CAR T cells engineered to target urokinase plasminogen activator receptor (uPAR) demonstrated the ability to eliminate both cancer cells and their supporting stromal infrastructure across diverse solid tumor models. The therapy achieved durable tumor regressions, eradicated systemic metastases, and showed enhanced efficacy when combined with senescence-inducing treatments, all without causing sustained immune suppression in humanized mouse models. This represents a potential breakthrough in solid tumor immunotherapy, an area where CAR T cells have historically struggled compared to their remarkable success in blood cancers. The dual-targeting approach addresses two fundamental limitations: tumor antigen heterogeneity and the immunosuppressive tumor microenvironment. By simultaneously attacking cancer cells and dismantling their protective stromal niche, uPAR CAR T cells could overcome the structural barriers that have made solid tumors largely resistant to cellular immunotherapies. The broad expression of uPAR across tumors with common TP53 and RAS mutations suggests this strategy could apply to many cancer types. However, translation to human patients will require careful safety evaluation, particularly regarding potential effects on normal tissues that express uPAR during wound healing and tissue remodeling processes.