Many patients with cancers have low levels of CD4+ in their peripheral blood.However,the molec-ular mechanism is still unclear.Here,we found that the blood levels of miR-221 and miR-222 were dramatically increased in patients with colorectal cancer (CRC),and both circulating miR-211 and miR-222 served as sensitive diagnostic markers with an area under the curve of 0.8790 and 0.9148,respectively.Transfection of either miR-221 or miR-222 resulted in the reduction of the surface CD4 antigen level but not the surface CD8 antigen level.The luciferase reporter assay showed that miR-221/222 directly regulated CD4 expression in human primary T cells.These data showed that miR-221/222 levels were upregulated in the blood of patients with CRC and that the expres-sion of CD4 in human primary T cells was inhibited by miR-221/222.These findings provide a novel strategy for modulating the number of CD4+ T cells in the blood and further adjusting the microenvironment suitable for immunotherapy.