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The clinical outcomes of programmed cell death protein‐1 (PD‐1)/programmed death ligand‐1 (PD‐L1) blockade are usually limited by the multiple immune evasion mechanism of the tumor, as well as the immune storm caused by "off‐target" effects of the PD‐1/PD‐L1 antibody. Here, a previously unknown strategy is proposed to synergize the "Ca2+ interference" mediated M2‐like tumor‐associated macrophages (TAM) re‐education and Ca2+‐activating locally PD‐L1 depletion for immunotherapy. The authors discover that calcium‐containing nanoparticles can induce significant "Ca2+ interference" effect and simultaneously reset TAM toward the M1 phenotype through activation of multiple inflammation‐related signaling pathways, as well as NLRP3 inflammasomes, and promoting in situ tumor‐associated antigen release. In addition, a circular aptamer‐DNAzyme conjugate (cAD) is designed with a tumor‐targeting ability and its catalytic shear activity can be specifically activated by Ca2+, which reduces potential autoimmune‐like disorders of PD‐L1 antibody. By simply integrating the ultra‐high pH‐sensitive calcium peroxide nanoparticles with cAD into one nanosystem, it is demonstrated that the nanosystem not only arrest primary tumor progression and lung metastasis but also provides a long‐term immunological memory, which can protect against tumor rechallenge. Therefore, this work provides an attractive strategy for boosting tumor immunotherapy. [ABSTRACT FROM AUTHOR]