Targeting lysosomal ion channels to overcome cancer treatment resistance: emerging mechanisms and therapeutic opportunities

Abstract

Lysosomes are critical cellular organelles that not only regulate metabolic regulation but also play pivotal roles in cell death, signal transduction, and tumorigenesis. The various ion channels expressed on the lysosomal membrane are central to these physiological functions; they intricately maintain lysosomal pH homeostasis, calcium ion homeostasis, and membrane potential. Consequently, the dysregulation of these channels has emerged as a potential target of tumor cells, driving tumor cell proliferation, metastasis, apoptosis, and drug resistance. This review summarizes the structure and function of major lysosomal ion channels, emphasizing their central roles in regulating the tumor microenvironment, cell survival, and treatment resistance. Specifically, we highlight their involvement in mediating resistance to chemotherapy, radiotherapy, and immunotherapy, elucidating the associated molecular mechanisms. Furthermore, we explore the prospects and challenges of developing targeted therapeutic strategies towards these ion channels to overcome tumor drug resistance.