Sema7a drives an immunosuppressive microenvironment of breast cancer via Kdm4a-mediated DNA replication regulation.

Breast cancer remains a leading cause of cancer-related mortality worldwide, largely due to the persistence of an immunosuppressive tumor microenvironment that limits therapeutic efficacy. However, the molecular mechanisms underlying this immune suppression are not fully understood. Here, we identify Semaphorin 7 A (Sema7a) as a key regulator of antitumor immunity in breast cancer through its interaction with Lysine Demethylase 4 A (Kdm4a). Transcriptomic analyses of The Cancer Genome Atlas (TCGA) dataset revealed Sema7a as an immune-related hub gene using Weighted Gene Co-expression Network Analysis and Least Absolute Shrinkage and Selection Operator algorithms. Functional experiments in breast cancer cell lines demonstrated that loss of Sema7a reduced Kdm4a expression, induced DNA replication stress, and activated the cGAS-STING signaling pathway, thereby increasing IFN-β and CXCL10 secretion. These changes enhanced CD8⁺ T cell chemotaxis and cytotoxic activity, suppressing tumor growth and metastasis in vivo. Conversely, Kdm4a overexpression reversed the antitumor effects of Sema7a deficiency. Our findings establish the Sema7a-Kdm4a axis as a crucial mechanism shaping the immunosuppressive microenvironment in breast cancer and highlight its potential as a therapeutic target to enhance antitumor immunity.