Targeting bromodomain and extra-terminal proteins reprograms macrophages and inhibits breast cancer progression
ZBC260 inhibited tumor growth in SCID mice but not in NOD‑SCID mice, with impaired macrophages and partially compromised NK cells, implicating the innate immune system.
The study investigates the role of bromodomain and extra‑terminal (BET) proteins in innate anti‑tumor immunity using the BET degrader ZBC260. In immunocompetent BALB/c mice bearing D2A1 breast tumors, ZBC260 significantly inhibited tumor growth; depletion of macrophages or NK cells reduced this effect, highlighting the importance of innate immune cells. Single‑cell RNA sequencing revealed a shift in myeloid populations, with a decrease in immunoregulatory MRC1⁺ tumour‑associated macrophages and an enrichment of CD74⁺ antigen‑presenting macrophages. In vitro, ZBC260 down‑regulated M2‑associated markers, promoted macrophage phagocytosis, induced tumor cell apoptosis, and suppressed macrophage‑driven cancer‑stem‑cell formation. These findings demonstrate that BET degradation by ZBC260 remodels the tumour microenvironment, reprograms macrophages toward an anti‑tumor phenotype, and shows translational potential for breast cancer therapy.
This study provides evidence that targeting BET proteins with a degrader can remodel the tumour microenvironment by re‑educating macrophages and enhancing their anti‑tumour functions, offering a new avenue to improve immune‑based therapies for breast cancer.
Evidence level: Korai humán adat. Kis vagy feltáró emberi adat.
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