脂肪靶向电刺激抑制肥胖相关TNBC的转移

Obesity makes triple-negative breast cancer (TNBC) more lethal by amplifying adipocyte-tumor crosstalk, with excess lipids and chronic inflammatory cytokines as key drivers of metastasis. However, no effective, well-tolerated therapy directly targets this axis in obesity-associated TNBC. Systemic anti-obesity pharmacotherapy may be limited by tolerability and unclear interactions with cancer therapy. Therapies that directly and locally disrupt this adipose-driven axis remain limited. This unmet need motivates a local, nonpharmacologic electroceutical approach-electrical stimulation (ES)-directed at adipose tissue remodeled by obesity and tumor signaling. ES is designed to disrupt metastasis-promoting adipocyte-tumor crosstalk while minimizing systemic exposure, primarily by modulating adipokine secretion, lipid metabolism, and adipocyte remodeling. We hypothesized that adipose-targeted ES could reverse pro-metastatic adipose remodeling, reshape a metastasis-permissive microenvironment, and ultimately limit metastatic dissemination in obesity-associated TNBC. To identify effective ES conditions, we developed an in vitro 3D adipocyte-TNBC coculture and ES screening platform (HiTESOC) that delivers adipocyte-specific, spatially uniform stimulation across defined pulse conditions. We quantified free fatty acid (FFA) release, adipokine profiles, and EMT-related gene expression in tumor cells to identify anti-metastatic ES parameters. The top regimen was then applied in an orthotopic, diet-induced obese TNBC BALB/c model by implanting tumor cells into the mammary fat pad and stimulating the contralateral pad with a surface electrode on the abdominal skin every other day for 4 weeks. ES significantly reduced metastatic burden in obese mice without altering primary tumor weight, as shown by lower lung weight and decreased lung bioluminescence signal. ES preserved the stimulated fat pad and partially reversed tumor- and obesity-induced adipocyte remodeling. Systemically, ES decreased circulating TNFalpha, modestly increased adiponectin, and lowered plasma FFAs, indicating dampened inflammatory tone and reduced lipid fuel availability. Within tumors, ES increased tumor-infiltrating lymphocytes, consistent with conversion to a less metastasis-permissive immune microenvironment. In obesity-associated TNBC, where systemic metabolic inflammation fuels metastasis, our data show that localized adipose electroceutical stimulation can decouple adipose dysfunction from metastatic spread-providing a practical, drug-sparing strategy to limit dissemination while avoiding systemic toxicity.