The Interplay Between Circadian Clocks and the Tumour Microenvironment in Breast Cancer

Cancer is a heterogeneous systemic disease that is strongly influenced by dynamic interactions with the tumour microenvironment (TME). Despite major advances in understanding spatial and molecular tumour heterogeneity, the temporal dynamics of tumours have received far less attention. Growing evidence has linked circadian clocks to cancer risk, progression, and treatment response, including in breast cancer. However, temporal regulation has yet to be recognized as a cancer hallmark, and its interaction with the TME remains poorly understood. This review examines how circadian rhythms organize breast cancer biology through bidirectional interactions with the TME. Circadian clocks coordinate proliferation, DNA damage responses, metabolism, and immune surveillance. Ageing, chronic stress, and obesity, all of which are established breast cancer risk modifiers, disrupt these rhythms and are reciprocally exacerbated by circadian dysfunction, establishing feed-forward loops that accelerate disease. Within the TME, the extracellular matrix (ECM) plays a central role in mediating this bidirectional control. Stiffened fibrotic stroma dampens epithelial clock amplitude, while circadian rhythms in turn shape collagen turnover and ECM remodelling. These dynamics can foster inflammation, stem cell expansion, and metastatic dissemination, including time-of-day-dependent release of circulating breast tumour cells. Systemically, circadian clocks gate immune cell trafficking, creating predictable windows of immunosurveillance and therapeutic vulnerability. By integrating insights from mechanobiology, metabolism, immune regulation, and ageing, we position circadian timing as a unifying layer that connects cell-intrinsic programmes with the evolving breast TME. Understanding these connections opens new opportunities for chronotherapeutic strategies in which treatment timing is aligned with circadian rhythms to improve outcomes.