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Simple Summary: Colon cancer is a solid tumor that is a prominent contributor to global mortality. Immune cells genetically engineered with a chimeric antigen receptor (CAR) that can recognize cancer-specific targets is a new innovative therapy approach that has had success in treating blood cancers but is still in development for treating solid tumors such as colon cancer. Part of the reason for the added difficulty in targeting solid tumors is the tumor microenvironment that acts as a protective barrier around a solid tumor. In this research paper, we have developed a new cellular approach for the targeted treatment of colon cancer that is designed to overcome the tumor microenvironment. We tested this new CAR cell therapy against multiple solid colon cancer models, and confirmed its efficacy and functionality in finding and eliminating solid tumors. Colorectal carcinoma (CRC) presents a formidable medical challenge, demanding innovative therapeutic strategies. Chimeric antigen receptor (CAR) natural killer (NK) cell therapy has emerged as a promising alternative to CAR T-cell therapy for cancer. A suitable tumor antigen target on CRC is carcinoembryonic antigen (CEA), given its widespread expression and role in tumorigenesis and metastasis. CEA is known to be prolifically shed from tumor cells in a soluble form, thus hindering CAR recognition of tumors and migration through the TME. We have developed a next-generation CAR construct exclusively targeting cell-associated CEA, incorporating a PD1-checkpoint inhibitor and a CCR4 chemokine receptor to enhance homing and infiltration of the CAR-NK-92 cell line through the TME, and which does not induce fratricidal killing of CAR-NK-92-cells. To evaluate this therapeutic approach, we harnessed intricate 3D multicellular tumor spheroid models (MCTS), which emulate key elements of the TME. Our results demonstrate the effective cytotoxicity of CEA-CAR-NK-92 cells against CRC in colorectal cell lines and MCTS models. Importantly, minimal off-target activity against non-cancerous cell lines underscores the precision of this therapy. Furthermore, the integration of the CCR4 migration receptor augments homing by recognizing target ligands, CCL17 and CCL22. Notably, our CAR design results in no significant trogocytosis-induced fratricide. In summary, the proposed CEA-targeting CAR-NK cell therapy could offer a promising solution for CRC treatment, combining precision and efficacy in a tailored approach. [ABSTRACT FROM AUTHOR]