uPAR CAR T Cells Crack the Code on Solid Tumor Immunotherapy

CAR T cell therapy has revolutionized treatment of blood cancers, but solid tumors have largely resisted this approach due to antigen heterogeneity and a hostile, fibrosis-rich microenvironment. Finding a target that is broadly expressed across tumor types — and within the supporting stroma — has been a long-standing challenge in the field.

This study from Memorial Sloan Kettering and collaborating institutions centers on uPAR (urokinase plasminogen activator receptor), a surface protein previously shown to be elevated on senescent and pro-fibrotic cells. The team conducted integrative analyses revealing that uPAR is broadly upregulated in solid tumors enriched for TP53 and RAS pathway mutations — two of the most common oncogenic alterations across human cancers. These tumors adopt a progenitor-like cellular state supported by a uPAR-positive stromal niche with senescence characteristics.

Human uPAR-directed CAR T cells were tested across diverse preclinical models. The cells eliminated both tumor cells and the stromal architecture supporting them, inducing durable regressions and eradicating systemic metastases. Importantly, combining uPAR CAR T cells with senescence-inducing therapies further potentiated antitumor activity, suggesting a rational combination strategy.

A key safety finding is that robust antitumor responses were achieved without sustained myelosuppression in mice reconstituted with human immune systems — addressing a major concern for clinical translation. The prior demonstration that uPAR CAR T cells can reverse fibrosis safely in mice adds further translational confidence.

Caveats include that data are preclinical, derived from mouse models including humanized systems but not yet human clinical trials. The long-term durability, optimal dosing, and safety profile in humans remain to be established. Patent filings suggest active clinical translation is underway.