Fig. 7

Synthetic TLR7/8, TLR9, and STING agonists in clinical trials. The immunostimulatory adjuvants can directly activate pDCs in vivo by targeting TLR or STING signaling pathways. Various TLR7/8, TLR9 and STING agonists are being used in multiple clinical trials, as monotherapy or in combination with ICB, to enhance anti-cancer immunity by exogenous activation of pDCs. IMQ is the first TLR7 agonist approved for the topical treatment of non-melanoma skin cancer. The TLR7/8 agonists include the second-generation (e.g. R848/resiquimod, BDB001, LHC165) and the third-generation (e.g. BDC-1001, NJH395) synthetic compounds. The unmethylated CpG oligodeoxynucleotides (CpG-ODN) are ligands of TLR9 and can be distinguished into three major classes: CpG-A (CpG ODN 2216, Vidutolimod/CMP-001), CpG-B (CpG ODN 1668, Tilsotolimod/IMO-2125, Cavrotolimod, CpG ODN 7909/PF-3512676, TAC-001), and CpG-C (SD101). Beyond natural cyclic dinucleotides (CDN), STING agonists include a variety of synthetic CDN (ADU-S100/ML RRS2 CDA, MK-1454, BMS-986301, BI 1387446, E7766, IMSA101, SB11285, SYNB189) and non-cyclic dinucleotides (non-CDN; MK-2118, GSK3745417, SNX281, TAK-676). Dashed lines indicate the potential binding of synthetic compounds to TLRs or STING. Solid lines indicate the well-known signaling pathways triggered upon TLR7/9 or STING activation. Created with BioRender.com