Core sequences of shRNA against target gene

Figure S2.High expression of ABHD16A is associated with poor prognosis of gastric cancer.

Figure S8. IL-22 upregulates PD-L1 expression in GC cells.

PA-ACSL5 induced COX2 expression and PGE2 accumulation activates EP4 to foster DTCs survival and proliferation through PI3K/AKT and ERK signaling

Figure S6. ILC3s aggregation is associated with poor prognosis in GC patients.

Figure S3. The elevated ABHD16A expression is highly associated with an immunosuppressive TME of gastric cancer.

Figure S1. Enhanced ABHD16A is associated with nerve infiltration in GC patients.

Figure S10. Combination therapy enhances anti-PD-L1 immunotherapeutic effect in gastric cancer.

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.

COX2 promotes PGE2 production, cell survival and growth of lung metastatic breast cancer cells

Antibodies and regents utilized in the study

List of primer sequences utilized in the study

Figure S4. The IL-22 level and ILC3s population are increased in GC tissues with high ABHD16A expression.

Table S1 contains core sequences of shRNA against target genes. Table S2 contains core sequences of sgRNA against target genes. Table S3 contains primer sequences used for qRT-PCR analysis. Table S4 contains primer sequences used for PCR analysis in ChIP assay

ACSL5 mediates adaptation to palmitic acid of lung metastatic breast cancer cells

ACSL5/COX2/EP4 axis was activated in lung metastases of multiple cancer types

Lung metastatic breast cancer cells display increased lipid metabolism and growth advantage

The Mouse XL Cytokine Array coordinates and semiquantitative analysis

Lung metastatic breast cancer cells display increased lipid metabolism

LM3-derived exosome promotes fatty acid synthesis of lung resident-AT2