High-throughput phenotypic screen and transcriptional analysis identify new compounds and targets for macrophage reprogramming

Nat Commun. 2021 Feb 3;12(1):773. doi: 10.1038/s41467-021-21066-x.


Macrophages are plastic and, in response to different local stimuli, can polarize toward multi-dimensional spectrum of phenotypes, including the pro-inflammatory M1-like and the anti-inflammatory M2-like states. Using a high-throughput phenotypic screen in a library of ~4000 FDA-approved drugs, bioactive compounds and natural products, we find ~300 compounds that potently activate primary human macrophages toward either M1-like or M2-like state, of which ~30 are capable of reprogramming M1-like macrophages toward M2-like state and another ~20 for the reverse repolarization. Transcriptional analyses of macrophages treated with 34 non-redundant compounds identify both shared and unique targets and pathways through which the tested compounds modulate macrophage activation. One M1-activating compound, thiostrepton, is able to reprogram tumor-associated macrophages toward M1-like state in mice, and exhibit potent anti-tumor activity. Our compound-screening results thus help to provide a valuable resource not only for studying the macrophage biology but also for developing therapeutics through modulating macrophage activation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Inflammatory Agents / chemistry
  • Anti-Inflammatory Agents / pharmacology*
  • Biological Products / chemistry
  • Biological Products / pharmacology*
  • Cell Line, Tumor
  • Cells, Cultured
  • Gene Expression / drug effects
  • Gene Ontology
  • High-Throughput Screening Assays / methods*
  • Humans
  • Macrophage Activation / drug effects*
  • Macrophages / classification
  • Macrophages / drug effects*
  • Macrophages / metabolism
  • Mice, Inbred C57BL
  • Neoplasms, Experimental / metabolism
  • Neoplasms, Experimental / pathology
  • Neoplasms, Experimental / prevention & control
  • Phenotype
  • THP-1 Cells
  • Thiostrepton / chemistry
  • Thiostrepton / pharmacology


  • Anti-Inflammatory Agents
  • Biological Products
  • Thiostrepton