During the Society of Immunotherapy of Cancer (SITC) 2025 Annual Meeting, held November 5 – 9 at the Gaylord National Resort and Convention Center in National Harbor, Maryland, novel preclinical developments in macrophage-targeting CAR monocytes to improve immunotherapy outcomes in breast cancer were among the study results presented.[1]
Murine and human TREM2-CAR-Mo selectively phagocytose TREM2+ macrophages in vitro, and significantly reduceD breast tumor growth, increaseD intratumoral T-cell accumulation, and enhanceD Immune checkpoint blockade sensitivity in vivo.
Results from a study, supported by the BWH Innovation Fund, the Harvard Ludwig Center, and the National Cancer Institute,
presented a first-in-class platform of using CAR-monocytes to limit tumor-associated macrophage (TAMs) function in breast cancer tumors.
In his presentation, Daniel E. Michaud, Ph.D., Research Fellow in Surgery at the Brigham and Women’s Hospital, Department of Surgery, Harvard Medical School, Boston, MA, United States, explained that Tumor-associated macrophages or TAMs, have been well-characterized as inhibitory hurdles for T-cell function in solid tumors, and are recognized to promote angiogenesis, metastasis, and immunosuppression in breast cancer, contributing to resistance to immune checkpoint blockade (ICB).
TAM-targeting CAR T-cells have demonstrated anticancer activity in mouse models of ovarian cancer. Still, trafficking and infiltration of CAR T-cells into tumors and the immunosuppressive tumor microenvironment (TME) of solid tumors remain challenging and have not yet been fully realized.
Monocytes typically thrive in the TME of solid tumors, and prior studies have shown that CAR monocytes exhibit significantly greater tumor trafficking and persist for up to 10 times longer in the TME than CAR macrophages. Therefore, a novel study explored the use of CAR monocytes to infiltrate solid tumors and differentiate to CAR macrophages (CAR macs) that target and destroy immunosuppressive TAMs by phagocytosis.
Study
The researchers used two publicly available single-cell RNA-seq (scRNA-seq) datasets of treatment-naïve patients across all breast tumor subtypes to identify TAM subpopulations. They identified SSP1 TAMs (a transcriptomic subtype characterized by high SPP1) that express the TREM2 receptor as the most immunosuppressive. TAMs expressing TREM2 were found to be associated with poor survival outcomes in breast cancer and hypoxic phenotypes.
In addition, the researchers found that TREM2 TAMs are present across a wide range of solid tumors. In contrast, non-cancerous tissues express TREM2 at low levels, suggesting that TREM2 is a strong tumor-specific target.
Human TREM2 CAR macs were developed by transducing U-937 AML cells with a TREM2-targeting CAR. TREM2 CAR macs secreted the proinflammatory cytokine in response to TREM2 in vitro and exhibited significant and TREM2-specific phagocytic activity against TREM2-positive macrophages compared to non-TREM2-targeting CAR macs.
Syngeneic murine TREM2 CAR monocytes and TREM2 CAR macs were developed. TREM2 CAR macs demonstrated significant TREM2-specific phagocytic activity against TREM2-expressing macrophages.
Delaying tumor growth
Murine TREM2 CAR monocytes significantly delayed tumor growth of syngeneic orthotopic EO771 tumors (murine triple-negative breast cancer model) and increased CD8 T-cell infiltration of tumors in vivo. Furthermore, the combination of TREM2 CAR monocytes and anti-PD-1 antibodies improved survival.
Future development
These results support further clinical development of TAM-targeting CAR monocytes as a strategy to improve immunotherapy outcomes in breast cancer and other solid tumors.
Michaud and his colleagues suggested that future studies need to explore the role of TREM2 TAMs in metastasis and develop approaches to engineer more effective TREM2-targeting CAR monocytes.
__
Reference
[1] Michaud DE, Tarannum M, Nelson A, Gottlieb AP, Romee R, Guerriero JL. 254 Targeting tumor-associated macrophages with CAR-monocytes as a first-in-class approach for cellular therapy in breast cancer. Journal for ImmunoTherapy of Cancer. 2025;13:. https://doi.org/10.1136/jitc-2025-SITC2025.0254
Featured image: Boston Public Garden. Photo courtesy © 2026 – 2025 Sunvalley Communication, LLC. Used with permission.
DOI
