新型口服 TLR7 激动剂通过 I 型 IFN 通路协调免疫应答并与 PD-L1 阻断在肺癌中协同

Despite the groundbreaking impact of immune checkpoint blockade (ICB), response rates in non-small cell lung cancer remain modest, particularly in immune-excluded or immune-desert microenvironments. Toll-like receptor 7 (TLR7) emerges as a latent target bridging innate and adaptive immunity, offering a promising avenue for combination therapies to augment ICB efficacy.

Here, we explored the anti-tumor activity of the novel oral TLR7 agonist TQ-A3334 and its potential to enhance anti-programmed death ligand 1 (PD-L1) therapy through a combination strategy in a syngeneic murine lung cancer model. Oral administration of TQ-A3334 significantly alleviated tumor burden in C57BL/6J mice, modulated by type I interferon (IFN), and exhibited low toxicity.

This therapy elicited activation of both innate and adaptive immune cells in tumor tissue, particularly increasing the abundance of CD8 + TILs through type I IFN pathway and subsequent CXCL10 expression. In vitro examinations validated that IFN- -stimulated tumor cells exhibited increased secretion of CXCL10, conducive to the promoted trafficking of CD8 + T cells.

Furthermore, combining TQ-A3334 with anti-PD-L1 treatment exceeded tumor control, with a further increase in CD8 + TIL frequency compared to monotherapy.

These findings suggest that TQ-A3334 can mobilize innate immunity and promote T cell recruitment into the tumor microenvironment; a combination of TQ-A3334 and anti-PD-L1 antibodies can intensify the sensitivity of tumors to anti-PD-L1 therapy, which demonstrates significant potential for treating poorly immune-infiltrated lung cancer.