Macrophages, the professional scavenger cells of the immune system, have long presented immunotherapists with a paradox. When they are steered toward tumors, they often arrive as allies of the cancer rather than its executioners, adopting an immunosuppressive identity that blunts the very therapies designed to weaponize them. A new study published in Cancer Immunology, Immunotherapy by researchers at the University of Lille and their collaborators suggests that a single receptor on the surface of these cells may act as the molecular brake responsible for that transformation, and that releasing the brake could dramatically improve a promising but still immature form of cellular therapy.
The receptor in question is TREM2, short for triggering receptor expressed on myeloid cells 2. Over the past several years, TREM2 has attracted intense interest in tumor immunology because it is preferentially expressed by myeloid cells within tumors and appears to reinforce their suppressive, tissue-repair-like behavior. In the new work, the team led by co-first authors Jassaud Marius and Ziane-Chaouche Lydia, with Michel Salzet and Marie Duhamel as co-senior authors, began by mining breast cancer transcriptomic datasets. They found that TREM2 is enriched in breast tumors relative to healthy tissue and that its expression correlates with myeloid gene signatures and immunoregulatory networks, the molecular circuits that dampen antitumor immune responses.
That correlation set the stage for the central experiment. The researchers engineered chimeric antigen receptor macrophages, or CAR-M, macrophages fitted with a synthetic receptor that directs them to recognize and engulf cells expressing HER2, a growth factor receptor amplified in a substantial subset of breast cancers. CAR macrophages are an emerging class of engineered immune cells, distinct from the CAR T cells that have transformed treatment of blood cancers. Because macrophages naturally infiltrate solid tumors and physically devour malignant cells, they are attractive candidates for solid tumor therapy, but their tendency to adopt anti-inflammatory, tumor-promoting states inside the hostile tumor microenvironment has limited their effectiveness.
To build their CAR-M, the team used the THP-1 human monocytic cell line, a widely employed model for generating macrophage-like cells in the laboratory. A key observation emerged early: when the cells were stimulated under anti-inflammatory conditions, the very conditions that resemble the immunosuppressive milieu of a tumor, TREM2 expression rose. In other words, the receptor appeared to be part of the machinery that macrophages deploy when they shift into their pacified, repair-oriented mode. That finding made TREM2 an obvious suspect in the failure of CAR-M to maintain an aggressive, tumor-killing phenotype.
The researchers then tested what happens when TREM2 is removed from the equation, using two complementary strategies. The first was genetic: interfering with the receptor’s expression directly. The second was pharmacological: blocking the receptor’s activity with inhibitory compounds. Both approaches produced the same directional result, reducing the anti-inflammatory polarization signatures that normally accumulate in the engineered macrophages. The consistency between genetic and pharmacological inhibition strengthens the conclusion that TREM2 itself, rather than an off-target effect of any single intervention, functions as a checkpoint holding macrophages in their suppressive state.
To understand the reprogramming at molecular depth, the team turned to data-independent acquisition proteomics, a mass spectrometry technique that quantifies thousands of proteins in a single experiment. The proteomic landscape of TREM2-blockaded CAR macrophages told a coherent story. Programs associated with the anti-inflammatory cytokines IL-4, IL-13 and IL-10, the classic drivers of suppressive macrophage polarization, were attenuated. In their place, the researchers observed enrichment of inflammatory signatures, interferon-related programs, cytoskeletal components, and metabolism-related pathways. Each of these categories makes functional sense for a cell being asked to hunt and consume cancer cells: interferon signaling primes antimicrobial and antitumor activity, cytoskeletal remodeling powers the physical machinery of engulfment, and metabolic reprogramming fuels the energetic demands of phagocytosis and inflammation.
The functional consequences were measured directly. TREM2 inhibition enhanced HER2-dependent phagocytosis, the ability of the CAR macrophages to recognize, bind and ingest HER2-expressing breast cancer cells, in experiments conducted on breast cancer cell lines. Critically, the team did not stop at simplified two-dimensional cultures. They extended their findings to patient-derived tumoroid models, three-dimensional clusters of tumor cells grown from patient samples that more faithfully recapitulate the architecture and immunosuppressive chemistry of real tumors. The phagocytosis advantage held in these more demanding models, an important benchmark for any cellular therapy claim.
