Biofouling, commonly referred to as the unwanted deposition of cells on wetted solids, is a serious operational and environmental issue in many underwater and biomedical applications. Over the past decade, lubricant-impregnated surfaces (LIS) arose as a potential solution to prevent fouling, owing to their unique layer of lubricant masking the solid from the outer environment, thereby preventing biofouling. However, living microorganisms alter their environment by reproducing and secreting biomolecules, which can threaten the stability of such coatings over time. In this paper, we show that secretion of biomolecules from aquatic cells and subsequent changes in the interfacial tension of the surrounding media can trigger dewetting of the lubricant, ultimately exposing the surface to the outer solution and therefore becoming prone to fouling. By observing LIS immersed in Nannochloropsis oculata algae solutions at various stages of population growth, we establish a correlation between the decrease in interfacial tension and wetting states of the surface. We also visualize dewetting of the lubricant through confocal imaging performed in situ. Finally, we establish a diagram providing fundamental insights to design sturdy LIS circumventing such dewetting, therefore ensuring long-term protection against biofouling upon extended immersion in living cell solutions.