Senescence is a critical risk factor for the development of triple‐negative breast cancer (TNBC), yet its specific impact on the disease remains inadequately understood. This study aims to elucidate the role of pivotal genes in mediating the effects of gene expression on cell senescence and TNBC progression. We employed a combination of Mendelian randomization (MR) and single‐cell RNA sequencing to investigate these relationships. A two‐sample MR approach was utilized to assess causal links between pivotal genes and TNBC. Single‐cell transcriptomic analysis of senescence and TNBC datasets from the Gene Expression Omnibus database revealed a significant association between the gene GZMK and increased TNBC risk. Our single‐cell analysis uncovered a complex network of ligand–receptor interactions in GZMK + central memory CD8+ T cells (CD8CM), which frequently interacted with macrophages, monocytes, and epithelial cells. GZMK expression was correlated with pseudotime progression, indicating its potential role in TNBC development. Enrichment analysis suggested that GZMK + CD8CM cells play a role in enhancing immune process regulation, pointing to a broader immune response. Bulk sequencing further confirmed the presence of GZMK expression in TNBC samples. Functional experiments demonstrated that GZMK significantly influences the proliferation, migration, and invasion of TNBC cell lines in vitro. Our findings reveal intricate interactions among immune cell composition, GZMK expression, senescence, and TNBC, highlighting GZMK as a potential molecular target for therapeutic intervention. This study advances the understanding of TNBC pathogenesis and opens new avenues for precision medicine in TNBC treatment.
Zhou et al. (Thu,) studied this question.