Induced proximity strategies for modulating immune checkpoints in cancer immunotherapy.

Immune checkpoints (ICs) serve as critical negative regulators of immune responses, which maintain tolerance and limit inflammation. Tumor cells evade immune surveillance by upregulating ICs and accumulating immunosuppressive molecules in the tumor microenvironment. Immune checkpoint inhibitors, especially monoclonal antibody-based immune checkpoint blockade therapy, demonstrate durable clinical efficacy but face limitations: immune-related adverse events (irAEs), acquired resistance, and limited patient response. Induced proximity strategies, exemplified by proteolysis-targeting chimeras (PROTACs), modulate protein-protein interactions. However, the characteristics of transmembrane ICs present inherent limitations to conventional targeted protein degradation (TPD) technologies like PROTACs. Emerging lysosome-dependent proximity approaches address these limitations and have made significant strides. This review summarizes emerging induced proximity strategies for immune checkpoints modulation, with a focus on design principles, degradation mechanisms, and therapeutic potential, aiming to guide the development of next-generation ICIs for cancer immunotherapy.