TREM2 blockade reprograms HER2 CAR macrophages toward inflammatory phagocytes in breast cancer models

Tumor-associated macrophages (TAMs) are key regulators of the breast tumor microenvironment and often display immunosuppressive functions that limit cellular immunotherapy efficacy. Triggering receptor expressed on myeloid cells 2 (TREM2) has emerged as a critical modulator of myeloid cell activity and a potential target to enhance the anti-tumor activity of engineered macrophages. Here, we show that TREM2 is enriched in breast cancer transcriptomic datasets and correlates with myeloid and immunoregulatory gene networks. Using HER2-directed CAR macrophages (CAR-M) generated from THP-1 cells, we found that anti-inflammatory stimulation increased TREM2 expression. Genetic or pharmacological inhibition of TREM2 reduced CAR-M anti-inflammatory polarization. Data-independent acquisition proteomics showed that TREM2 blockade attenuated IL-4/IL-13/IL-10-associated programs while enhancing inflammatory, interferon-related, cytoskeletal and metabolic signatures. Functionally, TREM2 inhibition enhanced HER2-dependent phagocytosis in both cell lines and patient-derived tumoroid models. These findings identify TREM2 as a macrophage-intrinsic immune checkpoint limiting CAR-M activity and support its targeting to improve macrophage-based immunotherapies in breast cancer.