One of the most striking details of the study is the role of interferon-gamma. The strongest enhancement of phagocytosis was observed when the TREM2-blockaded CAR macrophages were stimulated with IFN-γ, a potent inflammatory cytokine produced by activated T cells and natural killer cells. This suggests a potential combination strategy: pairing TREM2-targeted CAR macrophages with interventions that raise interferon-gamma levels in the tumor microenvironment, such as checkpoint inhibitor antibodies or other immunostimulatory agents. The finding also hints that the reprogrammed macrophages are not merely less suppressive but genuinely more responsive to inflammatory activation, a qualitative shift in their functional identity.
The concept of a macrophage-intrinsic checkpoint is the study’s most consequential idea. Immune checkpoint blockade, exemplified by antibodies against PD-1 and CTLA-4, works by releasing T cells from inhibitory signaling. TREM2 blockade would apply the same logic to a different arm of the immune system, releasing macrophages from their own inhibitory receptor. Because TREM2 is largely restricted to myeloid cells, targeting it could in principle reprogram the suppressive tumor-associated macrophage population itself, converting an obstacle to immunotherapy into an instrument of it. The Lille team’s data support TREM2 as a candidate target for exactly this purpose in macrophage-based therapies for breast cancer.
As with any preclinical study, important caveats apply. The CAR macrophages were generated from a cell line rather than primary human cells, and the tumoroid models, while more realistic than flat cultures, still fall short of intact tumors with their full vascular, stromal and immune complexity. Whether pharmacological TREM2 blockade can be delivered safely in patients, and whether the reprogrammed macrophages retain their inflammatory phenotype in vivo over time, remain open questions that will require animal studies and eventually clinical trials. Nevertheless, the study, which was supported by the French National Cancer Institute, the Ligue Contre le Cancer and regional funding, and approved by the ethics committees of the Oscar Lambret Cancer Center with written informed patient consent, provides a mechanistically grounded and proteomically detailed case that TREM2 is a druggable lever for flipping macrophages from tumor guardians into tumor executioners. For a field searching for ways to make solid tumor cellular immunotherapy work, that lever is one worth pulling.
Subject of Research: TREM2 blockade to enhance HER2 CAR macrophage immunotherapy in breast cancer
Article Title: TREM2 blockade reprograms HER2 CAR macrophages toward inflammatory phagocytes in breast cancer models
Article References: Marius, J., Lydia, Z.-C., Antonella, R.-R., Michel, S., & Marie, D. (2026). TREM2 blockade reprograms HER2 CAR macrophages toward inflammatory phagocytes in breast cancer models. Cancer Immunology, Immunotherapy. https://doi.org/10.1007/s00262-026-04576-9
Image Credits: AI Generated
DOI: 10.1007/s00262-026-04576-9
Keywords: TREM2, CAR macrophages, breast cancer, immunotherapy, phagocytosis, tumor-associated macrophages, HER2, proteomics, interferon-gamma, tumor microenvironment, cellular therapy, myeloid cells
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Nathaniel Bowman. (October 1, 2026). Immune Checkpoint TREM2 Emerges as a Switch to Supercharge CAR Macrophages Against Breast Cancer. Scienmag. https://scienmag.com/immune-checkpoint-trem2-emerges-as-a-switch-to-supercharge-car-macrophages-against-breast-cancer/
Nathaniel Bowman. “Immune Checkpoint TREM2 Emerges as a Switch to Supercharge CAR Macrophages Against Breast Cancer.” Scienmag, 1 October 2026, https://scienmag.com/immune-checkpoint-trem2-emerges-as-a-switch-to-supercharge-car-macrophages-against-breast-cancer/. Accessed 1 October 2026.
Nathaniel Bowman. “Immune Checkpoint TREM2 Emerges as a Switch to Supercharge CAR Macrophages Against Breast Cancer.” Scienmag. October 1, 2026. https://scienmag.com/immune-checkpoint-trem2-emerges-as-a-switch-to-supercharge-car-macrophages-against-breast-cancer/
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Tags: breast cancerbreast cancer tumor microenvironmentCAR macrophage enhancementCAR macrophagescellular therapyHER2immune checkpoint targets in cancer therapyimmune modulation in cancer treatmentImmunotherapyimmunotherapy strategies for breast cancerinterferon-gammamacrophage polarization in breast cancermacrophage-based cellular therapiesmyeloid cell receptor signalingmyeloid cellsphagocytosisProteomicsreversing macrophage immunosuppressionTREM2TREM2 as therapeutic targetTREM2 receptor role in tumor immunologytumor microenvironmenttumor-associated macrophagestumor-associated macrophages immunosuppressive mechanisms
