Reprogramming liver metastasis-associated macrophages towards an anti-tumoral phenotype through enforced miR-342 expression

Description

Upon metastatic seeding in the liver, liver macrophages, including Kupffer cells, acquire a transcriptional profile typical of tumor-associated macrophages (TAMs), which support tumor progression. MicroRNAs (miRNAs) fine-tune TAM pro-tumoral functions, making their modulation a promising strategy for macrophage reprogramming into an anti-tumoral phenotype. Here, we analyze the transcriptomic profiles of liver and splenic macrophages, identifying miR-342-3p as a key regulator of liver macrophage function. miR-342-3p is highly active in healthy liver macrophages but significantly downregulated in colorectal cancer liver metastases (CRLMs). Lentiviral vector-engineered liver macrophages enforcing miR-342-3p expression acquire a pro-inflammatory phenotype and reduce CRLM growth. We identify Slc7a11, a cysteine-glutamate antiporter linked to pro-tumoral activity, as a direct miR-342-3p target, which may be at least partially responsible for TAM phenotypic reprogramming. Our findings highlight the potential of in vivo miRNA modulation as a therapeutic strategy for TAM reprogramming, offering an approach to enhance cancer immunotherapy. Data and code availability: Next-generation sequencing data are deposited at the Gene Expression Omnibus (GEO) with the following accession numbers: GEO: GSE274043 (scRNA-seq), GSE274044 (RNA-seq on iKCs), GSE274045 (small RNA-seq on splenic and hepatic cell populations), and GSE274046 (bulk RNA-seq on splenic and hepatic cell populations). The code is available at GitLab: http://www.bioinfotiget.it/gitlab/custom/Bresesti_Cell_Reports_2025.

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All the steps to reproduce the data can be found on GitLab: http://www.bioinfotiget.it/gitlab/custom/Bresesti_Cell_Reports_2025

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