ACSL5 Mediates Adaptation to the Palmitic Acid–Enriched Pulmonary Microenvironment to Enhance Metastatic Breast Cancer Cell Survival and Lung Metastasis

Solid tumors frequently preferentially metastasize to specific organs. Metabolites within metastatic niches have emerged as critical regulators of organotropic metastasis. In this study, we found that palmitic acid (PA) accumulated in both premetastatic and macrometastatic lung niches. Lung-preferential metastatic breast cancer (LM-BC) cells secreted exosomal USP47 that was taken up by lung-resident alveolar type II epithelial cells and enhanced fatty acid synthesis via YAP activation, resulting in PA enrichment and subsequent lung metastasis. ACSL5 in LM-BC cells facilitated PA adaptation by inducing COX2-mediated PGE2 accumulation and subsequent activation of the PI3K/AKT and ERK signaling pathways through EP4, which promoted cell survival and lung metastasis. Moreover, ACSL5 boosted levels of palmitoyltransferases, further enhancing COX2 expression, which could be inhibited by the palmitoylation inhibitor 2-bromopalmitate. Notably, the enrichment of PA, accumulation of PGE2, and activation of the ACSL5/COX2/EP4 axis in lung metastases of patients with breast cancer correlated with poorer clinical outcomes. Limiting PA intake or targeting the ACSL5/COX2/EP4 axis enhanced paclitaxel efficacy in a breast cancer mouse model. Collectively, these findings highlight the critical role of PA and ACSL5/COX2/EP4 signaling in lung metastasis, which can act as promising targets for enhancing the efficacy of chemotherapy in patients with breast cancer with lung metastasis. SIGNIFICANCE: Metastatic breast cancer cells promote a palmitic acid-enriched pulmonary microenvironment that supports lung metastasis but also confers a targetable metabolic vulnerability that can be exploited to improve patient outcomes.