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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). This special issue belongs to the section "Molecular Immunology".

Deadline for manuscript submissions: 31 July 2026 | Viewed by 919

Special Issue 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

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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-blind 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.

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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 (2 papers)

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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
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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 575
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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