High configurational entropy can reshape local electronic structures, yet its therapeutic relevance in nanozymes remains largely unexplored. Herein, we demonstrate that the incorporation of multiple transition-metal nodes into ligand-deficient Prussian blue analogues leads to unique asymmetric coordination environments and pronounced intersite electronic reconfiguration, thereby conferring significant catalytic activity. This catalytic electronic rewiring drives a persistent oxidative pressure in tumor cells, rapidly exhausting antioxidant defenses and triggering the accumulation of hydroxyl radicals (•OH). The resulting redox imbalance not only efficiently kills tumor cells but also reprograms the tumor immune microenvironment, promoting dendritic cell maturation, cytotoxic T-cell infiltration, and pro-inflammatory macrophage polarization, leading to strong tumor suppression in vitro and in vivo. This work establishes a direct link between high-entropy-mediated electronic reconfiguration and catalytic immunomodulation, providing a design principle for ligand-deficient high-entropy Prussian blue nanozymes for tumor-specific redox-immunotherapy.