Cancer-associated adipocyte promote progression and immunosuppression in triple-negative breast cancer

Triple-negative breast cancer (TNBC) is characterized by highmetastatic potential and a lack of effective targeted therapies. Within the tumor microenvironment (TME) of TNBC, adipocyte can undergo transformation into cancer-associated adipocytes (CAA) through interactions with cancer cells; however, the specific role in the progress of TNBC is still not well described. This study aimed to investigate the impact of CAA on the malignant behavior of TNBC and its underlying mechanisms. CAA model was successfully established by co-culturing 3T3-L1-induced adipocytes with 4T1 cells, which exhibited characteristic features such as reduced lipid accumulation. Functional assays demonstrated that co-culture with CAA significantly enhanced the migration and invasion capabilities of 4T1 cells. In vivo experiments showed that co-injection of CAA with tumor cells accelerated primary tumor growth and promoted lung metastasis in mice. Mechanistic analysis revealed that in tumor tissues coexisting with CAA, E-cadherin expression was downregulated, accompanied by increased Ki67 expression and activation of the PI3K/AKT signaling pathway. Furthermore, CAA induces an immunosuppressive TME, characterized by elevated PD-L1 expression and reduced CD8⁺T cell infiltration. In conclusion, this study demonstrates that CAA promotes TNBC progression by activating epithelial-mesenchymal transition (EMT) and the PI3K/AKT pathway, as well as remodeling an immunosuppressive microenvironment, providing experimental insight into tumor-adipocyte interactions and identifying potential therapeutic targets.