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

Xianan Bai1, Shanshan Cai2, Jie Jiang3

  • 1Department of Breast Surgery, The First People's Hospital of Lianyungang, Lianyungang, China.

Communications Biology
|December 9, 2025
PubMed

Insights

Researchers found that Semaphorin 7A (Sema7a) and Lysine Demethylase 4A (Kdm4a) regulate breast cancer immunity. Targeting this Sema7a-Kdm4a axis may enhance antitumor responses and overcome immune suppression in breast cancer.

Area of Science:

  • Oncology
  • Immunology
  • Molecular Biology

Background:

  • Breast cancer's high mortality is linked to an immunosuppressive tumor microenvironment limiting treatment effectiveness.
  • The precise molecular drivers of this immune suppression remain incompletely understood.
  • Identifying novel regulators is crucial for developing improved therapeutic strategies.

Purpose of the Study:

  • To identify key molecular regulators of antitumor immunity in breast cancer.
  • To elucidate the role of Semaphorin 7A (Sema7a) and its interaction with Lysine Demethylase 4A (Kdm4a) in shaping the tumor microenvironment.
  • To explore the therapeutic potential of targeting the Sema7a-Kdm4a axis.

Main Methods:

  • Transcriptomic analysis of The Cancer Genome Atlas (TCGA) dataset using Weighted Gene Co-expression Network Analysis and Least Absolute Shrinkage and Selection Operator algorithms to identify immune-related hub genes.
  • Functional experiments in breast cancer cell lines to investigate the effects of Sema7a loss on Kdm4a expression, DNA replication stress, and the cGAS-STING signaling pathway.
  • In vivo studies to assess the impact of the Sema7a-Kdm4a axis on tumor growth, metastasis, and CD8+ T cell activity.

Main Results:

  • Semaphorin 7A (Sema7a) was identified as a critical immune-related hub gene in breast cancer.
  • Loss of Sema7a led to reduced Kdm4a expression, induced DNA replication stress, and activated the cGAS-STING pathway, increasing IFN-β and CXCL10 secretion.
  • These molecular changes promoted CD8+ T cell chemotaxis and cytotoxicity, suppressing tumor growth and metastasis in vivo. Kdm4a overexpression counteracted these effects.

Conclusions:

  • The Semaphorin 7A (Sema7a)-Lysine Demethylase 4A (Kdm4a) axis is a key mechanism driving immunosuppression in the breast cancer microenvironment.
  • This axis represents a promising therapeutic target for enhancing antitumor immunity and improving treatment outcomes in breast cancer.
  • Further research into modulating the Sema7a-Kdm4a interaction could lead to novel immunotherapeutic strategies.

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