Colorectal cancer (CRC) metastases to the liver (CRC-LiMets) are a major unmet clinical need owed to their poor response to current treatments. Adoptive cell therapy (ACT) with tumor redirected T cells holds promise for cancer treatment; yet difficult T-cell trafficking into solid tumor tissues and suppressive cues generated in the tumor microenvironment (TME) of hinder their efficacy. CD1d-restricted invariant Natural Killer T (iNKT) cells offer a unique therapeutic opportunity due to their ability to modulate the TME by limiting tumor-supportive myeloid populations. We are exploring adoptive immunotherapy of CRC-LiMets with iNKT cells redirected against tumor cells by CAR-engineering, leveraging realistic orthotopic models of liver metastases in either syngeneic immunocompetent or humanized NSG mice. Preliminary results show that CAR-iNKT cells efficiently home to liver lesions and eradicate both small and advanced CRC-LiMets in preclinical models, outperforming conventional CAR-T cells, supporting further investigation towards clinical application.