Abstract：
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-α-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.
摘要：
尽管免疫检查点封锁（ICB）具有开创性的影响，非小细胞肺癌的反应率仍然适中，特别是在免疫排斥或免疫沙漠微环境中。Toll样受体7（TLR7）作为一个潜在的靶点桥接先天和适应性免疫，为联合治疗增加ICB疗效提供了一个有希望的途径。这里,我们探索了新型口服TLR7激动剂TQ-A3334的抗肿瘤活性及其在同基因鼠肺癌模型中通过组合策略增强抗程序性死亡配体1(PD-L1)治疗的潜力.口服TQ-A3334可显着减轻C57BL/6J小鼠的肿瘤负担，由I型干扰素（IFN）调节，并表现出低毒性。这种疗法在肿瘤组织中引起先天和适应性免疫细胞的激活。特别是通过I型IFN途径和随后的CXCL10表达增加CD8TIL的丰度。体外检查证实，IFN-α刺激的肿瘤细胞显示CXCL10分泌增加，有利于促进CD8T细胞的运输。此外，TQ-A3334与抗PD-L1联合治疗超过了肿瘤控制，与单一疗法相比，CD8+TIL频率进一步增加。这些结果表明，TQ-A3334可以动员先天免疫并促进T细胞募集到肿瘤微环境;TQ-A3334和抗PD-L1抗体的组合可以增强肿瘤对抗PD-L1治疗的敏感性。这证明了治疗免疫能力差的浸润性肺癌的巨大潜力。
