Diabetic nephropathy (DN) is a critical inflammatory condition linked to diabetes, affecting millions worldwide. This study employs Mendelian randomization (MR) to explore the causal relationship between immune cell signatures and DN, analyzing over 731 immune signatures and incorporating data from 1400 metabolites to investigate potential mediators. Despite no statistically significant influence of DN on immunophenotypes after FDR correction, some phenotypes with unadjusted low P-values warranted mention, including CD34 on Hematopoietic Stem Cell (Myeloid cell Panel), CD45 on CD33 HLA DR (Myeloid cell Panel). Furthermore, three immunophenotypes were identified to have a significant impact on DN risk: CD16CD56 on HLA DR NK (TBNK Panel), CD45 on HLA DR T cell (TBNK Panel), and CD33 HLA DR CD11b AC (Myeloid cell Panel). Our findings underscore the critical role of immune cells in DN, highlighting potential mediators and offering new insights into its underlying mechanisms.