Lys-ing the Resistance: Targeting Lysosomes to Overcome Chemoresistance in Ovarian Cancer

Lysosomes contribute to chemoresistance through various mechanisms, including increased lysosomal biogenesis, resulting from the enhanced activity of transcription factor EB, a master regulator of the autophagy-lysosome pathway, which enhances cellular capacity for drug sequestration. Lysosomal exocytosis allows the cell to secrete chemotherapeutic agents from OC cells. Lysosomal autophagy pathways enable OC cells to selectively recycle cell components during chemotherapeutic stress. Finally, lysosomal signaling pathways disrupt various cell death mechanisms such as apoptosis, necroptosis, and ferroptosis, which allow cancer cells to evade death under chemotherapeutic stress. Targeting lysosomal biogenesis, stage-specific autophagy modulation, and lysosome-dependent metabolic vulnerabilities are promising avenues for sensitization of chemoresistant OC cells.