Personalizing chronotherapy of immune checkpoint blockade

Emerging evidence highlights the critical role of time-of-day (ToD) in immunotherapy, with large-scale retrospective studies showing that administering immune checkpoint inhibitors (ICIs) earlier in the day is associated with significantly improved efficacy across all cancer types. This observation aligns with our growing understanding of the circadian system, our internal biological clock, which governs a range of physiological processes, including immune regulation, over a 24-hour scale. Each individual possesses a distinct pace in their circadian rhythm, known as their chronotype, which reflects their natural preference for morning or evening activity, performance and rest. Chronotype has already proven to be a valuable predictor of outcomes in other areas of healthcare, and its application in immuno-oncology holds promising potential. In this commentary, we propose leveraging chronotype as a low-cost and minimally invasive strategy to personalize the timing of ICI administration and enhance therapeutic effectiveness. Despite encouraging retrospective data on ToD effects, current treatment protocols remain largely time-agnostic, hindered by the scantiness of prospective, chronotype-informed clinical trials. We outline here the key steps required to validate and implement chronotype-based scheduling, including rigorous clinical-translational studies. Embracing this temporal dimension could represent a transformative shift toward more precise, personalized, and effective circadian-based cancer immunotherapy.