Time-of-Day Immunotherapy Administration and Outcomes in Advanced Cancers: A Systematic Review and Meta-Analysis

Circadian rhythms affect immunity, which could affect the effectiveness of immune checkpoint inhibitor (ICI). Whether the time of ICI administration is associated with clinical outcomes in advanced cancers remains unclear.

To evaluate the association between time of day of ICI administration and oncologic outcomes in patients with advanced solid tumors.

MEDLINE (via PubMed), Embase, and Web of Science Core Collection were searched in February 2026 to identify eligible studies.

Randomized clinical trials and prospective or retrospective cohort studies were included that compared early vs late time-of-day ICI administration and reported overall survival (OS) and progression-free survival (PFS).

This systematic review and meta-analysis adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses reporting guideline. Two authors independently extracted data and assessed risk of bias. Random effects meta-analyses with inverse-variance method were performed.

The primary outcomes were OS and PFS. These outcomes were reported as hazard ratios (HRs) with 95% CIs for early vs late ICI administration.

Of the 7892 records screened, 29 studies with 6129 patients were included. Among these studies, 1 was a randomized clinical trial in non-small cell lung cancer (NSCLC; 210 patients), 1 was a prospective cohort study in head and neck squamous cell carcinoma (62 patients), and 27 were retrospective cohort studies (5857 patients) across NSCLC, melanoma, gastric cancer, head and neck squamous cell carcinoma, renal cell carcinoma (RCC), esophageal cancer, small cell lung cancer, urothelial carcinoma, biliary tract cancer, hepatocellular carcinoma, and other cancers. Earlier ICI administration was associated with increased OS (HR, 0.60; 95% CI, 0.51-0.70) and PFS (HR, 0.62; 95% CI, 0.54-0.71). Subset analyses by cancer type confirmed significantly increased OS and PFS in NSCLC (OS: HR, 0.58 [95% CI, 0.46-0.74]; PFS: HR, 0.60 [95% CI, 0.46-0.76]), gastric cancer (OS: HR, 0.61 [95% CI, 0.49-0.77]; PFS: HR, 0.62 [95% CI, 0.43-0.89]), RCC (OS: HR, 0.60 [95% CI, 0.40-0.90]; PFS: HR, 0.70 [95% CI, 0.50-0.98]), small cell lung cancer (OS: HR, 0.37 [95% CI, 0.26-0.53]; PFS: HR, 0.48 [95% CI, 0.36-0.65]), and biliary tract cancer (OS: HR, 0.62 [95% CI, 0.41-0.93]; PFS: HR, 0.55 [95% CI, 0.38-0.79]).

In this systematic review and meta-analysis of studies including patients with advanced cancers, early immunotherapy administration was associated with improved outcomes. These findings suggest that treatment timing may have clinical relevance and warrant prospective evaluation to establish standardized timing strategies across cancer settings.