Endolysosomal dependencies in viral infection: context-dependent mechanisms and therapeutic translation

The endolysosomal system is increasingly recognized as a dynamic determinant of viral infection rather than a passive degradative endpoint. Depending on viral species, target-cell state, and infection stage, endosomal and lysosomal processes can either facilitate viral entry, intracellular trafficking, and egress or contribute to host restriction and cellular defense. However, lysosome-associated changes observed during infection do not necessarily represent functional dependencies, and antiviral effects detected in simplified cell systems may not persist in physiologically relevant models. This review therefore examines virus-endolysosome interactions through a dependency-oriented framework that distinguishes organelle-associated phenotypes from mechanistically causal host requirements. We synthesize comparative evidence from representative RNA and DNA virus systems on the roles of endolysosomal processes in viral entry, organelle remodeling, host defense, and egress, emphasizing studies that link defined perturbations to direct virological outcomes. The review also evaluates host-directed and compartment-targeted antiviral strategies involving endolysosomal trafficking, ion and lipid homeostasis, lysosomal degradation programs, and selective delivery, highlighting model-dependent antiviral activity and the limited clinical evidence, including trials that did not establish benefit for selected preclinically active candidates. We propose that endolysosome-directed antiviral development should prioritize mechanistically defined, context-specific host dependencies that are reproducible across physiological models and can be modulated without compromising essential lysosomal functions.