Innovative strategy has the potential to revolutionize the treatment of breast cancer, particularly for patients who have developed resistance to targeted therapies.
A ground-breaking study conducted by researchers from McGill University, the Lady Davis Institute for Medical Research (LDI) at the Jewish General Hospital, Princess Margaret Cancer Centre and MIT, has identified a novel approach to combat aggressive breast cancers by retraining neutrophils, the body’s first responders, to directly kill tumour cells. This research offers new hope for patients with breast cancers that do not respond well to existing immunotherapies.
Traditional immunotherapies primarily focus on reactivating tumour-specific T cells, which have limited effectiveness in breast cancers classified as immune cold—tumours that lack significant T cell infiltration. The new study, published in Science Advances, presents an alternative approach that harnesses the innate immune system by educating neutrophils to acquire tumoricidal properties. The researchers discovered that combining systemic Toll-like receptor (TLR) agonists with mitochondrial complex I inhibitors stimulates neutrophils to produce reactive oxygen species (ROS) and cytotoxic granules, thereby directly attacking breast cancer cells independently of cytotoxic T cell activity.
According to John Heath, former postdoctoral fellow at the LDI now at the Princess Margaret Cancer Centre in Toronto and first author of the study, “Our research has shown that by leveraging the power of innate immunity, we can develop a new class of therapies that can effectively target and kill breast cancer cells, even in the absence of T cell inflammation.”
“Our findings demonstrate that neutrophils can be reprogrammed to become potent anti-cancer agents in tumours that are otherwise resistant to current immunotherapies,” concurs Josie Ursini-Siegel, Principal Investigator and Director of the Molecular Oncology Group of the Cancer Research Axis at the LDI, and lead author of the study. “This approach could open new avenues for treating aggressive breast cancers, particularly triple-negative breast cancer, which currently has limited treatment options due to the tumour’s ability to evade the immune system. This has great potential for patients who have limited treatment options and are in dire need of new and effective therapies.”
The study highlights that TLR agonists elevate NF-κB signaling in neutrophils, increasing the production of secretory granules and components of the NADPH oxidase complex, necessary for a respiratory burst that elicits cytotoxic responses. Meanwhile, complex I inhibitors amplify this effect by potentiating the capacity of neutrophils to undergo a respiratory burst, leading to oxidative damage of breast cancer cells. Importantly, neutrophil depletion in experimental models abolished the anti-tumour effects, underscoring the critical role of these immune cells in the therapy’s success. This dual treatment approach not only mobilizes neutrophils into the tumour microenvironment but also enhances their cytotoxic functions, offering a promising new therapeutic strategy for immune cold breast tumours that have so far eluded effective immune-based treatments.
The research also brings to light the importance of understanding the complex interactions between the tumour microenvironment and the immune system. By targeting key biological processes required for the survival of heterogeneous cancer cell populations, researchers can develop more effective therapies that abrogate the activation of a pro-tumorigenic immune microenvironment and instead engage novel modes of tumour immune surveillance. “Our findings have significant implications for the development of new treatments for breast cancer, particularly for patients with limited options,” says Ursini-Siegel. “It highlights the need for a multifaceted approach to cancer treatment, one that takes into account the complex interactions between the tumour and the immune system.“
In conclusion, this research builds on the understanding that breast cancers often evade immune destruction through complex metabolic and inflammatory mechanisms, and it shifts the focus toward targeting innate immune cells rather than relying solely on adaptive immunity. While further research is needed to fully elucidate the mechanisms by which complex I inhibitors enhance neutrophil function, this study marks a significant step forward in precision oncology.
Heath J, Ahn R, Sabourin V, Im YK, Rezzara SR, Annett A, Mirabelli C, Worme S, Maritan SM, Mourcos C, Lazaratos AM, Maldonado E, Shen YY, White FM, Kleinman CL, Siegel PM, Ursini-Siegel J. Complex I Inhibition combined with TLR Activation in the Breast Tumor Microenvironment Educates Cytotoxic Neutrophils. Sci. Adv.11,eadu5915(2025).DOI:10.1126/sciadv.adu5915.
