Relevance of lysosomal Ca²⁺ signalling machinery in cancer

In comparison with normal cells, cancer cells are equipped with a higher number of lysosomes, involved in degradative and non-degradative roles. In particular, the lysosome is a Ca²⁺signalling hub, and the enhancement of this interconnected machinery in cancer cells has recently prompted investigations into the role that lysosomal ion channels play in oncology. The present review reports findings about the emerging role of lysosomal Ca²⁺channels: Two-Pore Channels (TPCs), Transient Receptor Potential Cation Channels (TRPMLs; mucolipins), and Purinergic X Receptor 4 (P2×4R), in a variety of cancer models, highlighting their impact on crucial functions such as the regulation of autophagy and the composition of the tumour microenvironment, including the secretion-mediated interplay with immune and endothelial cells. Notably, recent evidence indicates that, by regulating tumour secretome, lysosomal Ca²⁺ signalling can affect the composition of the tumour-infiltrating immune cell repertoire. Intriguingly, the data so far available show that the protumoral/antitumoral role of lysosomal Ca²⁺ channels can differ according to the specific genetic context, types of cancer and the malignancy stage, and signals from the microenvironment.