Natural killer cell-based immunotherapies for colorectal cancer: Current strategies, challenges, and future perspectives

Table 3 Target antigens for chimeric antigen receptor-natural killer cell therapy in colorectal cancer preclinical studies

Targets	Mechanism	Ref.
EpCAM	CAR-engineered NK-92 cells demonstrate specific recognition and potent cytotoxicity against EpCAM-expressing CRC cells, mediated through targeted release of effector molecules including IFN-γ, perforin and granzyme B	[136]
NKG2D ligands	The CAR construct incorporating NKG2D’s extracellular domain and DAP12 signaling module significantly enhances NK cell-mediated tumoricidal activity	[137]
CD70	CD70 represents an ideal therapeutic target in CRC due to its tumor-restricted expression profile. IL-15-aremed CAR-NK cells demonstrate potent elimination of CD70+ cancerous cells	[99]
CEA	Retrovirally transduced CEA-specific CAR-NK-92MI cells demonstrate significantly enhanced cytotoxic activity (2-3 fold increase) against CEA-expressing tumor models	[138,139]
MSLN	MSLN-directed CAR immunotherapy demonstrates potent efficacy against mesothelin-high CRC models, achieving > 80% tumor volume reduction	[140]
HER2	The HER2-targeted CAR-NK platform represents a novel therapeutic strategy for HER2-amplified CRC, a molecular subset occurring in approximately 5% of cases	[139]
EGFRvIII	EGFRvIII-specific CAR-NK-92 cells demonstrate potent cytotoxic activity against tumor organoids expressing this pan-cancer neoantigen, showing > 90% target cell elimination in preclinical evaluation	[141]
Frizzled receptors	Frizzled receptor-targeted CAR therapies demonstrate specific pro-apoptotic activity against the 15% of CRCs exhibiting Frizzled overexpression	[141]
CD133	CAR133-NK92 cells demonstrate specific cytotoxicity against CD133+ tumor cells through antigen-dependent recognition, while simultaneously synergizing with TLR5 agonist to activate host immune responses against antigen-negative (CD133-) tumor populations	[142]
CDH17	CDH17-CAR-NK cells exhibit potent and selective cytotoxicity against CDH17-high CRC cells. When combined with CD47 blockade, this approach demonstrates synergistic antitumor effects, resulting in enhanced tumor clearance	[143]

EpCAM: Epithelial cell adhesion molecule; CAR: Chimeric antigen receptor; NK: Natural killer; CRC: Colorectal cancer; IFN-γ: Interferon-gamma; NKG2D: Natural killer group 2, member D; DAP12: DNAX-activating protein of 12 kDa; IL: Interleukin; CEA: Carcinoembryonic antigen; MSLN: Mesothelin; HER2: Human epidermal growth factor receptor 2; EGFRvIII: Epidermal growth factor receptor variant III; TLR5: Toll-like receptor 5.