Findings may help explain why immunotherapies aren’t effective in certain patients with TNBC
BCRF investigator Dr. Xiang Zhang and his colleagues are examining the crosstalk between a breast tumor and the body’s immune system to understand why some cancers do not respond to treatment.
He and his team recently published results in Nature Cell Biology showing that they’d identified two specific immune cell abnormalities that may serve as blood biomarkers to determine whether patients with triple-negative breast cancer (TNBC) will respond to chemotherapy and immunotherapy.
Below, read more about these findings, other ongoing triple-negative breast cancer news, and what they mean for patients.
Immune cell development and tumor response to treatment
TNBC is so named for the fact that it lacks the three key targets for current treatments: estrogen and progesterone receptors and high levels of the HER2 protein. As such, this form of breast cancer can be difficult to treat. Recently, there have been significant advances in immunotherapy for treating TNBC but only about 15 to 20 percent of patients benefit.
One reason for this lack of efficacy is that tumors, including breast tumors, have been shown to influence their microenvironment to evade the body’s main defense: the immune system. This allows them to grow and spread uncontrollably. There are also other tumor-induced changes that occur because of how the body responds to the cancer. Dr. Zhang’s group was interested in finding out more about how certain TNBC tumors manipulate their surrounding environment and make immunotherapy ineffective.
Although most people have heard of the immune system, its components and complexity are relatively unknown. For example, the lymphatic system is part of the immune system. It’s composed of a large network of lymphatic vessels, lymph nodes, lymphoid organs, lymphatic tissue, and lymph, the clear fluid carried by the vessels back to the heart for re-circulation. In addition, there are several types of immune cells that are activated in response to perceived foreign factors in the body.
The immature form of immune cells—for example, myeloid, neutrophil, and B cells—originate from the bone marrow and migrate to other organs of the lymphatic system for further maturation. In prior work, Dr. Zhang’s team found that B cell development in the bone marrow is crucial for ensuring that effective B cells form. However, some tumors can block B cell development, thereby blunting an immune response and promoting therapeutic resistance. Without this effect, B cells can aggregate in tumors, which correlates with better prognosis and clinical outcomes from immunotherapy. Dr. Zhang is investigating these observations and specifically how B cell development is influenced by the presence of TNBC tumors and their role in tumor immunosuppression.
“Previous studies highlighted T cells as the major fighters of breast cancer. The role of B cells, another major population of adaptive immune cells, remains less understood,” Dr. Zhang said.
Study highlights the complexity of TNBC-induced changes in immune cells
Building on previous findings, Zhang’s team examined changes in B cells from patient blood samples and identified three distinct subgroups of tumor-induced B cell abnormality (TiBA). The first group (TiBA 0) shows no characteristic difference compared to the normal B cell population. TiBA 1 exhibits a global reduction in B cells, presumably due to competition with immature myeloid cells in the bone marrow. TiBA 2 results in an accumulation of immature B cells, which is likely due to an excessive number of neutrophils preventing the B cells from maturing.
In further studies, the team found that B cell changes in both TiBA 1 and TiBA 2 types lead to an immunosuppressive effect and poorer response to treatment. In a study of 35 patients with TNBC, 78.6 percent of TiBA 0 patients had a complete response to treatment with chemotherapy and immunotherapy, while only 33.3 percent of TiBA 1 and TiBA 2 patients had a complete response.
Their results also indicate that the interaction between myeloid, neutrophil, and immature B cells at the bone marrow level may determine the differences between TiBA 1 and TiBA 2, suggesting that immune-suppressive mechanisms go beyond the local tumor environment. Dr. Zhang’s work provides support for tracking early B and myeloid cells to potentially reveal differences in TiBA and B cell dysfunction in a patient’s bone marrow.
What’s next in immunotherapy for triple-negative breast cancer
Dr. Zhang’s team has shown that tumor-induced changes are complex within TNBC, as the same immune cells can be systemically altered in divergent directions to become effective or immunosuppressive. Looking ahead, the team will continue to conduct comprehensive molecular characterization to determine how B cells can be used as indicators of immune system status and biomarkers to predict therapeutic outcomes. They also hope to identify molecular targets that can be leveraged to improve therapies that rely on a functional immune system.
What this means for patients
This study reveals the potential of using early immune cell profiles as biomarkers to quantify dysfunctional immune cells in a patient’s blood and bone marrow. For patients, particularly those with TNBC, these profiles could predict their immune system status and how they might respond to therapy. Further studies are needed to determine the feasibility of clinical assays that are sensitive enough to inform treatment decisions and bring precision immuno-oncology into the clinic.
“With this new information, we can design novel blood assays to identify patients who may benefit from current therapies and who will need additional treatments to overcome the potential resistance,” Dr. Zhang said. “This work is supported almost exclusively by funding from BCRF, and we are genuinely grateful.”
Supplemental information (January 2026):
How immunotherapy is shaping treatment approaches for triple-negative breast cancer
Immunotherapy advances have become an important complement to other TNBC news, particularly because this subtype lacks the hormone and HER2 targets used in many standard treatments. Rather than acting directly on cancer cells, immunotherapies aim to strengthen the body’s own immune response, helping immune cells recognize and attack tumors. Research supported by BCRF and others is helping clarify why these approaches can be effective for some patients but not for others.
The first immunotherapies were designed to block the PD-1 receptor on immune cells from binding to PD-L1, a protein found on the surface of some cells. Normally, this interaction turns off immune T-cells, reducing the immune response against those cells. But researchers discovered that tumor cells can also express PD-L1, allowing them to hide from the immune system. They reasoned that immunotherapies that block that interaction might prevent tumors from suppressing immune activity, effectively releasing the “brakes” on immune cells. Immunotherapies like pembrolizumab (Keytruda®) were developed to do this. However, their success depends on the immune system being able to mount a coordinated response. Emerging research, including studies on immune cell development and how they present in the tumor microenvironment, suggests that both factors may influence how well these therapies work.
Other researchers are investigating immunotherapy for different stages of TNBC. In early-stage, high-risk disease, studies are exploring how immune-based treatments can work alongside chemotherapy to strengthen the immune system’s ability to recognize, suppress, and keep cancer cells in check over time, even if it does not eliminate them completely. In metastatic or advanced TNBC, which is often marked by more pronounced immune suppression, understanding systemic immune changes may be especially important for identifying which patients are most likely to benefit from these therapies.
These insights are fueling increased interest in combination treatment strategies. By pairing immunotherapy with chemotherapy or other modalities, researchers hope to overcome immune resistance and improve outcomes. Studies that identify immune cell biomarkers, such as those supported by BCRF, are critical to this effort. By revealing how tumors reshape the immune system, this research is laying the foundation for more personalized and more effective immunotherapy approaches for people living with triple-negative breast cancer.
