Aggressive Breast Cancer Research Reveals How Tumors Suppress Immune System

Researchers at multiple institutions revealed new mechanisms by which aggressive triple-negative breast cancer tumors suppress the immune system, according to a study published this week. The study found that tumors hijack immune checkpoint pathways and induce overproduction of regulatory T cells, creating an immune-privileged environment that hinders the body’s ability to attack cancer cells.

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.