中国博后一作Cell：新型CAR-T策略，摧毁肿瘤生态系统，突破实体瘤细胞治疗难题

Core Viewpoint - CAR-T cell therapy has revolutionized the treatment of hematological malignancies, but its potential in solid tumors remains largely untapped due to antigen heterogeneity and immunosuppressive microenvironments. Recent research identifies uPAR as a promising target to enhance CAR-T therapy effectiveness in solid tumors and potentially in fibrosis and degenerative diseases [2][4][12]. Group 1: CAR-T Cell Therapy in Solid Tumors - CAR-T cell therapy has shown significant success in treating hematological cancers, particularly with CD19 targeting in refractory leukemia and lymphoma, achieving durable remissions [4]. - The efficacy of CAR-T cells in solid tumors is limited due to antigen expression heterogeneity and the immunosuppressive, fibrotic tumor microenvironment (TME) [4][5]. - Current CAR-T strategies rely on lineage-restricted targets like CD19, FOLR1, or PSMA, which limits their applicability and fails to address aggressive tumor states that drive disease progression and resistance [4][5]. Group 2: uPAR as a Target - uPAR (urokinase-type plasminogen activator receptor) is a glycosylphosphatidylinositol-anchored receptor that regulates extracellular matrix remodeling and cell migration, with low expression in normal tissues but upregulated in malignant tumors and fibrotic environments [5][9]. - High levels of uPAR expression correlate with poor clinical outcomes and are associated with tumor aggressiveness and chronic inflammation [5][9]. - The research team established uPAR as a broadly expressed cancer target, particularly in solid tumors with TP53 and RAS pathway mutations, indicating its role in supporting a cancer-promoting ecosystem [9][12]. Group 3: Research Findings and Implications - The study demonstrated that uPAR-targeted CAR-T cells exhibit strong activity in various cancer models, including lung, pancreatic, and ovarian cancers, leading to tumor regression and eradication of systemic metastases [9][10]. - uPAR-targeted CAR-T cells can eliminate both malignant cells and the pathological stroma that supports tumor growth, thus addressing the challenges of immune evasion and treatment resistance [9][12]. - The findings suggest that uPAR could serve as a target not only for CAR-T therapy but also for antibody-drug conjugates (ADCs), antibody delivery radiotherapy, and CAR-NK cell therapies [12][13].