Significance Despite its success in treating hematological cancers, chimeric antigen receptor (CAR) T cell therapy does not so easily eliminate solid tumors. Solid tumors generally develop in a highly immunosuppressive environment and are difficult to target, mostly due to a lack of tumor-specific antigen expression, but other factors contribute as well. This study develops a strategy to target multiple solid tumor types through markers in their microenvironment. The use of single-domain antibody (VHH)-based chimeric antigen receptor (CAR) T cells that recognize these markers circumvents the need for tumor-specific targets. VHH-based CAR T cells that target the tumor microenvironment through immune checkpoint receptors or through stroma and ECM markers are effective against solid tumors in syngeneic, immunocompetent animal models.