Adipocytes Influence Skin Microenvironment Through STAT3-ANGPT2-PTGIS Pathway in Breast Cancer

Cutaneous metastatic breast cancer (CMBC) is an aggressive, understudied condition driven by tumor adaptation to the skin microenvironment, representing a significant unmet clinical need. Here, we identify adipocytes as critical drivers of this process. Using transcriptomic profiling, we found that CMBC is associated with poor prognosis and the upregulation of angiogenesis and lipid metabolism pathways (arachidonic/linoleic acid). Mechanistically, we demonstrate that adipocyte-derived signals activate STAT3 in breast cancer cells. This STAT3 activation subsequently drives the expression of ANGPT2, VEGFC, and PTGIS, directly linking signaling to angiogenesis and metabolic reprogramming. In preclinical mouse models, pharmacological inhibition of STAT3 markedly suppressed cutaneous metastasis. Furthermore, elevated expression of STAT3, ANGPT2, and PTGIS in patient tumors correlated strongly with reduced progression-free and disease-free survival. Collectively, our study identifies the adipocyte-driven STAT3-ANGPT2-PTGIS axis as a key, targetable pathway for CMBC, offering a promising therapeutic strategy for this clinically challenging disease. Citation Format: Mei-Ren Pan, Fu Ou-Yang, Shu-Jyuan Chang, Ming-Feng Hou, Chi-Wen Luo. Adipocytes remodel the skin niche via a STAT3-ANGPT2-PTGIS axis to promote breast cancer metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 6153.