From "lysosomal addiction" to targeted therapies: exploiting novel windows in colorectal cancer

Patients with advanced-stage or treatment-resistant colorectal cancer (CRC) face limited therapeutic options with conventional therapies, necessitating novel treatment strategies. CRC cells exhibit "lysosomal addiction" through enhanced autophagy-lysosomal flux and upregulated lysosome-associated genes including lysosomal-associated membrane protein 1/2 and cathepsin B/D, creating therapeutic windows for selective targeting. Lysosome-dependent cell death represents a distinct mode of regulated cell death characterized by lysosomal membrane permeabilization and cathepsin-mediated cytotoxic cascades, offering advantages over apoptosis-dependent mechanisms. Recent investigations have identified multiple druggable targets within lysosomal pathways, including autophagy modulators, cathepsin inhibitors, and innovative drug delivery systems. Lysosomes also play bidirectional roles in tumor immune microenvironment regulation, with implications for combination immunotherapy strategies. However, challenges remain in clinical translation, including autophagy's dual functionality and the need for reliable biomarkers. Targeting lysosomal dysfunction represents a promising therapeutic approach for CRC, particularly for overcoming resistance to traditional therapies. The unique metabolic dependency of cancer cells on lysosomal function provides exploitable therapeutic windows for precision medicine approaches.