Gemcitabine-loaded synthetic high-density lipoprotein preferentially eradicates hepatic monocyte-derived macrophages in mouse liver with colorectal cancer metastases

Feng-qin Xiong1,2, Wen Zhang1,2, Chao Zheng1,2, Yu Li3, Xiang Gong1,2, Yuan Zhang4, Hao Wang1, Peng-cheng Zhang2,5, Ya-ping Li2,3,6
1 China State Institute of Pharmaceutical Industry, Shanghai 201203, China
2 State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
3 School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China
4 Department of Pulmonary and Critical Care Medicine, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, China
5 School of Biomedical Engineering, ShanghaiTech University, Shanghai 201210, China
6 Bohai Rim Advanced Research Institute for Drug Discovery, Yantai 264000, China
Correspondence to: Hao Wang:, Peng-cheng Zhang:, Ya-ping Li:,
DOI: 10.1038/s41401-023-01110-w
Received: 17 March 2023
Accepted: 9 May 2023
Advance online: 24 May 2023


Liver metastasis of colorectal cancer (CRC) is the critical cause of CRC-related death due to its unique immunosuppressive microenvironment. In this study we generated a gemcitabine-loaded synthetic high-density lipoprotein (G-sHDL) to reverse immunosuppression in livers with CRC metastases. After intravenous injection, sHDL targeted hepatic monocyte-derived alternatively activated macrophages (Mono-M2) in the livers of mice bearing both subcutaneous tumors and liver metastases. The G-sHDL preferentially eradicated Mono-M2 in the livers with CRC metastases, which consequently prevented Mono-M2-mediated killing of tumor antigen-specific CD8+ T cells in the livers and thus improved the densities of tumor antigen-specific CD8+ T cells in the blood, tumor-draining lymph nodes and subcutaneous tumors of the treated mice. While reversing the immunosuppressive microenvironment, G-sHDL also induced immunogenic cell death of cancer cells, promoted maturation of dendritic cells, and increased tumor infiltration and activity of CD8+ T cells. Collectively, G-sHDL inhibited the growth of both subcutaneous tumors and liver metastases, and prolonged the survival of animals, which could be further improved when used in conjunction with anti-PD-L1 antibody. This platform can be a generalizable platform to modulate immune microenvironment of diseased livers.
Keywords: colorectal cancer; liver metastasis; synthetic high-density lipoprotein; gemcitabine; macrophages

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