REVIEW article
Front. Oncol.
Sec. Cancer Immunity and Immunotherapy
This article is part of the Research TopicExploring T Cell Driven Immunotherapies: From CAR T and TILs to T Cell EngagersView all 7 articles
Frontiers of Cytokine Engineering in CAR Cell Therapy for Cancer
Provisionally accepted
Yan-Ruide Li*
Yinghan Wu- University of California, Los Angeles, Los Angeles, United States
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Chimeric antigen receptor (CAR)-engineered T (CAR-T) cell therapy has revolutionized the treatment of hematologic malignancies, yet its efficacy in solid tumors remains limited by T cell exhaustion, restricted tumor infiltration, and an immunosuppressive tumor microenvironment (TME). Recent advances in cytokine engineering have introduced innovative strategies to overcome these barriers by modulating CAR cell survival, persistence, and cytotoxic function. This review provides a comprehensive analysis of emerging cytokine-augmented CAR platforms, highlighting mechanistic innovations such as IL-2 superkines that enhance selective CAR-T expansion, IL-15–armed CAR constructs that sustain in vivo persistence, and IL-12 and IL-18 co-expression systems that remodel the TME and recruit endogenous immune effectors. The roles of IL-7, IL-10, and IL-21 in preserving memory phenotypes, mitigating exhaustion, and improving metabolic fitness are also discussed in depth. Furthermore, the review explores synthetic and inducible cytokine circuits that enable spatial and temporal control of cytokine release, improving therapeutic precision and reducing systemic toxicity. Collectively, these innovations represent a paradigm shift toward next-generation, cytokine-engineered CAR therapies with enhanced efficacy, safety, and durability against both hematologic and solid tumors.
Keywords: Antitumor capacity, cancer therapy, CAR-engineered T (CAR-T) cell therapy, chimeric antigen receptor (CAR), cytokine, Immunotherapy, in vivo persistence, Invariant natural killer T (iNKT) cell
Received: 05 Jun 2025; Accepted: 11 Dec 2025.
Copyright: © 2025 Li and Wu. 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: Yan-Ruide Li
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