Programmable engineered bacteria as sustained-releasing antibody factory in situ for enhancing tumor immune checkpoint therapy

免疫系统 肿瘤微环境 免疫检查点 癌症研究 巨噬细胞 生物 巨噬细胞极化 抗体 免疫疗法 免疫学 生物化学 体外
作者
Xiao‐Ting Xie,Meng Guan,Kai Cheng,Yong Li,Bin Zhang,Yitong Zhou,Lin‐Fang Tan,Ping Dong,Si Chen,Bo Liu,Yuan‐Di Zhao,Jin‐Xuan Fan
出处
期刊:Science Advances [American Association for the Advancement of Science]
卷期号:11 (13)
标识
DOI:10.1126/sciadv.adt7298
摘要

Tumor immune checkpoint therapy (ICT) aims to block immune escape signals between tumor and immune cells. However, low delivery efficiency of immune checkpoint inhibitors (ICIs), narrow single-target approach, and reduced responsiveness notably hinder clinical development of ICT. Here, we developed a nanoliposome-bacteria hybrid system that acts as an antibody (Ab) factory, enabling precise tumor targeting and macrophage activation in hypoxic environments. We reprogrammed attenuated Escherichia coli MG1655 to synthesize CD47 antibodies (aCD47) in response to hypoxic tumor microenvironments while surface conjugating with redox-responsive macrophage colony-stimulating factor-loaded liposomes. This system leverages bacterial tropism to enhance macrophage infiltration and polarization. The low oxygen levels trigger in situ aCD47 expression, blocking the “do not eat me” signal and boosting macrophage antitumor activity. In addition, macrophage antigen presentation activates CD8+CD3+ T cells, amplifying systemic antitumor immunity. Analysis of the gut microbiome shows reduced pathogenicity and improved intestinal tolerance with increased probiotics.
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