Unleashing the power of CAR-M therapy in solid tumors: a comprehensive review

Abstract

Chimeric antigen receptor (CAR) macrophage therapy represents a promising new frontier in cancer immunotherapy, with the potential to overcome the limitations of CAR-T cell approaches, particularly in solid tumours. This comprehensive review focuses on the current state and future prospects of CAR macrophage technology, emphasising its applications in solid malignancies across preclinical and early clinical development. The key topics covered included CAR design optimisation, macrophage sources and engineering strategies, mechanisms of antitumour activity, in vivo efficacy in animal models, initial clinical trial results, and challenges for broader implementation. The unique properties of macrophages, including tumour penetration and microenvironment modulation, offer significant advantages over T cell-based therapies in solid-tumour settings. However, strategies to enhance persistence, maintain proinflammatory phenotypes, and improve manufacturing are required. Although early research suggests additional applications beyond oncology, including for infectious and inflammatory diseases, this review primarily concentrates on the oncologic potential of CAR-M therapies. Continued optimisation and larger randomised trials will be critical to establish clinical efficacy and define the role of this approach in the treatment of solid tumours.

Keywords: CAR-M; advances in research; cellular immunotherapy; chimeric antigen receptor; macrophages.

Figure 1

Schematic structure of a chimeric antigen receptor (CAR) with dual costimulatory domains. The diagram shows a CAR engineered with an extracellular single-chain variable fragment (scFv) for antigen recognition, connected via a hinge domain to a transmembrane region. The intracellular portion includes one costimulatory domain and a CD3z signalling module. This dual-costimulation configuration is designed to enhance cell activation, proliferation and persistance.

Figure 2

Evolution of the first three generations of chimeric antigen receptors in macrophages (CAR-Ms). The illustration depicts the progressive structural modifications introduced in CAR-M design from the first to the third generation. First-generation CAR-Ms consist of an scFv linked via a hinge and transmembrane domain to a single macrophage-activating signalling domain. Second-generation CAR-Ms incorporate one costimulatory domain to enhance activation and persistence. Third-generation CAR-Ms further include a second costimulatory module, aiming to maximise pro-inflammatory signalling, phagocytic activity, and resistance to tumour-induced immunosuppression. These architectural advances are designed to improve the therapeutic efficacy of CAR-Ms in the solid tumour microenvironment.

Figure 3

Antitumor mechanisms of CAR macrophages (CAR-Ms). (A) CAR-mediated phagocytosis of tumour cells through specific antigen recognition. (B) Enzymatic degradation of the extracellular matrix (ECM) within the tumour microenvironment, facilitating immune infiltration. (C) Secretion of proinflammatory cytokines that promote immune cell recruitment and activation. (D) Presentation of tumour-derived antigens to lymphocytes, contributing to the activation of adaptive immune responses.

Figure 4

Overview of the clinical procedure used in the CT-0508 trial evaluating anti-HER2 CAR macrophages. This schematic illustrates the clinical workflow of the CT-0508 phase I trial (NCT04660929), the first-in-human study of HER2-targeted chimeric antigen receptor macrophages (CAR-Ms) in patients with advanced HER2-positive solid tumours. The procedure includes leukapheresis for monocyte collection, ex vivo differentiation and CAR transduction of autologous macrophages, followed by infusion into the patient without prior lymphodepleting conditioning. The trial assesses safety, tolerability, and early signals of antitumor activity, alongside immunological changes in the tumour microenvironment.

Figure 5

Overview of the clinical procedure used in the MCY-M11 trial evaluating intraperitoneal mesothelin-targeted CAR macrophages. This schematic represents the clinical workflow of the MCY-M11 phase I trial (NCT03608618), a first-in-human study investigating intraperitoneal administration of mesothelin-targeted CAR-Ms in patients with advanced ovarian cancer and malignant peritoneal mesothelioma. The procedure involves leukapheresis, rapid non-viral mRNA transfection of autologous peripheral blood mononuclear cells (PBMCs), and fresh cell infusion via the peritoneal cavity without lymphodepleting preconditioning. The trial follows a dose-escalation design and aims to assess safety, tolerability, and feasibility of this localized CAR-M therapy.