REVIEW article
Front. Immunol.
Sec. NK and Innate Lymphoid Cell Biology
Volume 16 - 2025 | doi: 10.3389/fimmu.2025.1625426
This article is part of the Research TopicNovel Chimeric Antigen Receptor (CAR) Designs in engineering NK cells for CancerView all 5 articles
CAR-iNKT Cells: Redefining the Frontiers of Cellular Immunotherapy
Provisionally accepted
Magdalena Niedzielska
Amy ChalmersMartyna PopisEfrat Altman-SharoniStephen AddisRebekka BeulenNils-Petter RuqvistEleni ChantzouraMarco Purbhoo
Dhan Chand
Mark A. Exley*- MiNK Therapeutics, Lexington, United States
Select one of your emails
You have multiple emails registered with Frontiers:
Notify me on publication
Please enter your email address:
If you already have an account, please login
You don't have a Frontiers account ? You can register here
Despite significant advances in cancer therapies, many malignancies remain resistant to current treatments due to complex immunosuppressive mechanisms, limited neoantigen expression, and dynamic tumor adaptations, underscoring the need for innovative therapeutic strategies. Adoptive cell therapy (ACT), particularly with chimeric antigen receptors (CARs and recombinant TCRs) targeting cancer-associated antigens, has emerged as a transformative strategy. However, conventional CAR-T cell therapies face substantial limitations such as manufacturing challenges, severe toxicities, and limited efficacy against solid tumors. Invariant natural killer T (iNKT) cells, a unique lymphocyte subset bridging innate and adaptive immunity, have emerged as a compelling alternative platform for CAR-based therapies, due to their distinctive ability to persist, penetrate into and remodel the tumor microenvironment (TME). Unlike conventional T cells, iNKT cells exhibit rapid activation without priming, potent cytotoxicity, and extensive immunomodulatory functions through interactions with the monomorphic antigen-presenting molecule CD1d or stress ligands. Furthermore, the inherent immunomodulatory properties of iNKT cells augment endogenous anti-tumor immunity by activating NK cells and cytotoxic T lymphocytes, promoting dendritic cell maturation, and reducing immunosuppressive myeloid cells. CAR-and rTCR-engineered iNKT (CAR-iNKT) cells therefore leverage multiple targeting mechanisms through their native semi-invariant T-cell receptor (TCR), NK receptors (NKRs) and engineered CARs, enabling broader and more effective tumor recognition while actively reshaping immunosuppressive TME. Notably, iNKT cells lack alloreactivity, circumventing the risk of graft-versus-host disease (GvHD), positioning CAR-iNKT cells as ideal candidates for "offthe-shelf" allogeneic therapies that can overcome the limitations of existing immunotherapies.
Keywords: iNKT cells, CD1d, cancer immunotherapy, CAR, Adoptive cell therapy (ACT)
Received: 08 May 2025; Accepted: 09 Jun 2025.
Copyright: © 2025 Niedzielska, Chalmers, Popis, Altman-Sharoni, Addis, Beulen, Ruqvist, Chantzoura, Purbhoo, Chand and Exley. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Mark A. Exley, MiNK Therapeutics, Lexington, United States
Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.