A combined mathematical and experimental approach reveals the drivers of time-of-day drug sensitivity in human cells.

The circadian clock plays a pivotal role in regulating various aspects of cancer, influencing tumor growth and treatment responses. There are significant changes in drug efficacy and adverse effects when drugs are administered at different times of the day, underscoring the importance of considering the time of day in treatments. Despite these well-established findings, chronotherapy approaches in drug treatment have yet to fully integrate into clinical practice, largely due to the stringent clinical requirements for proving efficacy and safety, alongside the need for deeper mechanistic insights. In this study, we employ a combined mathematical and experimental approach to systematically investigate the factors influencing time-of-day drug sensitivity in human cells. Here we show how circadian and drug properties independently shape time-of-day profiles, providing valuable insights into the temporal dynamics of treatment responses. Understanding how drug efficacy fluctuates throughout the day holds immense potential for the development of personalized treatment strategies aligned with an individual's internal biological clock, revolutionizing cancer treatment by maximizing therapeutic benefits. Moreover, our framework offers a promising avenue for refining future drug screening efforts, paving the way for more effective and targeted therapies across diverse tissue types.