The discovery and investigation of Toll-like receptors (TLRs) has fundamentally reshaped our understanding of innate immunity and inflammation over the past four decades. These pivotal pattern-recognition receptors play a canonical role as sentinels that detect pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). In addition, TLR signaling is subject to exquisite multilayered regulation to prevent excessive inflammation and maintain immune homeostasis. Such regulation includes posttranslational modifications, epigenetic reprogramming, metabolic rewiring, and dynamic assembly of signaling condensates. This review comprehensively summarizes the intrinsic regulatory networks and tissue-microenvironment crosstalk that fine-tune TLR responses. We highlight the central roles of TLR signaling in infection, autoimmunity, cancer, inflammaging, cardiovascular diseases, and neurodegenerative disorders, underscoring how dysregulation drives pathology. Finally, we examine recent analyses and future prospects for pharmacological modulation of TLR pathways with agonists or antagonists as a promising therapeutic strategy for a broad spectrum of inflammatory and immune-mediated diseases. By bridging foundational mechanisms with clinical insights, this article illustrates how TLR research continues to illuminate immune regulation and offers novel avenues for targeted immunotherapy.
Qian et al. (2026) studied this question.