Induced pluripotent stem cell (iPSC)-derived CAR-macrophages: new kids on the block

Remarkable outcomes of chimeric antigen receptor (CAR)-T cell therapy in treating hematologic malignancies have inspired parallel efforts to harness the potential of other immune cell types for CAR-based immunotherapy. These efforts aim to overcome the existing limitations of CAR-T cell therapy. In recent years, CAR-macrophages (CAR-MACs) have shown astonishing efficacy in cancer treatment, leading to the approval of several CAR-MAC products for clinical trials. The lack of T-cell receptor (TCR) expression allows them to be used in allogeneic settings and as off-the-shelf products. Within the tumor microenvironment (TME), they can suppress tumor growth via multimodal mechanisms, including CAR-dependent and CAR-independent activities. They can also remodel the TME and prime other immune cells to enhance antitumor responses. Despite these merits, obtaining a sufficient number of MACs from traditional sources is challenging or is subject to regulatory hurdles. This review explores induced pluripotent stem cells (iPSCs) as an emerging source for generating iPSC-derived CAR-MACs (CAR-iMACs). In this regard, we began with an overview of MACs and their conventional sources and discussed the advantages of iPSCs over these traditional sources. After that, the technical procedures for generating iPSCs and differentiating them into functional CAR-iMACs were comprehensively discussed. Finally, we explored the preclinical and clinical advances in CAR-iMAC therapy.