Engineered Macrophages Emerge as a New Frontier in Cell Therapy for Solid Tumors

Chimeric antigen receptor T-cell therapy has transformed the treatment of blood cancers, delivering striking remissions in leukemias, lymphomas, and multiple myeloma. Yet when the same technology has been aimed at solid tumors, the results have been consistently disappointing. Dense stromal architecture blocks lymphocyte trafficking, immunosuppressive mediators blunt cytotoxic function, and antigen heterogeneity invites immune escape. A comprehensive review published in Bioengineering & Translational Medicine now argues that a different immune cell may succeed where T cells have struggled: the macrophage, an innate immune effector that is already abundant inside tumors and can be reprogrammed to attack the very tissue it once nurtured.

Chimeric antigen receptor macrophages, or CAR-M, are macrophages fitted with synthetic receptors that redirect them to recognize and destroy specific targets. The concept dates to 2006, when researchers first transduced human monocytes with a carcinoembryonic antigen–targeted receptor and demonstrated tumor suppression in mice. Interest has surged over the past five years, with encouraging preclinical results in both solid and hematologic tumor models and expanding applications to inflammatory and fibrotic diseases. Several early-phase clinical trials evaluating candidates such as MT-101, SY001, and CT-0508 have reported favorable safety profiles, underscoring the translational promise of the approach.

The architecture of a CAR-M construct mirrors that of its T-cell counterpart: an extracellular antigen-recognition domain, typically a single-chain variable fragment that binds targets independently of MHC; a hinge region providing structural flexibility; a transmembrane anchor; and intracellular signaling modules that trigger phagocytic and cytotoxic functions upon antigen engagement. First-generation CAR-M constructs carry a single activation domain such as CD3ζ, FcRγ, or Megf10, which induces relatively stable phagocytic activity. Second-generation designs add costimulatory domains such as 4-1BB, CD28, or DAP10, or incorporate cytokine-inducing modules including IFN-γ, CD147, or TLR4, to enhance phagocytosis and program stronger inflammatory activation. A third generation is now emerging based on chimeric cytokine receptors that use the extracellular sensors of IL-10 or TGF-β receptors fused to IFN-γ receptor signaling, effectively converting immunosuppressive cues within the tumor microenvironment into proinflammatory, antitumor signals.

Cell sourcing remains a central engineering challenge. Immortalized lines such as RAW264.7 and THP-1 are convenient for laboratory validation, but clinical products rely primarily on autologous peripheral blood mononuclear cells. In current trials, patients receive granulocyte colony-stimulating factor for several days to mobilize hematopoietic cells, after which CD14-positive monocytes are isolated and differentiated into macrophages with GM-CSF before CAR transfer via adenoviral vector. The entire manufacturing workflow takes roughly nine to thirteen days. For the CT-0508 product, mean viability reached 86.39 percent with a CAR transduction efficiency of 79.28 percent. Induced pluripotent stem cells and hematopoietic stem and progenitor cells offer scalable alternatives that could overcome the scarcity of mature macrophages, while biomaterial-based systems can edit resident macrophages directly at disease sites in animal models.

Gene delivery into macrophages is notoriously difficult because these cells exhibit innate resistance to viral transduction. Lentiviral systems engineered to carry the HIV-2 accessory protein Vpx achieve roughly 70 percent transduction in monocyte-derived macrophages, and adenoviral Ad5/F35 platforms have reached up to 80 percent in clinical settings. Intriguingly, viral transduction can activate inflammasomes, which itself enhances the proinflammatory phenotype and phagocytic capacity of the engineered cells. Nonviral alternatives are advancing rapidly. Lipid nanoparticles, the same platform proven in mRNA vaccines, can deliver CAR-encoding mRNA directly to tumor-associated macrophages in vivo, circumventing ex vivo manipulation entirely. Fluorinated ionizable lipids, metal-organic framework nanocarriers, engineered small extracellular vesicles, erythrocyte-based carriers, and even enucleated mesenchymal stem cells that home to glioblastoma have all demonstrated the ability to generate functional CAR-M within living tissue.

What distinguishes CAR-M from CAR-T is the breadth of its antitumor repertoire. Rather than relying solely on contact-dependent killing, engineered macrophages deploy antigen-specific phagocytosis, direct cytotoxicity through reactive oxygen and nitrogen species, and secretion of proinflammatory cytokines such as IL-6 and TNF-α that create a self-amplifying clearance loop. Critically, they process and present tumor antigens via MHC molecules, cross-priming CD8-positive cytotoxic and CD4-positive helper T cells to establish durable systemic immunity. They also remodel the tumor microenvironment itself: in pancreatic cancer models, CAR-M phagocytose fibroblast activation protein-positive stromal cells and reduce collagen deposition, while in breast cancer models, HER2-triggered CD147 signaling upregulates matrix metalloproteinases that degrade extracellular matrix and open the door for T-cell infiltration and improved drug penetration.

