Cannabidiol suppresses emergency MDSCs generation by disturbing EEF1B2-mediated C/EBP protein synthesis in colorectal adenomas.

[BACKGROUND] Colorectal cancer often develops from adenomas over years, necessitating early intervention. Myeloid-derived suppressor cells (MDSCs) are major immune suppressive cell types in colon cancer development from adenomas through early inflammation-induced emergency myelopoiesis. Cannabidiol (CBD) is reported to function in psychosis, coronavirus infection and some cancers through immune regulation. However, its target and underlying mechanisms in colorectal adenomas are unknown.

[METHODS] The antitumor effect of CBD was validated in two classical colorectal adenomas models including azoxymethane (AOM)/dextran sulfate sodium salt (DSS) induced mice model and high-fat fed mice model. Single-cell RNA sequencing was used to identified the immune environment change after CBD treatment in mice colorectal adenomas. Target responsive accessibility profiling was used to find the target of CBD in MDSCs. Subsequently, multiple immunology assays and molecular biology experiment were employed to explore the adenomas prevention mechanisms of CBD.

[RESULTS] Here, we found that CBD prevented the incidence of colorectal adenomas in AOM/DSS model and high-fat diet fed mice model. Our single-cell RNA sequencing data and the results of immunofluorescence revealed that CBD treatment significantly decreased the number of MDSCs in both two colon adenomas models. Mechanistically, CBD bound to the guanine nucleotide exchange factor domain of EEF1B2, inhibiting its function in translational elongation and subsequent C/EBP synthesis. This disruption suppressed the differentiation and generation of MDSCs, leading to enhanced T-cell activation and prevention of colorectal adenoma progression.

[CONCLUSION] Our findings reveal EEF1B2-mediated C/EBP protein synthesis as a crucial pathway in MDSC generation and highlight the potential of CBD as an early intervention strategy for colorectal adenomas.