Circadian rhythm in immunotherapy and cellular therapy: impacts on the tumor microenvironment

Immunotherapy, including cellular therapy, has emerged as a crucial pillar in cancer treatment, complementing established modalities such as surgery, chemotherapy and radiotherapy. The clinical observation that immunotherapy is effective in only a limited proportion of patients inspires mechanistic research on the complicated regulatory network within the tumor microenvironment (TME). Circadian regulation significantly affects immune cell behavior, including the activity of immune cells and cytokine production, and emerging evidence suggests the key role of circadian regulation in the TME, which subsequently affects the effectiveness of immunotherapy. Results from preclinical and clinical studies indicate that appropriate timing of adoptive cellular therapy and immune checkpoint blockade therapy improves their efficacy. Therefore, understanding the molecular mechanism of the circadian rhythm together with its role in immunotherapy is essential for optimizing cellular function, proliferation and persistence in the TME. Here, we review how circadian rhythms influence immunotherapy and the TME across different stages of tumor progression. Future clinical protocols may integrate concepts of circadian rhythm and immunotherapy to enhance treatment response.