AbstractAlthough vanadium‐based metallodrugs are recently explored for their effective anti‐inflammatory activity, they frequently cause undesired side effects. Among 2D nanomaterials, transition metal carbides (MXenes) have received substantial attention for their promise as biomedical platforms. It is hypothesized that vanadium immune properties can be extended to MXene compounds. Therefore, vanadium carbide MXene (V₄C₃) is synthetized, evaluating its biocompatibility and intrinsic immunomodulatory effects. By combining multiple experimental approaches in vitro and ex vivo on human primary immune cells, MXene effects on hemolysis, apoptosis, necrosis, activation, and cytokine production are investigated. Furthermore, V₄C₃ ability is demonstrated to inhibit T cell‐dendritic cell interactions, evaluating the modulation of CD40–CD40 ligand interaction, two key costimulatory molecules for immune activation. The material biocompatibility at the single‐cell level on 17 human immune cell subpopulations by single‐cell mass cytometry is confirmed. Finally, the molecular mechanism underlying V₄C₃ immune modulation is explored, demonstrating a MXene‐mediated downregulation of antigen presentation‐associated genes in primary human immune cells. The findings set the basis for further V₄C₃ investigation and application as a negative modulator of the immune response in inflammatory and autoimmune diseases.