PTPN2 and neoplasm: Herein, a programmable unlocking nano‐matryoshka‐CRISPR system targeting PD‐L1 and PTPN2 (PUN@Cas‐PT) was designed based on the characterizations of the tumor microenvironment (TME) for permanent, complete, and highly responsive immunotherapy, which own hierarchical responsive property for precise and efficient control of CRISPR/Cas9 activation (Scheme 1).