Impact of time-of-day on immune checkpoint inhibitor therapy in cancer patients: an up-to-date clinical review

Over the last decade, immune checkpoint inhibitors (ICIs) have become a cornerstone of the treatment of multiple cancer types. Several factors influence ICI efficacy and toxicity, and current research is investigating whether circadian timing of administration is one of them. This review is limited in scope to ICIs (anti-CTLA-4, anti-PD-1, anti-PD-L1, anti-LAG-3) and does not detail other immunotherapeutic modalities (oncolytic viruses, cytokine therapies, adoptive cell transfer, cancer vaccines). We synthesised the findings, which are consistent with a role for the circadian rhythm in modulating normal immune function, including reported circadian variation in the activity of specific checkpoint molecules and immune cell populations. Several studies, predominantly retrospective, have reported associations between earlier-in-the-day ICI infusion and more favourable efficacy outcomes; however, the evidence base is heterogeneous, and the first randomised phase III trial currently subject to a Nature Medicine Editor's Note suggests that time of day (ToD) of ICI administration may be associated with differences in efficacy, with more heterogeneous signals for toxicity. Given the risk of immortal-time bias, cycle-number confounding and scheduling bias in retrospective datasets, additional multicentre prospective randomised trials are required to establish causality and reproducibility, alongside research into circadian biomarkers that could help personalise timing in routine clinical care.