Redefining tear film Biology: Immune regulation, multi-omics integration, and systemic disease interfaces

Traditionally considered a passive lubricant, the tear film, comprising three functionally distinct yet interdependent layers (lipid, aqueous, mucin), is now recognized as a dynamic interface that integrates ocular and systemic immune regulation. It orchestrates innate, adaptive, and tolerogenic immune responses to preserve ocular surface homeostasis. In dry eye disease (DED), dysfunction of these regulatory pathways initiates inflammatory cascades, leading to goblet cell loss and epithelial injury. Advances in untargeted omics and high-plex targeted platforms (e.g., Olink proximity-extension assays) have established tear fluid as a microliter-scale reservoir of clinically relevant, non-invasive biomarkers. These technologies enable refined DED subtyping, grading of disease severity, and monitoring of systemic conditions. Autoimmune and metabolic disorders, such as SS and diabetes, leave distinct molecular imprints in tears, compromising film stability and exacerbating inflammation. Chronic tear-film instability disrupts neuroimmune balance, contributing to corneal nerve degeneration and visual impairment. Pathophysiological hallmarks include lubricin (PRG4) deficiency and hyperosmolar "hot spots" at tear break-up (TBU) regions. Emerging wearable biosensors and Artificial Intelligence (AI)-based analytics now permit real-time, minimally invasive tracking of tear dynamics. However, translation of immune-modulatory therapies remains challenging due to high late-stage failure rates. This review redefines the tear film as a sentinel of ocular and systemic health, highlighting how multi-omics and AI technologies are advancing precision diagnostics and targeted interventions for DED.