Artesunate reverses alveolar macrophage immunometabolic collapse and prevents breast cancer lung metastasis via the SREBP1- and FATP4-dependent fatty acid axis.

Background

Alveolar macrophages (AMs) are critical sentinels of the lung microenvironment, however, the metabolic mechanisms driving their functional reprogramming within the breast cancer pulmonary pre-metastatic niche (PMN) remain poorly defined.

Purpose

This study aimed to elucidate the metabolic-immune crosstalk governing AM dysfunction during breast cancer lung metastasis and evaluate the therapeutic potential of artesunate (AS) as a fatty acid metabolic remodeler.

Methods

Utilizing 4T1-based spontaneous lung metastasis and post-surgical recurrence models, we integrated single-cell RNA sequencing (scRNA-seq) and flow cytometry (FCM) to delineate the functional and lipid metabolic landscape of AMs in the breast cancer pulmonary PMN. Bulk RNA-seq, metabolomics, immunofluorescence, and FCM were subsequently employed to elucidate how AS remodels fatty acid metabolism in AMs. The underlying mechanisms were elucidated through in vitro and in vivo functional rescue assays and further valuated by publicly available clinical datasets and human clinical tissue samples.

Results

We identified a disruption of fatty acid metabolism in AMs resident within the breast cancer pulmonary PMN, characterized by coordinated impairment of both fatty acid uptake and lipid accumulation. This metabolic defect correlated with reduced phagocytic capacity and an immunosuppressive phenotype. Notably, AS treatment effectively restored fatty acid uptake and lipid accumulation in AMs, reestablished immunological surveillance within breast cancer pulmonary PMN, and effectively suppressed primary tumor growth and lung metastasis. Subsequent in vitro study confirmed that AS-remodeled AMs reboot anti-tumor immunity by enhancing phagocytosis and promoting T-cell activation. Functional intervention experiments further demonstrated that AS-induced immunometabolic reprogramming of AMs depends, at least in part, on SREBP1 driven lipogenesis and FATP4 mediated fatty acid uptake. Notably, these two metabolic pathways also serve as conserved prognostic signatures in human lung cancer cohorts.

Conclusion

Our findings define the disruption of fatty acid homeostasis as a hallmark of AM dysfunction in the breast cancer pulmonary PMN and establish artesunate as a promising candidate for intercepting breast cancer lung metastasis by targeting metabolic fitness in AMs.