The response of breast cancer to neoadjuvant chemotherapy (NAC) varies substantially, even when tumours belong to the same molecular or histological subtype¹. Here we identify the oestrous cycle as an important contributor to this heterogeneity. In three mouse models of breast cancer, we show reduced responses to NAC when treatment is initiated during the dioestrus stage, when compared with initiation during the oestrus stage. Similar findings were observed in retrospective premenopausal cohorts of human patients. Mechanistically, the dioestrus stage exhibits systemic and localized changes, including (1) an increased number of cells undergoing epithelial-to-mesenchymal transition linked to chemoresistance^2,3,4 and (2) decreased tumour vessel diameter, suggesting potential constraints to drug sensitivity and delivery. In addition, an elevated presence of macrophages, previously associated with chemoresistance induction⁵, characterizes the dioestrus phase. Whereas NAC disrupts the oestrous cycle, this elevated macrophage prevalence persists and depletion of macrophages mitigates the reduced therapy response observed when initiating treatment during dioestrus. Our data collectively demonstrate the oestrous cycle as a crucial infradian rhythm determining chemosensitivity, warranting future clinical studies to exploit optimal treatment initiation timing for enhanced chemotherapy outcomes.

乳腺癌对新辅助化疗 （NAC） 的反应差异很大，即使肿瘤属于相同的分子或组织学亚型 ¹ 也是如此。在这里，我们将发情周期确定为造成这种异质性的重要因素。在三种乳腺癌小鼠模型中，与发情期开始治疗相比，在发情期开始治疗时，我们对 NAC 的反应降低。在人类患者的回顾性绝经前队列中观察到类似的发现。从机制上讲，二发情期表现出全身性和局部变化，包括 （1） 经历与化疗耐药 ^2,3,4 相关的上皮到间充质转化的细胞数量增加和 （2） 肿瘤血管直径减小，表明药物敏感性和递送的潜在限制。此外，以前与化疗耐药诱导 ⁵ 相关的巨噬细胞的存在增加是发情期的特征。虽然 NAC 破坏了发情周期，但这种巨噬细胞患病率升高持续存在，巨噬细胞的耗竭减轻了在发情期间开始治疗时观察到的治疗反应降低。我们的数据共同证明发情周期是决定化疗敏感性的关键 infradian 节律，值得未来的临床研究利用最佳治疗开始时机来增强化疗结果。