Fig. 3: Various ways to modulate lysosomes and their functions.

Lysosomes are associated with various pathways which makes it possible to target them in different ways. Lysosomotropic agents can disrupt the lysosomal membrane and release cathepsins into the cytosol leading to LCD. Other lysosomotropic agents such as chloroquine (or hydroxychloroquine) can impede lysosomal membrane fusion which is important for turnover in autophagy. Due to the protective role of HSP70 against lysosomotropic agents, HSP70 inhibitors can be used to intensify their effect. During oncogenic activation, lysosomal exocytosis causes release of cathepsins into extracellular space, which promotes extracellular matrix degradation and invasion of malignant cells. This makes protease inhibitors targeting cathepsins also a therapeutic option. Autophagic pathways have context-dependent roles in cancer and thus, there may be several strategies to either block or stimulate the pathways. Upstream pathways such as mTORC1 and 2 can be inhibited to stimulate autophagy in an indirect manner. V-ATPase inhibitors can elevate lysosomal pH, thus impairing the function of many pH-sensitive lysosomal enzymes. Created with BioRender.com.