靶向蛋白降解破解不可成药靶点，逆转癌症免疫逃逸和治疗耐药

Targeted protein degradation (TPD) harnesses endogenous proteolytic machineries-the ubiquitin-proteasome system and lysosomal pathways-to selectively eliminate disease-causing proteins that are refractory to conventional inhibition.

In cancer immunotherapy, TPD dismantles critical immunosuppressive nodes across extracellular, membrane and intracellular compartments, reprogramming the tumor microenvironment from an immunologically 'cold' to a 'hot' state. This Review examines the molecular engineering principles of bifunctional degraders and summarizes clinical progress demonstrating synergy with immune checkpoint blockade and adoptive cell therapy.

We discuss how catalytic protein elimination overcomes primary immune evasion and adaptive resistance driven by compensatory signaling, target mutation and metabolic rewiring.

Finally, we outline translational roadblocks in cell-specific delivery, therapeutic window optimization and on-target/off-tissue toxicity mitigation, and propose engineering strategies to advance the clinical implementation of targeted protein degradation in immuno-oncology.