Colorectal cancer (CRC) metastatic dissemination to the liver is one\nof the most life-threatening malignancies in humans and represents\nthe leading cause of CRC-related mortality. Herein, we adopted a\ngene transfer strategy into mouse hematopoietic stem/progenitor\ncells to generate immune-competent mice in which TEMsââ?¬â?a subset\nof Tie2+ monocytes/macrophages found at peritumoral sitesââ?¬â?\nexpress interferon-alpha (IFNa), a pleiotropic cytokine with antitumor\neffects. Utilizing this strategy in mouse models of CRC liver\nmetastasis, we show that TEMs accumulate in the proximity of\nhepatic metastatic areas and that TEM-mediated delivery of IFNa\ninhibits tumor growth when administered prior to metastasis challenge\nas well as on established hepatic lesions, improving overall\nsurvival. Further analyses unveiled that local delivery of IFNa does\nnot inhibit homing but limits the early phases of hepatic CRC cell\nexpansion by acting on the radio-resistant hepatic microenvironment.\nTEM-mediated IFNa expression was not associated with\nsystemic side effects, hematopoietic toxicity, or inability to respond\nto a virus challenge. Along with the notion that TEMs were detected\nin the proximity of CRC metastases in human livers, these results\nraise the possibility to employ similar gene/cell therapies as tumor\nsite-specific drug-delivery strategies in patients with CRC.
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