CAR-iNKT cells: redefining the frontiers of cellular immunotherapy
File(s)
Published version
Author(s)
Type
Journal Article
Abstract
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 in and remodel the tumor microenvironment (TME). Unlike conventional T cells, iNKT cells exhibit rapid activation without priming, potent cytotoxicity, and extensive immunomodulatory functions. Furthermore, the inherent immunomodulatory properties of iNKT cells through interactions with the monomorphic antigen-presenting molecule CD1d or stress ligands augment endogenous anti-tumor immunity by activating NK cells and cytotoxic T lymphocytes, promoting dendritic cell maturation, and reducing immunosuppressive myeloid cells, unlike other Innate T cells. CAR-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 “off-the-shelf” allogeneic therapies that can overcome the limitations of existing immunotherapies.
Date Issued
2025-07-11
Date Acceptance
2025-06-09
Citation
Frontiers in Immunology, 2025, 16
ISSN
1664-3224
Publisher
Frontiers Media S.A.
Journal / Book Title
Frontiers in Immunology
Volume
16
Copyright Statement
© 2025 Niedzielska, Chalmers, Popis, Altman-Sharoni, Addis, Beulen, Rudqvist, 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) and the copyright owner(s) 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.
License URL
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/40718496
Subjects
adoptive cell therapy (ACT)
AFFINITY
ANTITUMOR-ACTIVITY
cancer immunotherapy
CAR
CD1d
CHIMERIC ANTIGEN RECEPTOR
EFFICACY
Immunology
INDUCTION
iNKT cells
INVARIANT NKT CELLS
KILLER-T-CELLS
Life Sciences & Biomedicine
PHASE-I
RECOGNITION
Science & Technology
SPACER DOMAIN
Publication Status
Published
Coverage Spatial
Switzerland
Article Number
1625426
Date Publish Online
2025-07-11