Breast cancer (BC) is a leading cause of mortality among women globally. Emerging evidence suggests that the immune system is involved in BC pathogenesis, with distinct subtypes showing unique immune responses. Inflammation correlates closely with these immune responses. However, the causal role of immune cell characteristics across BC subtypes and the mediating influence of inflammatory proteins remains unclear. We used bi-directional two-sample Mendelian Randomization (MR) to evaluate causal relationships between 731 immune traits and BC risk, including its subtypes, followed by a two-step mediation analysis with 91 inflammatory proteins. The Inverse Variance Weighted (IVW) method served as the primary analysis, supported by sensitivity and reverse MR analyses. Sixteen immune traits showed significant causal associations with BC and its subtypes, with 108 relationships potentially mediated by inflammatory proteins. Traits such as CD25 on CD24+ CD27+, CD25 on IgD- CD38dim, and HLA DR++ monocyte %monocyte acted as protective factors, while CD40 on CD14- CD16+ monocytes posed risks. Notably, CD40L receptor levels mediated up to 73% of the relationship between IgD-CD27- %B cells and ER+BC. Sensitivity analyses indicated no horizontal pleiotropy or reverse causality. This study underscores immune cells' potential role in BC risk and the mediating impact of inflammatory proteins across subtypes. Targeting specific inflammatory proteins may offer novel strategies for BC risk reduction, informing clinical decision-making and therapeutic development.

The authors have declared no competing interest.

This research was funded by Talent Development Foundation of The First Dongguan Affiliated Hospital of Guangdong Medical University (PF100-2-02), and the Key Discipline Construction Project of Guangdong Medical University (Grant No. 4SG23004G).

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Publicly available datasets were analyzed in this study. The GWAS summary statistics for 731 immune traits could be publicly available in the GWAS Catalog (https://www.ebi.ac.uk/gwas/). Summary statistics for breast cancer and its subtypes are available at http://bcac.ccge.medschl.cam.ac.uk/bcacdata/.