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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\u2013PD-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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Significance:<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1158\/2159-8290.cd-25-1627","type":"journal-article","created":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T11:18:49Z","timestamp":1774610329000},"page":"1550-1572","update-policy":"https:\/\/doi.org\/10.1158\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Senescent Cancer-Associated Fibroblasts Drive Early-Stage Lymph 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