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Mechanisms and Innovations in Natural Killer Cell-Based Immunotherapy
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Mechanisms and Innovations in Natural Killer Cell-Based Immunotherapy

A Special Issue of International Journal of Molecular Sciences (ISSN 1422-0067) belonging to the section "Molecular Immunology".

Deadline for manuscript submissions: 28 February 2027 | Viewed by 2793

Editor

Dr. Dipnarine Maharaj

E-Mail Website
Guest Editor
Department of Medicine, The Maharaj Institute of Immune Regenerative Medicine, Boynton Beach, FL 33437, USA
Interests: immune-regenerative medicine; stem cell biology; G-CSF-mobilized hematopoietic stem cells and their secretome; functioning natural killer cells as well as B and T cells

Special Issue Information

Dear Colleagues,

Natural Killer (NK) cells are pivotal in innate immunity, offering rapid and potent cytotoxic responses against tumors and virally infected cells without prior sensitization. NK cell-based immunotherapy represents a transformative approach in oncology and infectious disease treatment, leveraging NK cells’ unique ability to recognize stress ligands and modulate adaptive immunity.

This Special Issue aims to highlight advances in NK cell biology, adoptive transfer strategies, CAR-NK engineering, and combination therapies to overcome tumor immune evasion.

We welcome original research and reviews addressing NK cell expansion, activation, tumor microenvironment interactions, and clinical translation. By fostering interdisciplinary collaboration, this Special Issue seeks to accelerate the development of safe and effective NK cell-based therapies for cancer and beyond.

Dr. Dipnarine Maharaj
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 250 words) can be sent to the Editorial Office for assessment.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-anonymized peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • natural killer cells
  • immunotherapy
  • CAR-NK
  • cancer therapy
  • adoptive cell transfer
  • immune modulation
  • tumor microenvironment
  • cell engineering
  • hematologic malignancies
  • viral infections

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Published Papers (3 papers)

