The Urokinase Receptor (uPAR) as a Trojan Horse in Targeted Cancer Therapy: Challenges and Opportunities

Simple Summary: Discovered more than three decades ago, the urokinase-type plasminogen activator receptor (uPAR) has now firmly established itself as a versatile molecular target holding promise for the treatment of aggressive malignancies. The copious abundance of uPAR in virtually all human cancerous tissues versus their healthy counterparts has fostered a gradual shift in the therapeutic landscape targeting this receptor from function inhibition to cytotoxic approaches to selectively eradicate the uPAR-expressing cells by delivering a targeted cytotoxic insult. Multiple avenues are being explored in a preclinical setting, including the more innovative immune- or stroma targeting therapies. This review discusses the current state of these strategies, their potentialities, and challenges, along with future directions in the field of uPAR targeting. One of the largest challenges to the implementation of precision oncology is identifying and validating selective tumor-driving targets to enhance the therapeutic efficacy while limiting off-target toxicity. In this context, the urokinase-type plasminogen activator receptor (uPAR) has progressively emerged as a promising therapeutic target in the management of aggressive malignancies. By focalizing the plasminogen activation cascade and subsequent extracellular proteolysis on the cell surface of migrating cells, uPAR endows malignant cells with a high proteolytic and migratory potential to dissolve the restraining extracellular matrix (ECM) barriers and metastasize to distant sites. uPAR is also assumed to choreograph multiple other neoplastic stages via a complex molecular interplay with distinct cancer-associated signaling pathways. Accordingly, high uPAR expression is observed in virtually all human cancers and is frequently associated with poor patient prognosis and survival. The promising therapeutic potential unveiled by the pleiotropic nature of this receptor has prompted the development of distinct targeted intervention strategies. The present review will focus on recently emerged cytotoxic approaches emphasizing the novel technologies and related limits hindering their application in the clinical setting. Finally, future research directions and emerging opportunities in the field of uPAR targeting are also discussed.

Automated summary

The urokinase-type plasminogen activator receptor (uPAR) has emerged as a promising therapeutic target for aggressive malignancies due to its abundant expression in cancerous tissues. Therapeutic strategies targeting uPAR have shifted towards cytotoxic approaches to selectively eradicate cancer cells expressing this receptor. Research is focusing on innovative immune- or stroma targeting therapies to enhance treatment efficacy.