Sleep Deprivation Inhibits CD8⁺ T Cell Function by Elevating Galectin-9 Expression in Colorectal Cancer Cells

Sleep disturbance is thought to impair immune regulation and reduce the effectiveness of cancer immunotherapies such as immune checkpoint blockade, but the mechanisms in colorectal cancer are not well defined. This study investigated how recurrent sleep deprivation influences colon cancer progression and immune responses, with particular attention to the role of Galectin-9. A murine CT26 colon carcinoma model was established to examine tumor growth dynamics and host immune responses under scheduled cycles of sleep deprivation. For tumor implantation, mice were injected with CT26 cells stably transduced to overexpress Galectin-9 (Gal-9 OE) or with vector-transduced wild-type control CT26 cells. Immune phenotyping was conducted using flow cytometry, and chromatin immunoprecipitation assays were employed to assess regulatory mechanisms at the Gal-9 promoter. To further evaluate therapeutic potential, a bispecific CD3/Gal-9 antibody was administered to determine its capacity to restore immune activity and restrain tumor growth under sleep-disrupted conditions. Sleep deprivation significantly increased tumor burden and induced immune suppression, characterized by elevated Gal-9 expression, increased regulatory T cell infiltration, and diminished cytotoxic T cell activity. Treatment with the bispecific CD3/Gal-9 antibody reversed these effects, reducing tumor growth and enhancing antitumor immune responses in Gal-9-overexpressing tumors. Sleep deprivation promotes immune evasion and reduces ICB efficacy in colorectal cancer through Gal-9-mediated pathways. Targeting Gal-9 with bispecific antibodies may represent a viable approach to restore immune competence in sleep-disrupted conditions. These findings highlight the importance of sleep quality in cancer progression and suggest that integrating lifestyle interventions with immunotherapy may improve clinical outcomes.