Circadian rhythms and lung cancer biology and immunotherapy: Emerging opportunities and challenges

The circadian rhythm is an intrinsic timekeeping system that precisely regulates a wide range of physiological and pathological processes. Its core molecular mechanisms and regulatory networks are gaining increasing attention in the field of lung cancer research. Substantial evidence indicates that circadian clock genes are not only deeply involved in lung cancer initiation and progression but also profoundly influence the dynamic remodeling of the tumor immune microenvironment (TIME) in lung cancer. This review summarizes the expression patterns and functional mechanisms of circadian clock genes in various cancers. It specifically elaborates on their regulatory roles in immune cell function, malignant behaviors of tumor cells, and interactions with stromal cells. The review also details how circadian disruption drives lung cancer development, progression, and immune evasion. Besides, we explore the potential impact of heterogeneity in circadian gene expression on the efficacy of immune checkpoint inhibitors (ICIs) in lung cancer, synthesize current knowledge on how circadian rhythms influence clinical responses to and adverse effects of immunotherapy in lung cancer, and highlight the translational potential of chronotherapy-optimizing drug administration timing based on circadian principles-to enhance therapeutic outcomes and reduce toxicity. By integrating recent preclinical and clinical evidence, this review provides a theoretical foundation for circadian-based precision immunotherapy in lung cancer and outlines future directions for innovative therapeutic strategies targeting the circadian machinery.