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Review
. 2024 Aug 23;12(1):86.
doi: 10.1186/s40364-024-00637-2.

CAR Macrophages: a promising novel immunotherapy for solid tumors and beyond

Jialin Lu #  1 , Yuqing Ma #  1 , Qiuxin Li #  2 , Yihuan Xu  1 , Yiquan Xue  3 , Sheng Xu  4   5
Affiliations
Review

CAR Macrophages: a promising novel immunotherapy for solid tumors and beyond

Jialin Lu et al. Biomark Res. .

Abstract

With the advent of adoptive cellular therapy, chimeric antigen receptor (CAR)-T cell therapy has gained widespread application in cancer treatment and has demonstrated significant efficacy against certain hematologic malignancies. However, due to the limitations of CAR-T cell therapy in treating solid tumors, other immune cells are being modified with CAR to address this issue. Macrophages have emerged as a promising option, owing to their extensive immune functions, which include antigen presentation, powerful tumor phagocytosis, and particularly active trafficking to the tumor microenvironment. Leveraging their unique advantages, CAR-macrophages (CAR-M) are expected to enhance the effectiveness of solid tumor treatments as a novel form of immunotherapy, potentially overcoming major challenges associated with CAR-T/NK therapy. This review outlines the primary mechanism underlying CAR-M and recent progressions in CAR-M therapy, while also discussing their further applications.

Keywords: CAR-Macrophages; Chimeric antigen receptor; Macrophages; Solid tumor.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Therapeutic strategies aiming at altering the phenotype of TAMs from a protumoral to an antitumoral state. TAM reprogramming strategies fall into two main categories: polarization-based reprogramming and function-based reprogramming of TAMs. Polarization-based reprogramming strategy primarily targets macrophage polarization signaling pathways, using TLR agonists, CSF1-R inhibitors, PI3K inhibitors and certain epigenetic inhibitors. Function-based reprogramming of TAMs aims at specific TAM functions, such as phagocytosis by targeting “do not eat me” signals SIRP1α-CD47, LILRB1-β2M, Siglec10-CD24, and PD1-PDL1. Function-based reprogramming of TAMs can also target macrophage immunosuppressive activities by inhibiting Siglec1, PD-L1, MARCO and LILRB2. Macrophage reprogramming results in the secretion of proinflammatory cytokines and ROS, improvement of phagocytic ability and macrophage-mediated immune promotion through CD8 + T cells, NK cells and neutrophils
Fig. 2
Fig. 2
Mechanisms of CAR-M. The killing of tumor cells by CAR-M can be reflected in many aspects. a CAR-M mediate direct cytotoxic effects by releasing TNF, NO and ROS. b CAR-M exert ADCC and ADP effects through the binding of FcR on its surface to Ab coated on the tumor cells. c Collaborative immune response can be achieved when CAR-M presents tumor antigens to helper T cells and recruit other immune cells. d CAR-M can play different roles depending on the CAR design. CCL19-CAR-M—promotes the engulfment of CCR7-positive tumor cells, which can slow tumor progression and metastasis. CD147-CAR-M—triggers MMPs production to degrade ECM, and promotes more immune cell infiltration
Fig. 3
Fig. 3
The various generations of CAR-M. According to CAR structural design, first-generation CAR-M includes a, b and c. a The inclusion of CD3ζ as an intracellular domain can promote the capacity of CAR-M. b The intracellular domain Megf10 significantly enhanced phagocytosis. And the whole cell eating ability was further promoted by the addition of PI3K. c The intracellular CD147 signal led to the degradation of ECM, thereby recruiting more T cells to the TME. Second-generation CAR-M includes d, e and f. d Ad5f35 was utilized to transfer the anti-HER2 CAR into macrophages, which tilted macrophages toward the M1 phenotype. (e) IPSC-differentiated CAR-expressing macrophages provided a sufficient source of CAR-M. The anti-tumor activity of macrophages expressing CD86-FcRγ-CAR was significantly enhanced, f while macrophages with CD3ζ-TIR-CAR can sustain long-term M1 polarization. Third-generation CAR-M includes g and h. g IFN-γ was added to the intracellular domain via CAR-IFN-γ nanocomplex, markedly enhancing anti-tumor efficacy. h Nanocomplex carrying RP-182 peptide not only promoted the macrophage phenotype to M1 but also delivered the CAR-ErbB2 gene to macrophages, thereby improving their phagocytosis
Fig. 4
Fig. 4
Innovative CAR-M therapies. a CAR-M and CAR-T can synergistically induce the death of tumor cells. IFN-γ and GM-CSF secreted by CAR-T cells not only promoted the transformation of macrophages to M1, but also improved the expression of CD80/86, thereby feedback-activating CAR-T activities. Moreover, their collaboration leads to elevated levels of inflammatory cytokines, fostering a conducive environment for anti-tumor immune responses. b Nanoparticle coating transferred CAR genes targeting S. aureus into macrophages to generate CAR-M, while simultaneously silencing Caspase-11 to facilitate the recruitment of mitochondria to the phagosome, increasing the killing ability of macrophages. These super CAR-Ms efficiently eradicated S. aureus and triggered robust bactericidal immunologic responses at the bone-implant interface. c Macrophages treated with SHED-CM exhibited characteristics of the M2 phenotype, a special phenotype known for its anti-inflammatory and anti-fibrotic effects.This observation suggests that CAR-M could also be utilized for the treatment of inflammatory diseases. d To mitigate atherosclerosis, CAR-Ms were engineered to selectively target CD47Hi ACs, thereby enhacing cell clearance and diminishing inflammation. Furthermore, the use of LNPs containing HPβ-CD increased the phagocytic capacity of CAR-M toward ACs
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