GLP-1標的薬はトリプルネガティブ乳がんの化学免疫療法の有効性を損なう

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.