Sophie Post, Lena Rueschpler, Sebastian Schloer
Emerging viruses exploit the endolysosomal system to enter host cells, subvert immune defenses, and promote their replication, underscoring the need for a deeper understanding of this compartment at the host-pathogen interface. This review synthesizes current advances that position endolysosomes as central gatekeepers of cellular homeostasis and viral control. We illustrate how emerging viruses co-opt endolysosomal trafficking pathways for entry, uncoating, and propagation; how they manipulate autophagy and key signaling nodes such as mTORC1, TFEB, and the ESCRT machinery; and how they strategically disrupt innate immune signaling orchestrated from endolysosomal platforms. We further highlight recent discoveries revealing viral interference with endosomal pattern-recognition receptors, antigen presentation circuits, and downstream inflammatory signaling. Finally, we critically assess emerging therapeutic strategies that target endolysosomal functions to restrict viral infection. Together, these insights provide an integrated framework for understanding how endolysosomes shape host antiviral responses and how their dysregulation is exploited by diverse, rapidly evolving viral pathogens. Nevertheless, the clinical translation of endolysosome-targeted antiviral strategies remains constrained by pathway complexity, potential off-target effects, and the absence of reliable biomarkers to guide therapeutic precision, underscoring key limitations and opportunities for future investigation.