Endoglin-targeted cancer therapies: current status and opportunities

INTRODUCTION: Endoglin has been extensively studied as an anti-angiogenic target, with preclinical work highlighting its critical role in tumor vasculature. TRC105 (carotuximab), a monoclonal antibody against endoglin, progressed through multiple clinical trials and was well tolerated, yet outcomes were disappointing, revealing a gap between preclinical findings and patient benefit. Recent insights into endoglin biology in the tumor microenvironment suggest that more precise, informed strategies are needed to fully realize its therapeutic potential. AREAS COVERED: This review summarizes key advances in endoglin biology, including its endothelial and non-endothelial roles and context-dependent effects across tumor and stromal compartments. We discuss preclinical therapeutic strategies and clinical trial experience with TRC105 and examine the translational challenges and future considerations needed to achieve potential clinical benefit. EXPERT OPINION: Preclinical studies have greatly advanced our understanding of endoglin biology, but the key challenge lies in identifying the biologic context where endoglin drives tumor progression. Future progress requires a deeper mechanistic resolution of endoglin's roles across tumor type and disease stage, along with the development of biomarkers incorporating spatial expression patterns. Successful translation will depend on matching endoglin-targeted therapy to patients and tumor ecosystems most likely to benefit, shifting from broad anti-angiogenic application to precision stromal targeting.