HIF-1α/GPx7-mediated ER stress signaling drives vasculogenic mimicry and anti-angiogenic resistance in high tumor burden

Despite the established prognostic value of baseline tumor burden across multiple malignancies, the biological mechanisms linking tumor burden to responsiveness to anti-angiogenic therapy remain poorly understood. Here, we found that high tumor burden (HTB) was consistently associated with poorer treatment responses and shorter progression-free survival (PFS) across clinical cohorts of colorectal cancer (CRC), hepatocellular carcinoma (HCC), and lung adenocarcinoma (LUAD) receiving first-line anti-angiogenic therapy. Mechanistically, HTB-associated hypoxia promoted HIF-1α accumulation and nuclear translocation, thereby enhancing GPx7 transcription through direct binding to its promoter. Elevated GPx7 sustained an adaptive endoplasmic reticulum (ER) stress response and activated IRE1α–XBP1s signaling, leading to increased expression of MMP2, MMP9, and VE-cadherin and promoting vasculogenic mimicry (VM) formation in tumor cells. Notably, combining the ER stress inhibitor 4-phenylbutyric acid (4-PBA) with B20, a murine-reactive surrogate antibody against VEGF-A, suppressed VM formation and tumor growth more effectively than either treatment alone. Collectively, our findings identify an HTB-associated hypoxia–HIF-1α/GPx7–ER stress–XBP1s signaling axis that promotes VM-like plasticity and suggest that targeting ER stress may represent a potential strategy to improve responses to anti-angiogenic therapy in high-tumor-burden tumors.