The specific recognition of cancer cells by the body's immune system is an essential step in initiating antitumor immunity. However, the decreased expression of major histocompatibility complex class I (MHC-1) and overexpression of programmed death ligand 1 (PD-L1) causes insufficient tumor-associated antigens presentation and inactivation of T cells, which accounts for poor immunogenicity. To remodel tumor immunogenicity, herein, a dual-activatable binary CRISPR nanomedicine (DBCN) that can efficiently deliver a CRISPR system into tumor tissues and specifically control its activation is reported. This DBCN is made of a thioketal-cross-linked polyplex core and an acid-detachable polymer shell, which can maintain stability during blood circulation, while detaching a polymer shell to facilitate the cellular internalization of the CRISPR system after entering tumor tissues and ultimately activating gene editing under exogenous laser irradiation, thereby maximizing the therapeutic benefits and reducing potential safety concerns. With the collaborative application of multiple CRISPR systems, DBCN efficiently corrects both dysregulation of MHC-1 and PD-L1 expression in tumors, thus initiating robust T cell-dependent antitumor immune responses to inhibit malignant tumor growth, metastasis, and recurrence. Given the increasing abundance of CRISPR toolkits, this research provides an appealing therapeutic strategy and a universal delivery platform to develop more advanced CRISPR-based cancer treatments.