GLP-1 Targeting Agents Impair Chemoimmunotherapy Effectiveness in Triple-Negative Breast Cancer

Abstract Activation of glucagon-like peptide-1 receptor (GLP-1R) could affect cancer treatment responses through direct action in tumor or immune cells. However, the field lacks a comprehensive assessment of GLP-1R expression and activity across human tumors. Herein, we report detection GLP-1R across multiple human tumor types and focus on triple-negative breast cancer (TNBC) for deeper analysis. In TNBC, GLP-1R is present in immune and tumor cell compartments. GLP-1 treatment of cancer cells activated survival pathways, drove proliferation, induced paclitaxel resistance and dampened cytokine secretion, effects that required expression of GLP-1R. Spatial transcriptomics of human tumors revealed that GLP-1 exposure remodeled the tumor microenvironment, promoted a mesenchymal transition in malignant cells and disrupted productive macrophage inflammation in tumor-proximate niches. Patients taking GLP-1 drugs during neoadjuvant chemotherapy experienced reduced pathological complete response rates (pCR: 30.8%) compared to controls (65%, p<0.001). Thus, GLP-1-exposure acts on tumor and immune cells to impair chemoimmunotherapy efficacy in TNBC.