Lysosome-directed targeted protein degradation technologies for overcoming cancer drug resistance: mechanisms, design principles, and therapeutic opportunities.

Targeted protein degradation (TPD) has emerged as a promising therapeutic strategy to address cancer drug resistance by enabling the selective and efficient degradation of disease-associated proteins through cellular mechanisms. Since 2020, lysosome-targeting chimeras (LYTACs) have gained attention for expanding targeted protein degradation to extracellular and membrane-associated disease-related proteins beyond the reach of proteolysis-targeting chimeras (PROTACs). In practice, LYTACs can overcome resistance by degrading instead of inhibiting them. This efficient and durable removal of resistance-associated drivers thereby suppresses compensatory signaling, restores drug sensitivity, and contributes to remodeling the tumor microenvironment. To facilitate the clinical translation of this emerging technology, this review systematically compares the mechanistic and functional advantages of LYTACs over PROTACs, summarizes key design principles, and categorizes major LYTAC modalities, including AbTACs, MoDE-As, and nano-LYTACs. We further discuss their in vivo pharmacological behaviors, with particular emphasis on stability, tumor selectivity, and degradation efficiency. Importantly, this article comprehensively highlights recent advances in the application of LYTACs for overcoming therapeutic resistance, including resistance to chemotherapy, targeted therapy, and immunotherapy. Finally, current translational bottlenecks, such as delivery efficiency, receptor heterogeneity, and pharmacokinetic limitations, are critically analyzed. Collectively, while still in its early stages of development, LYTAC-based lysosomal degradation represents a promising, paradigm-shifting strategy for targeting previously intractable mechanisms of cancer resistance.