Senescent cancer-associated fibroblasts drive early-stage lymph node metastasis in pancreatic cancer through lactate-mediated metabolic-epigenetic rewiring.

Lymph node metastasis (LNM) in early-stage PDAC predicts systemic dissemination and poor survival, yet its underlying mechanisms remain elusive. Here, we demonstrated that senescent cancer-associated fibroblasts (senCAFs) 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+ Tregs from the draining lymph nodes accumulated around lymphatic vessels, which established an immunosuppressive peri-lymphatic niche. High throughput drug screening determined selective clearance of senCAFs via chidamide, attenuated tumor progression and improved chemo-immunotherapeutic efficacy. We subsequently initiated a clinical trial (chidamide and nab-paclitaxel/gemcitabine plus anti-PD-1/CTLA-4) in metastatic PDAC patients 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 chemo-immunotherapy efficacy.