4.8 Article

miR-182 targeting reprograms tumor-associated macrophages and limits breast cancer progression

出版社

NATL ACAD SCIENCES
DOI: 10.1073/pnas.2114006119

关键词

miR-182; tumor-associated macrophage; breast cancer; RNAi therapeutics; extracellular vesicle

资金

  1. Ministry of Science and Technology of China [2017YFA0103502, 2020YFA0112300]
  2. Chinese Academy of Sciences [QYZDB-SSW-SMC013]
  3. National Natural Science Foundation of China [81725017, 81872367, 81802648]

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This study reveals the crucial role of the TGF beta/miR-182/TLR4 axis in the polarization of tumor-associated macrophages (TAMs) and provides a theoretical basis for RNA-based therapeutics targeting TAMs in cancer.
The protumor roles of alternatively activated (M2) tumor-associated macrophages (TAMs) have been well established, and macrophage reprogramming is an important therapeutic goal. However, the mechanisms of TAM polarization remain incompletely understood, and effective strategies for macrophage targeting are lacking. Here, we show that miR-182 in macrophages mediates tumor-induced M2 polarization and can be targeted for therapeutic macrophage reprogramming. Constitutive miR-182 knockout in host mice and conditional knockout in macrophages impair M2-like TAMs and breast tumor development. Targeted depletion of macrophages in mice blocks the effect of miR-182 deficiency in tumor progression while reconstitution of miR-182-expressing macrophages promotes tumor growth. Mechanistically, cancer cells induce miR-182 expression in macrophages by TGF beta signaling, and miR-182 directly suppresses TLR4, leading to NF kappa b inactivation and M2 polarization of TAMs. Importantly, therapeutic delivery of antagomiR-182 with cationized mannan-modified extracellular vesicles effectively targets macrophages, leading to miR-182 inhibition, macrophage reprogramming, and tumor suppression in multiple breast cancer models of mice. Overall, our findings reveal a crucial TGF beta/miR-182/TLR4 axis for TAM polarization and provide rationale for RNA-based therapeutics of TAM targeting in cancer.

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