Toll-like receptor-targeted nanoparticles: A powerful combination for tumor immunotherapy

Toll-like receptors (TLRs), found on antigen-presenting cells including macrophages and dendritic cells, are essential for identifying infections and initiating adaptive immunity. Therefore, among the many strategies for cancer immunotherapy, methods based on TLR agonists have been one of the most pursued directions. In addition to these immunologic activation functions, TLR agonists also contribute to reshaping immunosuppressive "cold" tumors into "hot" tumors. Despite their remarkable immunomodulatory properties, TLR agonists exhibit a low therapeutic index. Non-specific stimulation of various immune cells may produce excessive levels of inflammatory cytokines, leading to systemic side effects. The continuous development in nanotechnology has presented the possibility of innovative therapies to improve the efficacy and safety of TLR agonist-based immunotherapy. In this review, we describe the functions of TLRs in the tumor microenvironment, as well as, the pathways that activate immune responses, in addition to summarizing and discussing recent developments in nanotechnology for immunomodulation with TLR agonists, including platforms such as nanocapsules, micelles, liposomes, nanogels, and others. Nanotechnology can effectively improve the efficacy of TLR agonist-based immunotherapy, while playing a pivotal role in solving the limitations of the current treatment.