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

Table 1 Regulatory mechanisms of natural killer cell function: Key activating and inhibitory receptors, and molecular interactions

NK cell receptors		Corresponding ligands	Function	Ref.
Activating receptors	CD16 (FcγRIIIa)	Fc segment of IgG	Mediates ADCC through Fc receptor engagement, significantly potentiating tumor cell elimination	[22]
	NKG2D (CD314)	MICA/B. ULBP1-6	Identifies stress-induced ligands on cancerous/infected cells, initiating cytotoxic responses and IFN-γ production	[25,26]
	NKp46 (CD335)	Viral hemagglutinin. Tumor-associated glycoproteins	Mediates targeted cytolysis of virus-infected cells while playing a pivotal role in antitumor immunosurveillance through direct cytotoxic activity	[27,28]
	NKp30 (CD337)	B7-H6. BAT3	Modulates dendritic cell maturation process while potentiating antitumor cytotoxic activity through enhanced immune recognition	[29]
	NKp44 (CD336)	Tumor-associated glycoproteins	Predominantly expressed in activated NK cells, this molecule significantly potentiates the specific cytolytic activity against solid malignancies	[30]
	DNAM-1 (CD226)	CD112 (PVR). CD155 (NECTIN-2)	Forms a corecognition complex with NKG2D to detect MHC-I-deficient cancer cells, initiating perforin-dependent cytolytic pathways for their selective elimination	[31,32]
Inhibitory receptors	KIR family	MHC-I molecules (HLA-A/B/C)	Recognize autologous MHC-I molecules to deliver inhibitory signals that maintain immune tolerance	[33,34]
	NKG2A (CD159a)	HLA-E (binds to MHC-I-derived peptide segments)	Suppresses NK cell activation and preserves self-tolerance through inhibitory receptor signaling	[33,35]
	TIGIT	CD155 (NECTIN-2)	Competes with DNAM-1 for shared ligand binding, thereby attenuating its tumor-suppressive signaling cascade	[31]

NK: Natural killer; IgG: Immunoglobulin G; ADCC: Antibody-dependent cellular cytotoxicity; MICA/B: Major histocompatibility complex class I chain-related proteins A and B; ULBP: UL16-binding protein; IFN-γ: Interferon-gamma; BAT3: Human leukocyte antigen-B-associated transcript 3; PVR: Poliovirus receptor; NKG2D: Natural killer group 2, member D; KIR: Killer cell immunoglobulin like receptor; MHC-I: Major histocompatibility complex class I; HLA: Human leukocyte antigen; TIGIT: Tyrosine-based inhibitory motif domain; DNAM-1: DNAX accessory molecule-1.