PURPOSE: The incidence of candidemia, mediated by systemic METHODS: The candidemia mice models (named CA mice) were established by tail intravenous injection of RESULTS: In CA mice, we observed that NECA and A2AR agonist treatment significantly alleviated the sepsis score and increased the survival rate. Moreover, the renal injury and fungal load were reduced by NECA and A2AR agonist treatment. However, the other adenosine receptors (ie, A1R, A2BR and A3R) activation have no effect on survival and tissue damage of CA mice. A2AR activation could reduce macrophage infiltration in kidney and the production of inflammatory cytokine IL-6 in CA mice. Moreover, adenosine-A2AR signaling activation could enhance antifungal capacity of macrophages and promoted macrophage polarization toward the M2 subtype. CONCLUSION: Activation of adenosine-A2AR axis promoted macrophage M2 polarization, enhanced host defense against systemic