c-Myc alone is enough to reprogram fibroblasts into functional macrophages

Area of Science:

• Cell Biology
• Immunology
• Cancer Research
• Stem Cell Biology

Background:

• Macrophage-based cell therapy shows promise for solid tumors but faces challenges in efficient macrophage acquisition.
• Induced pluripotent stem cell (iPSC)-derived macrophages are a potential source but are time-consuming and costly to generate.
• Reprogramming somatic cells into macrophages offers a viable alternative for advancing cell-based cancer therapies.

Purpose of the Study:

• To establish a novel methodology for reprogramming fibroblasts into functional macrophages.
• To investigate the role of c-Myc in fibroblast reprogramming into macrophages.
• To evaluate the therapeutic potential of reprogrammed macrophages in preclinical cancer models.

Main Methods:

• Fibroblasts were reprogrammed into macrophages using c-Myc overexpression in iPSC medium.
• Flow cytometry and single-cell RNA sequencing analyzed myeloid-like cell complex (MCC) and induced macrophage (iMac) composition.
• Engraftment capacity, phenotype, phagocytosis, and anti-tumor function of iMacs were assessed in vitro and in vivo using various cancer models.

Main Results:

• c-Myc overexpression reprogrammed fibroblasts into CD45+ MCC intermediates with hematopoietic engraftment capacity.
• MCC intermediates continuously generated functional, pure iMacs upon M-CSF stimulation, exhibiting NF-κB activation and a pro-inflammatory phenotype.
• iMacs demonstrated enhanced in vivo persistence and significant inhibition of tumor progression in leukemia, breast cancer, and patient-derived xenograft models.

Conclusions:

• c-Myc alone is sufficient to reprogram fibroblasts into functional, phagocytic macrophages.
• This c-Myc-mediated reprogramming strategy provides a method for generating "off-the-shelf" macrophages.
• The findings support the potential of this approach to overcome obstacles in macrophage acquisition for anti-cancer immunotherapy.