Tumour-associated macrophages (TAMs) are abundant in many cancers, and often display an immune-suppressive M2-like phenotype that fosters tumour growth and promotes resistance to therapy. Yet macrophages are highly plastic and can also acquire an anti-tumourigenic M1-like phenotype. Here, we show that R848, an agonist of the toll-like receptors (TLRs) TLR7 and TLR8 identified in a morphometric-based screen, is a potent driver of the M1 phenotype in vitro and that R848-loaded β-cyclodextrin nanoparticles (CDNPs) lead to efficient drug delivery to TAMs in vivo. As a monotherapy, the administration of CDNP-R848 in multiple tumour models in mice altered the functional orientation of the tumour immune microenvironment towards an M1 phenotype, leading to controlled tumour growth and protecting the animals against tumour rechallenge. When used in combination with the immune checkpoint inhibitor anti-PD-1, we observed improved immunotherapy response rates, also in a tumour model resistant to anti-PD-1 therapy. Our findings demonstrate the ability of rationally engineered drug-nanoparticle combinations to efficiently modulate TAMs for cancer immunotherapy.

中文翻译：

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载有TLR7 / 8激动剂的纳米颗粒可促进肿瘤相关巨噬细胞的极化，从而增强癌症免疫疗法。

肿瘤相关的巨噬细胞（TAM）在许多癌症中都很丰富，并且通常表现出免疫抑制性的M2样表型，可促进肿瘤生长并增强对治疗的抵抗力。然而，巨噬细胞是高度可塑性的，并且还可以获得抗致瘤性的M1样表型。在这里，我们显示R848（在基于形态计量学的屏幕中确定的Toll样受体（TLRs）TLR7和TLR8的激动剂）是体外M1表型的有效驱动力，并且R848负载的β-环糊精纳米颗粒（CDNPs ）导致体内有效地将药物递送到TAM。作为一种单一疗法，在小鼠的多个肿瘤模型中施用CDNP-R848可以改变肿瘤免疫微环境朝M1表型的功能方向，从而导致可控的肿瘤生长并保护动物免受肿瘤再攻击。当与免疫检查点抑制剂抗PD-1组合使用时，我们还观察到在抗PD-1治疗耐药的肿瘤模型中免疫治疗应答率提高。我们的发现证明了合理设计的药物-纳米颗粒组合有效调节TAM用于癌症免疫治疗的能力。