Mechanistic insights into lysosomal stress response network in carcinogenesis and therapeutic opportunities

Lysosomes are vital organelles that maintain cellular homeostasis and orchestrate dynamic adaptations during physiological and pathological stress. Lysosomal damage, caused by various extrinsic and intrinsic factors, impairs its integrity and simultaneously disrupts the normal functioning of other organelles, including the endoplasmic reticulum and mitochondria. Lysosomal homeostasis through the lysosomal stress response (LSR) network aids cells in adapting to organelle damage, nutrient fluctuations, oxidative stress, and metabolic irregularities. This coordinated network is primarily governed by proteins, including mTOR, TFEB/TFE3, AMPK, Rag GTPases, Ragulator, and TRPML1, which integrates mechanisms involving rapid lysosomal membrane repair, selective elimination of extensively damaged lysosomes, de novo lysosomal biogenesis, and lysosomal reformation pathways. Dysregulation of the LSR network leads to different types of diseases, including cancer. This review summarizes the current understanding of lysosomal damage mitigation, particularly in cancer, where remodeling of the LSR network not only enables cancer cells to maintain metabolic plasticity by resisting therapeutic stress and promoting malignancy but also identifies the LSR network as a critical determinant in tumorigenesis. We further provide a detailed discussion of emerging evidence on the disruption of lysosomal homeostasis, highlighting strong links between lysosome-targeting drugs and cancer therapeutics. Altogether, we establish the LSR network as a central regulator of cellular homeostasis, thereby emerging as a promising therapeutic target in cancer and other lysosome-associated disorders.