Despite the remarkable success of engineered chimeric antigen receptor (CAR) T cells in the treatment of B cell malignancies, their application to solid cancers has been far less successful. One of the major challenges limiting their utility is the difficulty in identifying ideal surface antigens that can be used to discriminate between cancer and normal tissues ? many potential targets that are highly expressed in solid tumors are also found at lower levels in normal epithelial organs, leading to off-tumor toxicity. Nonetheless, we know that solid tumors comprise a complex and sophisticated tissue with a distinct ecosystem of malignant, immune and stromal cells. From first principles, one would predict that there should be ample discriminatory information in the tumor, if one could design therapeutic T cells that could integrate information from across different cells in the tumor ecosystem. We have recently developed new CAR T cell recognition circuits that can sense and respond to combinations of antigens, even if they are present on distinct cells within the same tissue microenvironment. These circuits utilize a synNotch receptor to detect a priming antigen, which in turn induces the expression of a CAR that kills cells based on a killing antigen. In preliminary results, we have shown that T cells with this kind of prime-and-kill circuit can recognize unique combinations of neighboring cells to induce killing. These types of engineered T cells are one of the first known therapeutic agents that can integrate molecular information from across different cells within the same tissue. In this proposal, we hypothesize that this prime-and-kill T cell recognition circuit could be used to recognize solid tumors based on information distributed across the tumor ecosystem. Specifically, we will target combinatorial integration of signals that are present in cancer cells and cancer-associated stromal cells, which play a central supportive role in a number of solid cancers. As a test case, we propose to investigate whether antigens from cancer associated fibroblasts can be used to locally prime CAR T cells to then kill based on a cancer associated antigen. Even if this cancer associated antigen in not perfectly specific (i.e., it is expressed in other normal tissues), the combination of stromal and cancer cell signals should be far more specific for the tumor. Prior efforts have unsuccessfully explored using single antigen CARs to target stromal or cancer cells individually, but here we test whether using integrated combinatorial recognition of the cancer cell/stromal cell ecosystem can result in significantly improved recognition specificity. If so, then this kind of integrated tumor ecosystem recognition could be applied to a large number of solid cancers.