TLR Agonists as Vaccine Adjuvants Targeting Cancer and Infectious Diseases (2021, Pharmaceutics)

Modern vaccines often use specific parts (subunits) of a pathogen rather than the whole, weakened or killed pathogen. This can make them safer, but also less effective at stimulating the immune system, and the addition of adjuvants can help strengthen the immune response.
This review summarises our knowledge of adjuvants based on activating Toll-like receptors (TLRs). TLRs are found mainly on innate immune cells, acting as sensors in recognising pathogen-associated molecules ("danger" signals). Each TLR has a part that recognizes the pathogen molecule (the leucine-rich repeat, LRR) and another part that triggers an immune response (the TIR domain). By connecting the innate immune recognition with the more targeted adaptive response TLR agonists are ideal as vaccine adjuvants, helping create strong and long-lasting immune protection. mRNA vaccines also engage TLRs. This review focuses on TLR-activating molecules as vaccine adjuvants and in immunotherapies, with particular emphasis on current clinical application.
TLR4 and TLR9 agonists are the most clinically advanced, used in several approved vaccines (Cervarix, Shingrix, Heplisav-B), and being studied in other infectious diseases and cancer. A key challenge with TLR agonists in cancer immunotherapy is the development of resistance by cancer cells, and combining TLR agonists with other immune stimulators may overcome this. Overall, TLR agonists are powerful immune activators with great potential for vaccines and immunotherapy, but careful formulation and delivery are crucial for maximising benefits and minimising side effects.