Clinical translation is now underway. Twelve CAR-M studies have been identified worldwide, most targeting HER2- or mesothelin-overexpressing solid tumors. The first phase 1 trial to report human data evaluated CT-0508, a HER2-directed CAR-M, in fourteen patients with HER2-overexpressing solid tumors. No grade 3 or 4 cytokine release syndrome and no neurotoxicity were observed, and notably the protocol did not require lymphodepleting chemotherapy. Among thirteen radiographically evaluable patients, 40 percent experienced reductions in target lesions, and the engineered cells were detectable in 92 percent of on-treatment biopsies, remaining present in 27 percent at week four. Single-cell sequencing revealed remodeling of the tumor microenvironment with enhanced adaptive immunity. A mesothelin-targeted product, SY001, showed no grade 3 or higher adverse events in two ovarian cancer patients, both maintaining stable disease at day 28.

The technology extends well beyond oncology. FAP-targeted CAR-M have reduced cardiac fibrosis after myocardial infarction by phagocytosing activated fibroblasts, and similar designs have alleviated liver, lung, and renal fibrosis in mice. Aβ-targeted CAR-M that secrete M-CSF to support their own persistence have significantly lowered amyloid plaque burden in Alzheimer’s disease models. CD47-directed CAR-M enhanced with reactive oxygen species-responsive nanoparticles have increased cholesterol efflux in atherosclerosis. In infectious disease, SasA-targeted CAR-M generated by implantable nanoparticle coatings reduced Staphylococcus aureus infections, and CR3022-based CAR-M engulfed SARS-CoV-2 viral particles in vitro. An anti-TNF CAR-M with an IL-4 signaling switch has even shown efficacy in acute and chronic inflammatory liver and kidney injury.

Safety and controllability remain the field’s central preoccupation. Excessive activation risks cytokine release syndrome and off-tumor toxicity, particularly in liver, lung, and kidney. Synthetic biology tools are being marshaled to address this: logic-gated CARs using AND, OR, and NOT operations restrict activation to cells coexpressing multiple antigens or spare healthy tissue carrying safety markers; switchable universal CAR platforms allow antigen specificity to be redirected with soluble adapters; and hypoxia- or lactate-responsive designs keep cells transcriptionally silent in normal tissue. Suicide switches such as inducible caspase-9 permit pharmacologic elimination of engineered cells, and one biodistribution study showed that AP1903 could control CAR-M lifespan even after the cells persisted for up to sixty days.

The review’s authors propose a “4S framework” of specificity, switchability, synergy, and safety to guide next-generation development. Combination strategies appear especially promising: pairing CAR-M with chemotherapy exploits immunogenic cell death to feed phagocytosis, checkpoint blockade prevents T-cell exhaustion, CD47 blockade removes the “don’t eat me” signal that otherwise suppresses macrophage engulfment, and CAR-T coadministration creates a positive feedback loop in which each cell type amplifies the other’s cytotoxicity. Clinical experience remains limited to observational and phase 1 studies, and efficacy endpoints, manufacturing scale-up, and standardized response criteria all require rigorous validation. Nevertheless, with favorable early safety data, a mechanistic toolkit that addresses the very barriers that defeated CAR-T in solid tumors, and applications stretching from cancer to fibrosis and neurodegeneration, CAR-M is positioning itself as one of the most consequential frontiers in cellular immunotherapy.

Subject of Research: Chimeric antigen receptor-engineered macrophage (CAR-M) cell therapy for cancer and other macrophage-driven diseases

Article Title: Chimeric antigen receptor‐macrophages: A new paradigm for cell therapy

Article References: Wang, H., Li, Y., Shi, Y., Zhou, Y., & Zheng, G. (2026). Chimeric antigen receptor‐macrophages: A new paradigm for cell therapy. Bioengineering & Translational Medicine, 11(5), Article e70157. https://doi.org/10.1002/btm2.70157

Image Credits: AI Generated

DOI: 10.1002/btm2.70157

Keywords: CAR-M, CAR-T cells, macrophages, cell therapy, solid tumors, cancer immunotherapy, tumor microenvironment, phagocytosis, lipid nanoparticles, clinical trials, synthetic biology, fibrosis