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Table. 5.

Table 5 Overview of in vitro and in vivo strategies evaluated based on CAR or non-CAR genetic materials for improving NK functionality in cancer immunotherapy

CAR/non-CAR	Genetic molecule	Strategy	NK cell source	Malignancy	Genetic manipulation method	Reference
CAR	αEGFR CAR	Cytotoxicity plus targeting	NK92MI	Breast cancer	Multifunctional nanoparticles	[45]
	αGPC3 CAR	Cytotoxicity plus targeting	NK92MI, mouse primary NK cells, and human primary NK cells	Liver, breast, renal, and colon cancer cells, hepatocellular carcinoma	DOTAP-based lipid nanoparticle	[57]
	αCD19 CAR	Cytotoxicity plus targeting	Human primary NK cells	Human patients (CD19⁺ B-cell malignancy)	Retrovirus	[11]
	αCD33 CAR	Cytotoxicity plus targeting	Human primary NK cells	Acute myeloid leukemia	Lentivirus	[63]
	αCD73 CAR	Cytotoxicity plus targeting, infiltration, and cytokine production	Human primary NK cells	Lung adenocarcinoma	Electroporation and lentivirus	[71]
	αGD2 CAR	Cytotoxicity plus targeting	NK92	Patient-derived diffuse intrinsic pontine gliomas (DIPG) cells, DIPG	Lentivirus	[64]
	Soluble PD-1 with αHER2 CAR	Cytotoxicity plus targeting and immune activation	NK92	Breast cancer cells, mammary carcinoma	Lentivirus	[62]
	HER2/synNotch GAL4 αCEA CAR	Cytotoxicity plus targeting	NK92	Breast adenocarcinoma cell, colorectal carcinoma cell, colorectal adenocarcinoma cell, colorectal adenocarcinoma	Lentivirus	[65]
	αEPCAM CAR with IL-15	Cytotoxicity plus targeting and proliferation	NK92	Leukemia cells, triple-negative breast cancer cells, melanoma cells	Lentivirus	[61]
	αNKG2D CAR	Cytotoxicity plus targeting	Human primary NK cells	Multiple myeloma	Lentivirus	[66]
	αNKG2D CAR	Cytotoxicity plus targeting	Human primary NK cells	Metastatic colorectal cancer	Electroporation	[67]
	αNKG2D CAR with IL-15	Cytotoxicity plus targeting and persistence	Human primary NK cells	Acute myeloid leukemia	piggyBac system	[68]
	αDelta-like ligand 3 (αDLL3) CAR	Cytotoxicity plus targeting and cytokine production	NK92	Small cell lung cancer	Lentivirus	[69]
	αMesothelin/αCD19 CAR	Cytotoxicity plus targeting and cytokine production	NK92	Gastric cancer	Lentivirus	[70]
	CCR5	Chemoattractive capacity	Human primary NK cells	Colon cancer	Lentivirus	[77]
	CCR7	Chemoattractive capacity	NK92	B-cell lymphoma	Electroporation	[44]
	CXCR1	Chemoattractive capacity	Human primary NK cells	Pancreatic cancer	Lentivirus	[78]
	CXCR2	Migration and calcium flux	Human primary NK cells	Renal cell carcinoma	Retrovirus	[25]
	CXCR2	Chemoattractive capacity and cytotoxicity	NK92	Colon cancer	CRISPR-Cas9	[74]
	TGFBR2	Activation and cytotoxicity	Human primary NK cells	Neuroblastoma	Retrovirus	[75]
	TGFBR2 (siRNA)	Infiltration and cytotoxicity	NK92	Lung cancer cells	Manganese dioxide nanoparticles (MnO₂ NPs)	[46]
	IGF-1 siRNA or miR-486-5p	Cytolytic function	Human primaryNK cells	Hepatocellular carcinoma	HiPerfect transfection reagent	[50]
	IL-15 with CD8 α transmembrane domain (mbIL-15)	Survival and cytotoxicity	Human primary NK cell	In vitro (leukemia, lymphoma, and solid tumor cells) In vivo (sarcoma)	Retrovirus	[72]
	IL-21	Autocrine (persistence and antitumor activity)	Human primary NK cells	In vivo (glioblastoma)	Retrovirus	[73]

Abbreviations: NK, natural killer; IGF, insulin-like growth factor; DOTAP, 1,2-dioleoyl-3-trimethylammonium-propane; EGFR, epidermal growth factor receptor; NK92, allogeneic NK cell line (IL-2 dependent NK cells); PD-1, programmed cell death protein 1; GAL4, galactose-responsive transcription factor; CEA, carcinoembryonic antigen; NP, nanoparticle

Ann Lab Med 2025;45:146~159 https://doi.org/10.3343/alm.2024.0380