Cancer immunotherapy is limited by immune escape, which is driven by the overexpression of immunosuppressive proteins in the tumor microenvironment (TME). Targeted protein degradation (TPD) technology utilizes cellular mechanisms to eliminate specific proteins, providing a powerful strategy to overcome this resistance. However, the clinical translation of TPD degraders is severely hindered by the severe delivery challenges. Its inherent physical and chemical properties lead to poor oral bioavailability, difficulty in crossing biological barriers, rapid metabolism, and insufficient tumor accumulation, which impede effective target binding. This review focuses on the combination of TPD technology with advanced drug delivery systems (DDS) to enhance the potential of cancer immunotherapy. We detail how TPD reshapes the TME by degrading key immune regulatory targets. The key point is that this review deeply analyzes the main delivery bottlenecks that currently limit the efficacy of TPD degraders. Additionally, it introduces advanced delivery strategies aimed at overcoming these obstacles, including nanocarriers, hydrogels, microneedles, and various stimulus-responsive delivery systems. Successfully overcoming these delivery barriers is crucial for releasing the full therapeutic effects of TPD. These advancements have the potential to reprogram the immunosuppressive TME, overcome the resistance of existing immunotherapies, expand the patient population with treatment response, and ultimately bring lasting clinical benefits to more cancer patients. This study was published under the title "Harnessing targeted protein degradation to enhance cancer immunotherapy: from molecular mechanisms to delivery strategies" in Advanced Drug Delivery Reviews.
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DOI: 10.1016/j.addr.2026.115776