Dissecting the Genetic Causality Between Immune Cell Traits and ER-Negative Breast Cancer Outcomes

Abstract Estrogen receptor-negative (ER−) breast cancer is an aggressive subtype with limited therapeutic options. The immune system plays a critical role in tumor progression and patient prognosis, yet the causal relevance of specific immune traits remains unclear.We performed a bidirectional two-sample Mendelian randomization (MR) analysis to assess the causal relationships between 731 peripheral immune cell phenotypes and overall survival in ER − breast cancer. Genetic instruments were derived from GWAS of 3,757 individuals of European descent, and ER − breast cancer survival data were obtained from a meta-analysis of 37,954 patients. Causal estimates were primarily calculated using the inverse-variance weighted (IVW) method, supported by multiple sensitivity analyses.In the forward MR analysis, 22 immune traits—spanning CD4⁺ and CD8⁺ T cells, regulatory T cells, B cells, and activated monocytes—were significantly associated with improved survival. These included elevated levels of memory T cells, CD28⁺ CD8⁺ T cells, IgD⁻ CD38⁻ B cells, and increased CD40/CD64 expression on monocytes. In contrast, 18 immune traits—including exhausted T cell subsets, naïve CD4⁺ T cells, and IgD⁺ B cells—were associated with poorer outcomes. Reverse MR analysis revealed 46 immune traits positively and 23 negatively influenced by ER − breast cancer survival.This study provides robust genetic evidence for bidirectional causal relationships between immune phenotypes and ER − breast cancer prognosis. Our findings highlight both protective and detrimental immune signatures, offering insights into tumor-immune interactions and potential immunotherapeutic targets in ER − breast cancer.