Imidazoloquinoline optical isomers as TLR7 selective agonists promote macrophage activation for cancer immunotherapy

The chirality of drugs profoundly influences their efficacy, safety, and biological functions, particularly in single-enantiomer structures. Toll-like Receptor 7 (TLR7) activation represents a promising tumor immunotherapy strategy by bridging innate and adaptive immunity. Herein, we design a chiral TLR7 Agonist SMU-L11-R based on an imidazoquinoline scaffold. Compared to its enantiomer, it exhibits nearly 10-fold enhanced excitatory activity in HEK Blue hTLR7 cells (EC₅₀ = 0.012 ± 0.003 μM). Mechanistic studies reveal SMU-L11-R specifically activates TLR7, recruits MyD88, and triggers MAPK/NF-κB pathways, eliciting TNF-α/IL-1β/IL-6 secretion in both mouse and human peripheral blood mononuclear cells. The macrophage polarization experiments revealed SMU-L11-R remarkably upregulated the M1-like macrophage, accounting for 61.1 %, compared to 26.3 % in the control group. In the MC38 mouse model, SMU-L11-R can significantly inhibit tumor growth and exhibit excellent synergistic anti-tumor effects with PD-L1 inhibitors by upregulating CD8⁺T cells. Taken together, the optical isomer SMU-L11-R exhibits a superior TLR7 activation effect compared to its enantiomer, and demonstrates excellent tumor immune efficacy as a single drug or in combination with PD-L1 inhibitors.

CD8(+)T cells; Cancer immunotherapy; Inflammatory cytokines; PD-L1; TLR7 agonist.