IL-13Rα2 in liver cancer: Endothelial target for precision therapy

Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality worldwide, and durable responses to current systemic therapies is still limited. Tumor-associated endothelial cells (TECs) actively shape the immunosuppressive tumor microenvironment and contribute to therapeutic resistance, yet they remain underexploited as therapeutic targets in HCC. Interleukin-13 receptor alpha 2 (IL-13Rα2), long regarded as a decoy receptor for IL-13, has recently emerged as a context‑dependent molecule with therapeutic relevance across several malignancies. In the liver, single-cell and spatial transcriptomic studies indicate that IL-13Rα2 is highly compartmentalized and enriched within endothelial populations, offering a new explanation for previously inconsistent expression data in HCC. In this review, we summarize IL-13Rα2 biology across chronic liver disease and HCC, discuss its compartment‑specific functions, and highlight key mechanistic and translational questions. We further propose a framework for aligning IL‑13Rα2‑targeted strategies with its spatial distribution within tumors, with particular emphasis on endothelial‑directed intervention. This perspective may expand therapeutic opportunities beyond the toxicity and resistance associated with current anti-angiogenic therapies.