Adipocyte-driven STAT3-ANGPT2-PTGIS axis promotes cutaneous metastasis in breast cancer and represents a targetable pathway

Cutaneous metastatic breast cancer (CMBC) exhibits aggressive behavior driven by tumor adaptation to the skin microenvironment, yet research specifically addressing breast cancer metastasis to the skin remains limited, representing a significant unmet clinical need. In this study, transcriptomic profiling, functional assays, and mouse models revealed that CMBC is associated with poor prognosis and upregulation of angiogenesis, inflammatory signaling, and lipid metabolism, particularly arachidonic and linoleic acid pathways. Adipocyte-derived signals enhanced cutaneous metastasis through STAT3 activation, leading to increased Angpt2, Vegfc, and Ptgis expression. Pharmacologic inhibition of STAT3 suppressed metastasis in vitro and in vivo. Elevated STAT3, ANGPT2, and PTGIS levels correlated with reduced progression-free and disease-free survival. These findings highlight STAT3-mediated signaling and metabolic reprogramming as key drivers of CMBC progression and suggest a promising therapeutic target for this understudied and clinically challenging condition.