Chrono-immunotherapy has emerged as a compelling precision-oncology strategy based on the premise that immune checkpoint blockade is modulated by circadian biology. The immune system is organized across daily oscillations in leukocyte trafficking, cytokine production, antigen presentation, endocrine signaling, and tissue accessibility, while the tumor microenvironment itself exhibits rhythmic changes in vascular permeability, suppressive myeloid activity, and stromal reprogramming. Together, these temporal fluctuations create biologically distinct windows during which immunotherapy may be more or less effective. Retrospective clinical studies have repeatedly suggested that earlier time-of-day administration of immune checkpoint inhibitors is associated with superior survival outcomes across several malignancies, although confounding by clinic workflow and patient selection has limited causal inference. More importantly, prospective randomized evidence in non-small cell lung cancer has now demonstrated longer progression-free survival with early-day immunochemotherapy delivery, strengthening the rationale for time-directed treatment scheduling. This review synthesizes the molecular, cellular, and clinical foundations of chrono-immunotherapy, discusses biomarker strategies for chronotype assessment, and proposes a translational framework for incorporating internal biological time into routine oncology practice. We also highlight implementation barriers, methodological limitations, and future research directions required to establish chrono-immunotherapy as a clinically actionable component of precision cancer care.
