Triple-negative breast cancer (TNBC) is characterized by higher immune infiltration compared with other breast cancer subtypes.¹ Parity and breastfeeding are established protective factors for breast cancer, particularly TNBC, reducing risk by approximately 7% per full-term birth and an additional 4.3% for every 12 months of breastfeeding.¹ Historically, these effects have been largely attributed to hormonal and differentiation changes during pregnancy, yet the underlying immune mechanisms have not been defined.¹ The presence of T cells in normal breast tissue raises the possibility that immune modulation may contribute to this protection.¹ At the ESMO Congress 2025, Professor Sherene Loi from the Peter MacCallum Cancer Centre, Melbourne, Australia, presented new evidence demonstrating that pregnancy, lactation, and involution establish durable CD8⁺ T cell-mediated immune protection against TNBC.¹ She presented a set of studies to determine whether pregnancy, lactation, and involution induced long-lived CD8⁺ T cells in the breast that promote immune surveillance and protection against TNBC.¹

The study first compared CD8⁺ T cell levels in normal breast tissue from parous vs. nulliparous women to evaluate whether pregnancy remodels breast immunity.¹ Breast tissue from parous women had significantly more CD8⁺ T cells compared with nulliparous women, particularly long-lived tissue-resident memory (TRM)-like CD69⁺ and CD103⁺ subsets, in both average- and high-risk breast cancer cohorts.¹ Another set of studies conducted with murine mammary glands showed that full lactation and involution similarly remodelled breast immunity by increasing CD8⁺CD103⁺ resident T cells compared to virgin mice.¹ At day 10 postpartum, macrophages predominated with smaller T cell increases, which reflects the mechanisms associated with poor outcomes in early postpartum breast cancer.¹

Following this confirmation, mammary tumor implantation experiments assessed the mediatory effect of T-cell infiltration on tumor growth.¹ Parous mice completing a full reproductive cycle showed increased T-cell infiltration and restrained mammary tumor growth compared with virgin mice, but the effect was neutralized at day 10 postpartum.¹ Additionally, reduced tumor growth was accompanied by higher intra-tumoral CD8⁺ T-cells that were antigen-positive, expressed programmed cell death protein 1 (PD-1), and increased type 1 dendritic cells.¹ This protective effect was subsequently proven to be CD8⁺ T-cell-dependent as CD8⁺ T-cell depletion abolished tumor control, whereas CD4⁺ T-cells depletion had minimal impact.¹ However, although this effect is CD8⁺ T-cell mediated, the complementary role of circulating memory T-cells is also required in long-term immune protection.¹

Human datasets were analysed to evaluate if breastfeeding confers additional immune advantage in real-world BRCA-mutated postpartum cohorts.¹ In the MyBRCA dataset of 634 Malaysian women, prior pregnancy and breastfeeding history were associated with increased intra-tumoral CD3⁺ and CD8⁺ T cell infiltration in postpartum breast cancer.¹ In a cohort of 270 Australian women carrying germline BRCA mutations who developed estrogen receptor negative (ER–) breast cancer postpartum, breastfeeding was linked to increased tumor-infiltrating lymphocyte density and improved survival, independent of other prognostic factors.¹ These findings align with prior epidemiologic observations linking longer breastfeeding duration to lower TNBC risk, supporting that breastfeeding augments CD8⁺ T cell-mediated immune surveillance in the breast.¹

In conclusion, parity, breastfeeding, and involution collectively remodel breast and systemic immunity, establishing durable CD8⁺ T cell-mediated protection against TNBC and providing clear mechanistic insight into long-recognized protective effects of reproductive history.¹ These findings highlight the importance of routinely documenting reproductive details, including parity and breastfeeding duration, in future breast cancer immuno-oncology trials.¹ Translating parity-driven immune pathways may lead to new preventive and therapeutic strategies such as vaccines or immunotherapy, while reframing breast immunity not only as a therapeutic target but also as a modifiable determinant of tumor control.¹