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

Abstract

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 modulator of myeloid cell activity and a potential target to enhance the antitumor 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 anti-inflammatory polarization signatures in CAR-M. Data-independent acquisition proteomics showed that TREM2 blockade was associated with attenuation of IL-4/IL-13/IL-10-associated programs and enrichment of inflammatory, interferon-related, cytoskeletal, and metabolism-related signatures. Functionally, TREM2 inhibition enhanced HER2-dependent phagocytosis in breast cancer cell lines and patient-derived tumoroid models, with the strongest effects observed in IFN-γ-stimulated conditions. These findings support TREM2 as a macrophage-intrinsic checkpoint candidate that may be targeted to improve macrophage-based immunotherapies in breast cancer.