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.

The study, published this week, detailed how triple-negative breast cancer (TNBC) tumors exploit immune checkpoint pathways to evade immune detection by transforming the tumor microenvironment into an immune-privileged site, according to researchers from multiple institutions. The tumors induce an overproduction of regulatory T cells (Tregs), which suppress the immune system’s ability to attack cancer cells, the findings showed.

The protein NR0B2 was identified as a potential agent to slow or stop Tregs from suppressing the immune system.

TNBC tumors “kidnap” mechanisms normally responsible for immune privilege, officials said, suppressing immune checkpoints that typically activate immune responses. This suppression creates a microenvironment that blocks the body’s natural defenses. Immune checkpoint inhibitor (ICI) therapies aim to reactivate tumor-killing immune cells that have been suppressed within the tumor, but the research noted that targeting receptors such as MerTK or Axl in the tumor microenvironment can enhance immune response by increasing infiltration of cancer-clearing immune cells.

The study also highlighted the role of Tregs in immune suppression. According to researchers, aggressive breast cancer prompts the excessive production of these cells, which inhibit the immune response and facilitate tumor growth. Increased levels of NR0B2 correlated with fewer immune-suppressive T cells, the study reported. Historically, oncologists have struggled to directly target these cells and have relied primarily on therapies aimed at cancer cells themselves.

Further research revealed that fibroblastic reticulum cells (FRCs) drive lymph node reprogramming in aggressive breast cancer, according to a separate study cited by the authors. FRCs release cytokines CCL2 and CCL7, which attract monocytes to the lymph node microenvironment. In TNBC lymph nodes, these monocytes become corrupted and inhibit the activity of T cells responsible for attacking cancer cells. Targeted blockade of Toll-like receptor 4 (TLR4), combined with PD1 immunotherapy, restored T-cell activity and significantly reduced lung metastases in mouse models, the researchers said. Human TNBC patient samples confirmed the presence of similar lymph node reprogramming, suggesting potential pathways for targeted therapies.

In an effort to improve prediction of disease progression and treatment response, the Biomarker Research Integrating Data of Glyco-Immune Signatures and Clinical Evidence in Breast Cancer project was launched, according to project officials. This initiative focuses on identifying measurable biological markers in blood, tissue, or other samples that can indicate tumor growth rates or responsiveness to specific therapies. Using real patient samples, the project aims to develop clinical tools to guide personalized treatment decisions based on how the disease behaves in individual patients.

Researchers at King’s College London developed a triple-engineered antibody designed to bind more strongly to immune cells than existing treatments, according to a study led by Professor Sophia Karagiannis. This modified antibody activates immune cells already present in tumors, limiting growth in triple-negative and treatment-resistant breast cancers. The antibody also stimulated immune cells circulating in the bloodstream, potentially enhancing the body’s ability to detect and fight cancer. The design targets key immune cell receptors within breast tumors, including those resistant to chemotherapy and immunotherapy.

The study further identified the role of immunosuppressive myeloid cells in inhibiting anti-tumor immune responses. Tumor-associated macrophages (TAMs) produce interleukin-1 beta (IL-1β), which recruits additional immunosuppressive cells and suppresses adaptive immunity. Myeloid-derived suppressor cells (MDSCs) express ARG1 and produce nitrogen monoxide, reactive oxygen species, and prostaglandin E2 to further suppress cancer immunity. In TNBC mouse models, immune cell infiltration-corrupted lymph nodes (IMCGL) prevented effective response to immunotherapy, and expansion of circulating IMCGL in breast cancer patients correlated with worse prognosis.

Chemokine signaling was also implicated in the recruitment of immunosuppressive cells to the tumor microenvironment. Breast cancer cells produce chemoattractant chemokines that attract neutrophils, immature dendritic cells, and regulatory T cells, creating an inflammatory state that fosters immune evasion and tumor growth. Multiple mechanisms—including immune checkpoint suppression, Treg proliferation, and myeloid cell infiltration—act in concert to disable normal anti-cancer immunity, according to the researchers.

The findings underscore the complexity of immune suppression in aggressive breast cancers and highlight several potential targets for novel therapies. Ongoing research aims to translate these insights into clinical treatments capable of reversing immune evasion and improving patient outcomes.