Fig. 5.

This figure illustrates the process by which weak-base chemotherapy drugs become trapped in lysosomes, limiting their availability to cytosolic and nuclear compartments. Once inside the cell, drugs enter lysosomes through passive diffusion and are further concentrated by the P-gp/B1 transporter located on the lysosomal membrane. This sequestration reduces the drugs' therapeutic efficacy at their target sites, such as the nucleus. Lysosomal biogenesis and function are regulated by the CLEAR gene network, controlled by transcription factors TFEB, TFE3, and MITF is also depicted in the figure. The CLEAR network governs lysosomal size, abundance, and enzymatic activity, particularly under the influence of mTORC1 signaling. In cancer cells, this system can become dysregulated, enhancing the lysosome's capacity to sequester drugs, which can contribute to drug resistance. The figure was generated by using BioRender.com. N, nucleus; L, lysosome.