Data from The Macrophage-Associated LncRNA <i>MALR</i> Facilitates ILF3 Liquid–Liquid Phase Separation to Promote HIF1α Signaling in Esophageal Cancer

<div>Abstract<p>Tumor-associated macrophages (TAM) are among the most abundant immune cells in the tumor microenvironment and are important mediators of tumor development and progression. Here, we identified a macrophage-associated long noncoding RNA (lncRNA), <i>MALR</i>, that facilitates progression of esophageal squamous cell carcinoma (ESCC). TAM-mediated secretion of TNFα drove <i>MALR</i> upregulation in ESCC cells. <i>MALR</i> promoted aerobic glycolytic activity and facilitated angiogenesis by activating the HIF1α signaling pathway. Mechanistically, <i>MALR</i> bound the dsRBD1 domain of interleukin enhancer-binding factor 3 (ILF3), promoting ILF3 protein stability and ILF3-mediated liquid–liquid phase separation (LLPS), thereby enhancing HIF1α mRNA stability by preventing PARN-mediated degradation. Loss of <i>MALR</i> suppressed cell line–based and patient-derived xenograft tumor growth. Clinically, high expression of <i>MALR</i> positively correlated with HIF1α target gene expression and indicated poor prognoses for patients with esophageal cancer. Overall, this study uncovers the physiologic roles of <i>MALR</i>/ILF3-mediated LLPS in tumor microenvironment remodeling, highlighting the <i>MALR</i>–ILF3–HIF1α axis as a potential target for cancer therapy.</p>Significance:<p>Secretion of TNFα by tumor-associated macrophages stimulates cancer cells to upregulate lncRNA <i>MALR</i>, which induces ILF3 liquid–liquid phase separation and activation of HIF1α signaling to promote cancer progression.</p></div>