Nearly 80% of carcinomas and leukemia are positive for glycan structures from the Thomsen-Friedenreich antigen family, one of whose members is CD176 (Galβ1-3GalNAcα1-R). Due to different modifications (e.g. sialylation), CD176 is not accessible for ligand binding on healthy cells. Thus, CD176 is a potential target for immunotherapy of multiple carcinomas, which is why we designed a CAR to direct T cells against the carbohydrate epitope. Moreover, to approach a current limitation of CAR-T cells mainly being inefficient in the microenvironment of solid tumors, we generated CD176 TRUCKs (“T cells redirected for universal cytokine-mediated killing”), which, additionally to the CAR, contain an inducible cassette for IL-12 expression (iIL-12) that is activated upon CAR signaling. Upon co-cultivation with CD176-positive cell lines derived from different carcinomas (e.g. lung, breast, pancreatic cancer), CD176 CAR-T cells and TRUCKs with iIL-12 were specifically activated and released pro-inflammatory cytokines (e.g. IFN-γ, TNF-α). Moreover, the engineered T cells secreted cytotoxic mediators (e.g. granzyme B, granulysin) and exhibited cytotoxicity towards different cancer cell lines shown by flow cytometry and confirmed by real-time impedance measurements (xCELLigence). Interestingly, CD176-specific TRUCKs with iIL-12 showed an even improved functionality compared to CD176 CAR-T cells. Our results demonstrate that engineered T cells targeting CD176 are a promising approach for the treatment of several different carcinomas with potentially absent “on-target/off-tumor” toxicities. Utilizing the TRUCK approach even enhanced the functionality of CD176 CAR-T cells and might enable the fight against solid tumors with heterogeneous microenvironments by recruitment and reprogramming of bystander immune cells.