Such synergic effect was also found in MC38 tumor (Supplementary information, Fig. S6a–c) and lung metastatic B16F10 melanoma models (Fig. 6g), consistent with clinical observations that checkpoint blockade-caused tumor regression is achieved by the reactivation of CD8+ T cells within tumors.56 Strikingly, half dose of PD-1 blocking antibodies showed a significantly better effect to inhibit tumor growth when Mn2+ was simultaneously administrated (Fig. 6h). This evidence concerns the gene PDCD1 and melanoma.