Aggressive Breast Cancer Found to Suppress Immune Response Through Newly Identified Mechanism
Researchers at The Institute of Cancer Research, London, and King’s College London identified a mechanism by which the HORMAD1 gene suppresses immune response in triple-negative breast cancer, according to a study published recently in Nature Communications. The gene disrupts DNA safety mechanisms and promotes PD-L1 overexpression, which inhibits T cell activity and fosters tumor immune evasion, officials said.
The study, published on July 12, 2024, in Nature Communications (DOI 10.1038/s41467-026-69561-3), detailed how HORMAD1 gene activation disrupts DNA safety mechanisms in triple-negative breast cancer (TNBC), leading to the accumulation of DNA errors passed to daughter cancer cells. Researchers from the Breast Cancer Now Toby Robins Research Centre at The Institute of Cancer Research, London, and the Breast Cancer Now Research Unit at King’s College London found that this disruption promotes tumor growth and resistance to treatment by altering proteins critical for DNA replication. Officials from Breast Cancer Now described the findings as uncovering “a new weakness in triple negative breast cancer linked to a gene called HORMAD1.”
The study also elucidated how TNBC cells overexpress the immune checkpoint protein PD-L1 within the tumor microenvironment, suppressing antitumor immune responses.
This overexpression is driven by epigenetic mechanisms that inhibit T cell activation, proliferation, and cytotoxicity, officials said. The research identified that PD-L1 upregulation occurs through blockade of the RAS-MEK-ERK and PI3K-Akt-mTOR signaling pathways, which are essential for immune cell function. Additional suppression is mediated by the CTLA-4/B7 pathway, which enhances regulatory T cell (Treg) activity via metabolic reprogramming, fostering an immunosuppressive environment, according to a related study cited in PMC12624998.
Further contributing to immune evasion, the transcription factor HIF-1α was shown to increase levels of microRNA-210, which in turn elevates ARG1, Cxcl12, and IL-16 expression in myeloid-derived suppressor cells (MDSCs). These molecules collectively inhibit anti-tumor immunity, officials confirmed.
Complementing these findings, researchers at the Medical University of South Carolina’s Hollings Cancer Center developed an experimental antibody targeting secreted frizzled-related protein 2 (SFRP2), a protein that promotes angiogenesis, prevents programmed cell death, and impairs immune cell function in TNBC. Preclinical tests published in Breast Cancer Research demonstrated that the antibody slowed primary tumor growth, reduced lung metastases, and eliminated chemotherapy-resistant cancer cells. The antibody also reactivated immune cells within the tumor microenvironment, indicating potential for precision therapy, sources said.
Meanwhile, a team at King’s College London engineered a “triple-engineered antibody” designed to bind both TNBC cells and immune cells with higher affinity than existing treatments. Laboratory and animal model experiments revealed that this antibody activated both tumor-resident and circulating immune cells, limiting growth of triple-negative and treatment-resistant breast cancers. The development was announced in a King’s College London news release dated June 15, 2024, which highlighted the therapy’s ability to harness the body’s immune defenses to improve cancer detection and elimination.
Metabolic reprogramming in TNBC further contributes to immune suppression, according to a study published in Frontiers in Immunology (DOI 10.3389/fimmu.2026.1760782). TNBC cells alter glutamine metabolism to monopolize nutrients, creating a nutrient-depleted environment for immune cells and generating immunosuppressive metabolites. The study detailed how purinergic signaling via the adenosine checkpoint increases cyclic AMP levels, which inhibits T cell proliferation, interferon-gamma production, and cytotoxic activity, officials said.
Additional research from a Chinese team revealed that the long non-coding RNA FAM83H-AS1 rewires the cGAS-STING pathway in aggressive breast cancers. Instead of promoting an interferon-driven anti-tumor immune response, FAM83H-AS1 shifts signaling toward NF-κB-mediated chronic inflammation, which benefits tumor growth. Elevated FAM83H-AS1 levels were linked to weakened anti-tumor immunity and poorer patient survival. The molecule is frequently amplified in tumor tissue, contributing to an immunosuppressive tumor microenvironment, the researchers reported.
The role of regulatory immune cells and cytokines in breast cancer was also confirmed through various studies. Myeloid-derived suppressor cells promote regulatory T cells while suppressing cytotoxic T lymphocytes, dendritic cells, and natural killer cells within the tumor environment. Interleukin-6 (IL-6) was shown to establish a feed-forward loop that expands cancer stem cells, inhibits apoptosis, and promotes inflammation and angiogenesis. An abstract presented at the American Association for Cancer Research (AACR) annual meeting (Abstract 2875) reported increased FoxP3-positive regulatory T cells in ductal carcinoma in situ (DCIS), indicating immunosuppression at early stages of breast cancer. Elevated expression of the exhaustion marker Tim-3 on CD4+ and CD8+ T cells was observed prior to invasive cancer development, confirming early immune dysfunction.
Together, these findings provide a detailed map of the molecular and cellular mechanisms by which aggressive triple-negative breast cancers evade immune detection and resist treatment. Researchers emphasized that targeting these pathways, including HORMAD1 activity, PD-L1 expression, metabolic reprogramming, and regulatory immune cells, could inform the development of new therapeutic strategies aimed at improving patient outcomes.
