Circadian rhythm, oxidative stress, and cancer immunosuppression

Abstract

Circadian rhythm and oxidative stress are fundamental biological regulators whose intricate interplay plays a pivotal role in cancer progression and immunosuppression. These two factors engage in a bidirectional, self-reinforcing pathological loop that drives tumor progression and fosters an immunosuppressive tumor microenvironment. In the context of cancer, circadian rhythm disruption promotes immunosuppression by reducing cytotoxic CD8⁺ T cell infiltration while expanding populations of immunosuppressive cells such as regulatory T cells and myeloid-derived suppressor cells. Oxidative stress acts as a pivotal effector with dual roles, it promotes immunosuppression by polarizing macrophages toward an M2 phenotype, yet it is also strategically harnessed to disrupt immunosuppressive networks. Critically, oxidative stress serves as a central link, wherein circadian rhythm disruption, through the accumulation of ROS, drives the recruitment of immunosuppressive cells and upregulates immune checkpoints such as PD-L1, thereby suppressing anti-tumor immunity. Furthermore, emerging evidence highlights the potential of circadian rhythm as a prognostic biomarker and underscores the promise of chrono-immunotherapy, which strategically times interventions to align with the circadian rhythm to optimize anti-tumor immune function. Collectively, the circadian rhythm and redox balance represent novel therapeutic targets, with pharmacological agents that restore circadian rhythm and enable cell-selective modulation of oxidative stress. Thus, integrating circadian rhythm and oxidative stress into oncology offers a promising strategy to improve cancer prevention, prognosis, and treatment outcomes.