Melanoma, a malignant skin tumor, presents significant treatment challenges, particularly in unresectable and metastatic cases. While immune checkpoint inhibitors (ICIs) targeting PD-1/PD-L1 have brought new hope, their efficacy is limited by low response rates and significant immune-mediated adverse events (irAEs). Through multi-omics data analysis, it is discovered that the spatial co-localization of CD73 and PD-L1 in melanoma correlates with improved progression-free survival (PFS), suggesting a synergistic potential of their inhibitors. Building on these insights, a novel therapeutic strategy using calcium phosphate (CaP) nanoparticles is developed for the co-delivery of aPD-L1 and APCP, a CD73 inhibitor. These nanoparticles, constructed via a biomineralization method, exhibit high drug-loading capacity and pH-responsive drug release. Compared to free aPD-L1, the CaP-delivered aPD-L1 effectively avoids systemic side effects while significantly enhancing anti-tumor efficacy, surpassing even a 20-fold dose of free aPD-L1. Furthermore, the co-delivery of aPD-L1 and APCP via CaP nanoparticles demonstrates a synergistic anti-tumor effect, with substantial immune activation and prevention of tumor recurrence through immune memory effects. These findings suggest that the co-delivery of aPD-L1 and APCP using CaP nanoparticles is a promising approach for improving melanoma immunotherapy, achieving enhanced efficacy and reduced toxicity.