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

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.