Targeting uPAR-Positive Tumor and Stroma Enhances CAR T-Cell Efficacy

Chimeric antigen receptor (CAR) T-cell therapy has transformed the treatment of hematologic malignancies, but its efficacy in solid tumors remains limited due to antigen heterogeneity and fibrotic tumor environments that suppress immune responses. Building on prior findings that urokinase plasminogen activator receptor (uPAR) is upregulated in senescent, pro-fibrotic cells, and that uPAR-directed CAR T cells can reverse fibrosis in mice, Zhang and colleagues evaluated the potential of uPAR CAR T cells to overcome these barriers in solid tumors. They found that uPAR marks aggressive tumor cell states across multiple cancer types. The uPAR-encoding gene, PLAUR, was associated with tumors enriched for TP53 and RAS/MAPK pathway mutations, as well as conserved transcriptional programs linked to epithelial-to-mesenchymal transition, inflammation, and fibrosis. Furthermore, uPAR-positive tumor cells colocalized with uPAR-expressing cancer-associated fibroblasts (CAF) and myeloid cells, demarcating a fibrotic, immunosuppressive stromal niche. In cell line–derived xenograft models, uPAR CAR T cells demonstrated broad antitumor activity against lung, pancreatic, and ovarian cancers, with a single infusion inducing rapid and durable responses. Notably, in high-grade serous ovarian cancer models, uPAR CAR T cells eradicated both primary and metastatic tumors, achieving complete remission and eliminating residual disease in the adjuvant setting. Mechanistic studies confirmed dual targeting of tumor and stromal compartments, including CAFs and myeloid-derived suppressor cells. By leveraging the induction of uPAR in senescent cells, the authors used cisplatin to increase antigen density. Combination therapy enhanced CAR T-cell infiltration, tumor control, and survival compared to either treatment alone, without significant toxicity. Together, these findings highlight the potential of uPAR-targeted CAR T cells to overcome key challenges limiting the effectiveness of current CAR T-cell therapies in solid tumors.Zhang Z, Ho Y-J, Fang X, Kim M, Li M, Luan W, et al. A convergent uPAR-positive tumor ecosystem creates broad vulnerability to CAR T cell therapy. Cell 2026 March 30 Epub ahead of print.Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at https://aacrjournals.org/cdnews.