Adoptive cell therapies have the potential to create a new paradigm in solid cancer treatment. Patient T-cells can be engineered to express synthetic proteins such as chimeric antigen receptors (CARs) to redirect them to kill cancer cells. Current clinically approved CAR T-cells kill after recognizing one antigen on hematologic cancers. However, there are few known cancer-specific cell surface antigens and the repertoire of truly specific CAR targets is limited. As a consequence, CAR T-cells therapies are designed to target antigens that are overly expressed on cancer cells but are also on normal cells. Unfortunately, the high potency of CAR T-cells enables them to kill these normal cells resulting in severe toxicity, as seen in anti-HER2 CAR T-cell clinical trials and in anti-GD2 CAR and anti-ROR1 CAR T-cell preclinical models. However, cancer cells can express surface proteins that uniquely distinguish them from antigens on tissues in their metastatic sites. Hence, we developed “gated” (i.e. conditionally expressed) CAR T-cells that exclusively express their CARs only in the presence of cancer microenvironments in those metastatic sites, offering a safety and specificity advantage to current CAR T-cell therapies. These cellular constructs were achieved by designing microenvironment “sensors” on T-cells that initiate expression of the CARs reactive to tumor cells and not to surroundings cells. Termed the “Microenvironment Environment Actuated T-Cell (MEAT-cell)” system, these cells increase the repertoire of usable cancer target ligands by gating CAR therapies to actuate within tumor microenvironments and thus limit on-target, off-tumor toxicities.