SLC2A3-Mediated Senescence Escape in Endothelial Cells Promotes Dysfunctional Angiogenesis and Chemotherapy Insensitivity in PDAC
The efficacy of chemotherapy in pancreatic ductal adenocarcinoma (PDAC) is critically limited by its poorly functional vasculature. Although pro-angiogenic signaling could support the establishment of functional vasculature, the chemotherapy-induced senescence-associated secretory phenotype (SASP), which is rich in angiogenic factors, paradoxically promotes the formation of non-perfused, dysfunctional vasculature. Herein, we show that the escape of tumor endothelial cells (ECs) from therapy-induced senescence drives dysfunctional angiogenesis. These senescence-escaping ECs retain the DNA damage caused by chemotherapy but evade cell cycle arrest due to the absence of p21 expression, ultimately contributing to dysfunctional angiogenesis. Mechanistically, hypoxia-driven HIF1A upregulates the glucose transporter SLC2A3, which enhances glycolytic flux and lactate production. Lactate subsequently promotes p53 lactylation, which suppresses p21 transcription and facilitates cell cycle re-entry. Concurrently, lactate induces cyclic GMP-AMP synthase (cGAS) lactylation, impairing the cGAS-stimulator of interferon genes (STING)-mediated type I interferon response and enabling the immune evasion of senescence-escaping ECs. EC-specific knockout of SLC2A3 effectively suppresses escape from senescence, promotes functional vascular remodeling after chemotherapy, and restores chemosensitivity, thus nominating SLC2A3 as a promising therapeutic target for overcoming treatment insensitivity in PDAC.