Beyond the Cytosol: Extracellular Targeted Protein Degradation for Remodeling the Tumor Immune Microenvironment

Purpose: We aim to address the limitations of traditional proteolysis-targeting chimeras (PROTACs)—which are spatially restricted to the cytosolic ubiquitin–proteasome system—in targeting extracellular and membrane-bound immunoregulatory proteins, and to evaluate the potential of next-generation extracellular targeted protein degradation (eTPD) platforms in overcoming the "undruggable" barriers of the tumor immune microenvironment (TIME).

Methods: We systematically reviewed the recent literature and developmental pipelines concerning emerging eTPD modalities, including lysosome-targeting chimeras (LYTACs), transferrin receptor-targeting chimeras (TransTACs), and degrader–antibody conjugates (DACs). We analyzed their molecular architectures, mechanisms of trans-membrane degradation, and their biological impact on tumor–stroma immune interactions.

Results: Next-generation eTPD platforms successfully transcend cellular boundaries to physically eradicate immune checkpoints and metabolic mediators, thereby driving a profound, multidimensional remodeling of the highly immunosuppressive TIME. Furthermore, our examination of the latest clinical pipelines reveals significant translational progress alongside emerging challenges, including distinct pharmacokinetic barriers and novel adaptive resistance mechanisms associated with endolysosomal pathway defects.

Conclusion: eTPD represents a transformative paradigm in precision oncology, shifting the landscape from intracellular target inhibition to extracellular protein eradication. The strategic integration of artificial intelligence (AI) foundation models into molecular design and pharmacokinetic optimization offers a forward-looking approach to overcome current clinical bottlenecks and accelerate the translation of precision TPD immunotherapies.