A second-generation M1-polarized CAR macrophage with antitumor efficacy

Area of Science:

• Immunotherapy
• Cellular Engineering
• Oncology

Background:

• Chimeric antigen receptor (CAR) T cell therapy is effective against blood cancers.
• Macrophages are promising for immunotherapy due to tumor infiltration and phagocytosis.
• First-generation CAR-macrophages show antigen-dependent tumor cell phagocytosis.

Purpose of the Study:

• To engineer advanced CAR-macrophages (CAR-iMACs) for improved solid tumor treatment.
• To enhance macrophage-mediated phagocytosis and antitumor responses.
• To develop a second-generation CAR-iMAC with dual signaling for superior efficacy.

Main Methods:

• Engineered induced pluripotent stem cell-derived macrophages (iMACs) with toll-like receptor 4 intracellular toll/IL-1R (TIR) domain-containing CARs.
• Designed a tandem CD3ζ-TIR dual signaling CAR for enhanced iMAC function.
• Investigated CAR-iMAC-mediated phagocytosis, M1 polarization, M2 resistance, and tumor microenvironment modulation.

Main Results:

• Engineered iMACs with TIR-CARs demonstrated enhanced antitumor effects compared to first-generation CAR-macrophages.
• The dual signaling CAR-iMACs exhibited target engulfment and antigen-dependent M1 polarization with M2 resistance.
• CAR-induced efferocytosis of tumor cell apoptotic bodies was identified as a mechanism of tumor cell elimination.

Conclusions:

• Second-generation CAR-iMACs possess orthogonal phagocytosis and polarization capabilities.
• CAR-iMACs demonstrate superior antitumor functions for treating solid tumors compared to first-generation CAR-macrophages.
• This engineered CAR-iMAC platform offers a promising strategy for solid tumor immunotherapy.