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23 pages, 9639 KB  
Article
HLA-E-Directed Accumulation of KIR+NKG2C+ NK Cells upon HCMV Peptide Presentation In Vitro: Association with the Ex Vivo Phenotype
by Nadezhda A. Alekseeva, Maria O. Ustiuzhanina, Maria A. Streltsova, Julia D. Vavilova, Alexander M. Sapozhnikov and Elena I. Kovalenko
Int. J. Mol. Sci. 2026, 27(13), 6087; https://doi.org/10.3390/ijms27136087 - 7 Jul 2026
Viewed by 516
Abstract
NK cells co-expressing NKG2C and inhibitory KIRs represent promising effector candidates when directed against HLA-E+ tumors. These cells may propagate in vitro upon HCMV peptide (LFL) presentation within HLA-E by interacting cells due to KIR+NKG2C+ cell expansion or via [...] Read more.
NK cells co-expressing NKG2C and inhibitory KIRs represent promising effector candidates when directed against HLA-E+ tumors. These cells may propagate in vitro upon HCMV peptide (LFL) presentation within HLA-E by interacting cells due to KIR+NKG2C+ cell expansion or via NKG2C or KIR de novo expression. This study aimed to clarify whether these accumulation mechanisms are connected to the healthy individual’s ex vivo NK cell phenotype. The architecture of the phenotype was characterized by the distribution of markers known to be associated with NK cell differentiation and the HCMV adaptive response, including NKG2C, KIR2DL2/3, and HLA-DR. We also analyzed NK cells that differed in marker expression cultured with or without LFL in vitro. The most pronounced NKG2C expression de novo was observed in KIR+ NK cells, associated with a higher HLA-DR+ ex vivo proportion. Enhanced LFL-dependent KIR+NKG2C+ cell expansion of the CD57− fraction was associated with a high content of adaptive NK cells ex vivo, while the CD57+KIR+NKG2C+ expansion rate correlated with a high level of NKG2A ex vivo. Moreover, LFL-activated cultures more effectively eliminated HLA-E+ tumor spheroids. These data are of interest both for KIR+NKG2C+ NK cell therapeutic application and for widening understanding of virus-induced NK cell repertoire modulation. Full article
(This article belongs to the Special Issue Mechanisms and Innovations in Natural Killer Cell-Based Immunotherapy)
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22 pages, 11489 KB  
Article
Constitutive RLI Armoring Enhances CAR-NK Cell Effector Functions but Causes Lethal Toxicity In Vivo
by Zhiming Ling, Yi Wang, Geping Wu, Wei Lin, Tao Lu, Guohua Yu and Jianxun Wang
Int. J. Mol. Sci. 2026, 27(8), 3554; https://doi.org/10.3390/ijms27083554 - 16 Apr 2026
Viewed by 873
Abstract
Chimeric antigen receptor–natural killer (CAR-NK) cell therapy is a promising immunotherapy for hematological malignancies. While engineered interleukin15 (IL15) variants like membrane-bound IL15 (mbIL15) and the IL15/IL15Rα heterodimer (RLI) can enhance NK cell activity, their relative efficacy and safety as armor for CAR-NK cells [...] Read more.
Chimeric antigen receptor–natural killer (CAR-NK) cell therapy is a promising immunotherapy for hematological malignancies. While engineered interleukin15 (IL15) variants like membrane-bound IL15 (mbIL15) and the IL15/IL15Rα heterodimer (RLI) can enhance NK cell activity, their relative efficacy and safety as armor for CAR-NK cells remain unclear. This study systematically evaluated primary human CAR-NK cells co-expressing an anti-CD19 CAR (19ζ) with soluble IL15, mbIL15, or RLI. We found that 19ζ-RLI CAR-NK cells exhibited superior IL15 secretion, proliferation, cytotoxicity, and migration in vitro, and effectively controlled tumors in vivo. However, all IL15-armored constructs, particularly 19ζ-RLI, induced lethal toxicity in mice, characterized by CAR-NK hyperproliferation and elevated systemic IL15. Transcriptomic analysis revealed that this toxicity correlated with a hyperactive molecular state driven by persistent IL15 signaling. In conclusion, this study suggests that constitutive IL15 armoring can be a potent but risky strategy for enhancing CAR-NK cells, with RLI being the most potent yet toxic exemplar of this general principle. Our findings highlight the necessity of incorporating safety-optimized strategies, such as inducible cytokine expression, into the design of cytokine-armored CAR-NK therapies for clinical translation. Full article
(This article belongs to the Special Issue Mechanisms and Innovations in Natural Killer Cell-Based Immunotherapy)
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18 pages, 2299 KB  
Case Report
Interleukin-2 and Tretinoin for Myeloproliferative Neoplasms and to Target Type 1 Calreticulin-Driven Neoplasms: Advancements in Immune Regenerative Medicine
by Dipnarine Maharaj, Wen Zhang, Kawaljit Kaur and Jacqueline Gouvea
Int. J. Mol. Sci. 2026, 27(6), 2814; https://doi.org/10.3390/ijms27062814 - 20 Mar 2026
Viewed by 996
Abstract
Stem cells, also known as progenitor cells, can differentiate into specialized cells for specific tissues. Genetic mutations and epigenetic changes may cause normal stem cells to become cancer-initiating cells. Research indicates that cells acquiring a mutation for myeloproliferative neoplasm (MPN) are likely to [...] Read more.
Stem cells, also known as progenitor cells, can differentiate into specialized cells for specific tissues. Genetic mutations and epigenetic changes may cause normal stem cells to become cancer-initiating cells. Research indicates that cells acquiring a mutation for myeloproliferative neoplasm (MPN) are likely to be long-term hematopoietic stem cells (LT-HSCs) at the top of the hematopoietic hierarchy. Natural killer (NK) cells play a crucial role in combating cancer by targeting and eliminating cancer stem cells (CSCs) while promoting their maturation. NK cells do this through direct lysis of CSCs or by releasing cytokines like interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α), which inhibit tumor growth and metastasis by driving differentiation of CSCs. Interleukin-2 (IL-2) enhances the activity of CD4+ and CD8+ T cells and boosts NK cell cytotoxicity. This study highlights a case of MPN with a more clinically aggressive Type 1 calreticulin (CALR) mutation, where a combination of low-dose IL-2 immunotherapy and targeted therapy with oral tretinoin (all-trans retinoic acid, ATRA, a vitamin A derivative) improved immune cells, particularly NK-cell-mediated destruction of malignant cells, reduced CALR mutation levels to undetectable, and alleviated disease symptoms. The aim is to offer a new, low-toxicity personalized treatment strategy that eradicates cancer-initiating stem cells, reduces side effects, and provides an option for patients with limited conventional therapy alternatives. Full article
(This article belongs to the Special Issue Mechanisms and Innovations in Natural Killer Cell-Based Immunotherapy)
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