Since the 1980s, researchers have known that pregnancy and breastfeeding reduce women’s risk of later developing breast cancer — but the reason why has remained a mystery, with most scientists pointing to hormonal changes as the likely cause.
Now, 2023 ASPIRE II Award recipient Sherene Loi, MD, PhD, a researcher at the Peter MacCallum Cancer Centre in Melbourne, Australia, has turned that assumption on its head. In a landmark Nature paper out today, Loi and her coauthors show that the protective effect of breastfeeding stems from long-lasting immunological changes. Critically, they also show that these changes have the biggest effect on triple-negative breast cancer, an especially aggressive and deadly form of the disease that is more commonly found in women under 40 and Black women.
A Persistent Immune Shield
In the paper, Loi and her team report that women who have completed a full cycle of pregnancy, breastfeeding, and recovery have a significantly higher accumulation of specialized immune cells known as CD8⁺ tissue-resident memory (TRM) T cells in their breast tissue.
These cells, which the study found can persist in the breast for decades post-pregnancy, act as “local guards.” By analyzing data from over 1,000 breast cancer patients, the team confirmed this finding’s relevance: triple-negative breast cancer (TNBC) tumors from women who had breastfed showed greater T cell infiltration, a known marker for better prognosis. In a separate cohort, breastfeeding was linked to significantly longer overall survival after a TNBC diagnosis.
To confirm that these T cells were directly responsible for the protection, the team used preclinical mouse models. They found that mice that completed a full cycle of pregnancy, lactation, and recovery showed significantly reduced tumor growth. Crucially, this tumor-suppressing effect was seen only in the group that completed the full cycle (not in those that stopped lactating shortly after birth). Furthermore, when CD8⁺ T cells were removed, this protection was completely lost — confirming that these T cells are not just associated with the protective state but mediate it.
This new understanding—that breastfeeding-associated breast cancer protection is immunological, not just hormonal—underscores a crucial gap in medical science. For 40 years, an incomplete hormonal explanation was widely accepted, demonstrating how focused research into women’s unique physiological processes is essential.
Implications for Cancer Prevention and Therapy
In addition to their implications for women’s health research, Loi’s findings raise a transformative question for oncology: If nature can provoke the immune system in this way, can we develop therapies that artificially mimic this process? This could lead to entirely new strategies for cancer prevention, such as vaccines or other immunotherapies designed to “train” the immune system to create the same protective shield, particularly for individuals at high risk for TNBC or other cancers.
Loi’s work, part of a shared grant with Charles Swanton of the Francis Crick Institute, builds on a growing body of research that considers cancer not as a discrete disease, but as part of a broader system in which factors ranging from environmental factors like air pollution to life processes like breastfeeding all influence an individual’s likelihood of developing cancer. This “systems view” approach is most effective when it draws on global expertise (and data sets), one reason that The Mark Foundation for Cancer Research supports collaborative projects that cross international and interdisciplinary boundaries.
“Dr. Loi’s findings not only change our understanding of immunological processes in breast cancer but also open up a new paradigm for cancer prevention,” said Ryan Schoenfeld, PhD, CEO of The Mark Foundation. “These kinds of game-changing results can only come from a unified, global approach to cancer research that is not limited by geography. That’s why we remain committed to funding the most innovative science, wherever it takes place.”