CCR5 expression and conformational stability as potential cooperative modulators of immune phenotypes and therapy response in breast cancer

Sep 30, 2026

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CCR5 is a chemokine receptor central to immune regulation and tumor progression, yet its ability to forecast breast cancer therapy response remains uncertain. A clinical cohort of 66 NAC-treated patients was used to assess CCR5 protein expression and its relationship with pathological complete response (pCR), with prognostic relevance tested in the Kaplan–Meier Plotter database. Predictive value was evaluated in a chemo-immunotherapy cohort (GSE173839) using GSEA, immune deconvolution, and structural analyses of the V131I variant via AlphaFold and molecular dynamics.

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Abstract

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Hu etal. Discover Oncology (2026) 17:31 [https://doi.org/10.1007/s12672-025-04189-1](https://doi.org/10.1007/s12672-025-04189-1) Discover Oncology RESEARCH Open Access CCR5 expression and conformational stability as potential cooperative modulators of immune phenotypes and therapy response in breast cancer En Hu 1,2†, Peiyu Qiu3†, Andre Dekker2, Leonard Wee2, Chuntao Quan 1, Deju Zhang 1, Wenjie Liang2 and Ni Xie 1* †En Hu and Peiyu Qiu contributed equally to this work and shared first authorship. *Correspondence: Ni Xie [xn100@szu.edu.cn](xn100@szu.edu.cn) 1Department of biobank, Department of pathology, Shenzhen Second People’s Hospital, Shenzhen 518035, People’s Republic of China 2Department of Radiation Oncology (Maastro), GROW Research Institute for Oncology and Reproduction, Maastricht University Medical Centre+, Maastricht, The Netherlands 3Department of Respiratory Medicine, NUTRIM, Institute for Nutrition and Translational Research in Metabolism, Maastricht University Medical Center+, Maastricht, The Netherlands 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 hypothesisgenerating observation suggests that CCR5 could represent a potential prognostic and predictive biomarker, particularly in NAC-refractory or immune-inflamed breast cancers. Keywords CCR5, Breast cancer, Pathological complete response, Immunotherapy, Tumor microenvironment © The Author(s) 2025. Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need t

FAQs

What was the main objective of the study regarding CCR5 in breast cancer?

To determine whether CCR5 expression and CCR5 structural stability can cooperatively modulate immune phenotypes and predict therapy response in breast cancer.

How was CCR5 protein expression evaluated and linked to treatment outcomes?

CCR5 protein expression was assessed in a clinical cohort of 66 NAC-treated patients and tested for association with pathological complete response (pCR), with further prognostic validation using the Kaplan–Meier Plotter database.

What do the findings suggest about the effect of the CCR5 V131I variant?

Structural modeling indicates the V131I variant may increase conformational flexibility and reduce CCR5 stability, implying sensitivity to subtle structural perturbations relevant to immune dynamics.

Sep 30, 2026

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