uPAR-directed immunotherapies in solid tumors: current advances and future perspectives

Abstract

In cancer, elevated expression of the urokinase-type plasminogen activator receptor (uPAR) is a well-established adverse prognostic factor associated with enhanced tumor invasion, metastatic dissemination, cellular proliferation, and resistance to conventional therapies. Genetic ablation or silencing of uPAR has been shown to impair multiple protumorigenic functions both in vitro and in vivo, underscoring its pivotal role in tumor initiation, progression, and metastatic evolution. These findings establish uPAR not only as a clinically relevant prognostic biomarker but also as an attractive therapeutic target. Beyond its expression on malignant cells, uPAR is abundantly expressed within the tumor microenvironment (TME), including stromal components and immunosuppressive cell populations that actively support tumor progression and immune evasion. Notably, uPAR is highly expressed in several solid tumors characterized by TP53 and RAS pathway alterations. These tumors exhibit a progenitor-like phenotype sustained by a senescence-associated, uPAR-positive stromal niche, further highlighting the contribution of uPAR to tumor plasticity and therapeutic resistance. Collectively, these observations provide a strong biological rationale for the development of uPAR-directed immunotherapeutic strategies aimed at simultaneously targeting tumor cells and the supportive TME. Such approaches may be particularly effective in aggressive and treatment-refractory malignancies, including glioblastoma, non-small cell lung cancer, and ovarian cancer. This review summarizes the current understanding of the biological role of uPAR in solid tumors and discusses the rationale for its therapeutic targeting. Furthermore, it provides a comprehensive overview of the principal uPAR-directed immunotherapeutic strategies currently under investigation, including chimeric antigen receptor (CAR) T-cell therapies, multi-epitope vaccines, monoclonal antibodies, and radioligand-based approaches. Collectively, these emerging modalities position uPAR as a versatile and broadly applicable immunotherapeutic target with the potential to address several of the major challenges associated with the treatment of solid tumors.