Senescent Cancer-Associated Fibroblasts Drive Early-Stage Lymph Node Metastasis in Pancreatic Cancer through Lactate-Mediated Metabolic-Epigenetic Rewiring

UNLABELLED: Lymph node (LN) metastasis (LNM) in early-stage pancreatic ductal adenocarcinoma (PDAC) predicts systemic dissemination and poor survival, yet its underlying mechanisms remain elusive. In this study, we demonstrated that senescent cancer-associated fibroblasts (senCAF) drive lymphatic remodeling and LNM in early-stage PDAC. Mechanistically, senCAFs increased glucose metabolism and lactate production, which activated lactylation-mediated serine metabolism to protect lymphatic endothelial cells from oxidative stress. Moreover, we discovered CCR4+ regulatory T cells from the draining LNs accumulated around lymphatic vessels, which established an immunosuppressive perilymphatic niche. High-throughput drug screening determined selective clearance of senCAFs via chidamide, attenuated tumor progression, and improved chemoimmunotherapeutic efficacy. We subsequently initiated a clinical trial (chidamide and nab-paclitaxel/gemcitabine plus anti-PD-1/CTLA-4) in patients with metastatic PDAC and reported its preliminary promising results. Collectively, these findings reveal a closed link between cellular senescence and PDAC metastasis, offering the potential senolytic means to improve chemoimmunotherapy efficacy. SIGNIFICANCE: Our findings have revealed a closed link between cellular senescence, metabolic reprograming, and spatial immunosuppressive niche and PDAC metastasis, offering the potential senolytic drugs to improve chemoimmunotherapy efficacy in patients with PDAC.