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<h3>Background</h3> Despite the remarkable success of CAR T-cell therapies treating blood cancers, effectiveness in solid tumors has encountered additional obstacles impairing the function of these innovative therapies. A main barrier is the hostile tumor microenvironment (TME), which creates an immunosuppressive milieu and restricts T-cell infiltration into the tumor. Moreover, tumor antigen diversity or low expression of CAR-targeted tumor-associated antigens (TAA) in normal tissues can cause antigen-loss or on-target off-tumor toxicity, respectively, leading to relapse and posing serious challenges for therapeutic safety. To enhance efficacy and specificity of CAR T-cells against solid tumors, it is thus critical to incorporate additional functionalities, which in turn require tight regulation to avoid potential toxicities. Immune pathways provide an attractive variety of tightly regulated genes that can be engineered for this purpose. Here, we show different approaches to demonstrate this concept and improve CAR T-cell activity while preventing potential toxicities. <h3>Methods</h3> We use TALEN-mediated gene editing to generate allogeneic CAR T-cells while repurposing PD-1 function, a key factor of the T-cell activation pathway, for different objectives. We then demonstrate the increased efficacy and reduced toxicities using diverse <i>in vitro</i> and <i>in vivo</i> methodologies. <h3>Results</h3> We first engineered CAR T-cells by integrating IL-12 into PD-1 regulatory elements to confine IL-12 to the TME in a CAR-activation dependent manner. Moreover, we deleted TGFBR2 to overcome TGFB1-mediated resistance in the TME. Using extensive <i>in vitro</i> and <i>in vivo</i> experiments and various routes of CAR T-cell delivery, we demonstrate that multiple engineered cells enhance proliferation and infiltration of CAR T-cells thus reducing tumor burden, enhancing survival and limiting side effects in orthotopic triple-negative breast cancer animal models. To address the hostile TME and off-tumor toxicity, in our second strategy we designed inducible dual SMART CAR T-cells. We expressed a CAR targeting FAP, a biomarker expressed in cancer associated fibroblasts (CAFs) and linked to tumor immunosuppression. Concomitantly, we engineered CAR T-cells by integrating into PD-1 a CAR targeting Mesothelin, a well-studied TAA. This way, mesothelin CAR expression is limited to the TME when FAP-CAR is engaged. Using <i>in vitro</i> and <i>in vivo</i> techniques, we show that TME-restricted co-expression of FAP and mesothelin CAR increases anti-tumor cytotoxicity, while minimizing potential ‘on-target off-tumor’ toxicities. <h3>Conclusions</h3> Overall, our data show the potential of repurposing immune pathways to create allogeneic CAR T-cells with increased activity in immunosuppressive microenvironments while minimizing potential safety issues, potentially providing a therapeutic option for patients with solid malignancies. <h3>Ethics Approval</h3> All procedures involving animals were approved by The MISPRO Institutional Animal Care and Use Committee and were performed in accordance with the guidelines of the PHS (Public Health Service) Policy on Humane Care and Use of Laboratory Animals, OLAW (Office of Laboratory Animal Welfare), and the USDA (United States Department of Agriculture) AWA (Animal Welfare Act).