Natural Killer Cell and Extracellular Vesicle-Based Immunotherapy in Thyroid Cancer: Advances, Challenges, and Future Perspectives

Abstract

Thyroid cancer, the most frequently occurring endocrine neoplasm, comprises a heterogeneous group of histological subtypes, spanning from the indolent papillary thyroid carcinoma (PTC) to the rapidly progressive and lethal anaplastic thyroid carcinoma (ATC). Although conventional therapies, such as surgery and radioactive iodine (RAI), are effective for differentiated thyroid cancers, treatment resistance and poor prognosis remain major challenges in advanced and undifferentiated forms. In current times, growing attention has been directed toward the potential of Natural Killer (NK) cells as a promising immunotherapeutic avenue. These innate immune cells are capable of direct cytotoxicity against tumor cells, but their efficiency is frequently compromised by the immunosuppressive tumor microenvironment (TME), which inhibits NK cell activation, infiltration, and persistence. This review explores the dynamic interaction between NK cells and the TME in thyroid cancer, detailing key mechanisms of immune evasion, including the impact of suppressive cytokines, altered chemokine landscapes, and inhibitory ligand expression. We further discuss latest advancements in NK cell-based immunotherapies, including strategies for ex vivo expansion, genetic modification, and combinatorial approaches with checkpoint inhibitors or cytokines. Additionally, emerging modalities, such as NK cell-derived extracellular vesicles, are addressed. By combining mechanistic insights with advancing therapeutic techniques, this review provides a comprehensive perspective on NK cell-based interventions and their future potential in improving outcomes for patients with thyroid cancer.

Keywords: CAR-NK cells; immunotherapy; natural killer (NK) cells; thyroid cancer; tumor microenvironment.

Figure 1

Generation of CAR-NK Cells for Adoptive Immunotherapy in Cancer Patients. (A) The structural design of chimeric antigen receptors (CARs) has evolved from first- to fifth-generation constructs, incorporating NK cell-specific intracellular signaling domains. (B) CAR-NK cells mediate tumor cell destruction through both CAR-dependent mechanisms and CAR-independent pathways, leveraging their innate immune properties. (C) Various cellular sources are employed for the generation of CAR-NK cell products, each with specific protocols for expansion, genetic modification, and clinical-grade manufacturing. CAR: Chimeric Antigen Receptor; NK cell: Natural Killer cell; PBMCs: Peripheral Blood Mononuclear Cells; iPSCs: Induced Pluripotent Stem Cells; HPCs: Hematopoietic Progenitor Cells; mbIL21-41BBL: Membrane-bound Interleukin-21 and 4-1BB Ligand; IL-2: Interleukin-2; IL-15: Interleukin-15; IL-21: Interleukin-21; CD3ζ: Cluster of Differentiation 3 zeta chain; CM1: Costimulatory Molecule 1; CM2: Costimulatory Molecule 2; IL-2Rβ: Interleukin-2 Receptor Beta; ScFv: Single-chain Variable Fragment; PD-L1: Programmed Death-Ligand 1; PD1: Programmed Cell Death Protein 1; CTLA4: Cytotoxic T-Lymphocyte-Associated Protein 4; LAG3: Lymphocyte Activation Gene 3; TIGIT: T Cell Immunoreceptor with Ig and ITIM Domains; Ag: Antigen. Created in https://BioRender.com.

Figure 2

Schematic representation of NK cell-derived extracellular vesicles. NK-EVs carrying cytotoxic proteins, miRNAs, and surface ligands that mediate antitumor effects. These EVs interact with tumor cells, inducing apoptosis and modulating gene expression. CD16: Cluster of Differentiation 16; CD56: Cluster of Differentiation 56; Fas L: Fas Ligand; LFA-1: Lymphocyte Function-associated Antigen 1; LHR: Luteinizing Hormone Receptor; miRNA: MicroRNA; mRNA: Messenger RNA; NKG2D: Natural Killer Group 2D; NK: Natural Killer; NK-EVs: Natural Killer Cell-Derived Extracellular Vesicles; TRAIL: TNF-Related Apoptosis-Inducing Ligand. Created in https://BioRender.com.