Impact of time-of-day on immunochemotherapy efficacy in non–small cell lung cancer

Non–small cell lung cancer (NSCLC) accounts for the majority of lung cancer cases and remains a leading cause of cancer mortality worldwide. Pathophysiologically, NSCLC arises from genetic alterations such as EGFR, KRAS, and ALK mutations, which drive dysregulated signaling, uncontrolled proliferation, and immune evasion. Standard treatments include surgery, radiotherapy, platinum-based chemotherapy, and immunotherapy with PD-1/PD-L1 inhibitors, yet survival outcomes remain suboptimal. Emerging evidence suggests that circadian biology influences therapeutic efficacy, with time-of-day (ToD) immunochemotherapy offering a novel approach to optimize outcomes. Mechanistically, circadian rhythms regulate immune cell trafficking, cytokine release, and drug metabolism, thereby modulating treatment response and toxicity. Clinical trials in NSCLC demonstrate that early-day administration of immunochemotherapy improves progression-free and overall survival compared to late dosing. Similar chronotherapy benefits have been reported in colorectal, breast, pancreatic, and hepatocellular cancers, underscoring broad translational relevance. Despite promise, challenges include patient heterogeneity in circadian rhythms, logistical barriers in oncology clinics, and limited biomarker validation. Future strategies should prioritize multicenter validation, integration of chronobiological profiling, and exploration of combination therapies. Cost-effectiveness analyses, awareness campaigns, and clinical drives to evaluate safety and adherence will be essential to establish trust and optimize outcomes.