or immune-inflamed breast cancers.