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Barriers and solutions for CAR-T therapy in solid tumors

Cancer Gene Therapy volume 32, pages 923–934 (2025)Cite this article

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Abstract

Chimeric antigen receptor (CAR)-T cell therapy has emerged as a transformative approach for cancer treatment, particularly in hematologic malignancies. However, barriers in the development of effective CAR-T therapies for solid tumors, including antigenic escape, tumor immunosuppressive microenvironments, severe toxicities, and limitations in preclinical models, hinder its scalability and broader clinical implementation. To overcome these barriers, strategies have been developed in recent years, such as optimizing CAR designs, enhancing CAR-T cell infiltration, neutralizing immunosuppressive cells, remodeling metabolism of CAR-T cells, eliminating antigen escape, mitigating toxicities, advancing preclinical models, and in situ programming CAR-T cells. Here, we discuss current barriers and potential strategies for CAR-T cell therapy in solid tumors. Ultimately, we present perspectives on these advanced strategies for broader clinical adoption of CAR-T cell therapy.

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Fig. 1: Obstacles of CAR-T therapy in solid tumors.
Fig. 2: Approaches to enhance CAR-T efficacy in solid tumors.
Fig. 3: Schematic representation of CAR structures.

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Data availability

The data supporting this review are from previously reported studies and datasets, which have been cited.

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Acknowledgements

The figures were created with BioRender.com.

Funding

This work received financial support from the National Natural Science Foundation of China (Grant No. 82373242 and 82273307).

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  1. These authors contributed equally: Zhihao Tu, Yuelin Chen

Authors and Affiliations

  1. Department of Stomatology, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China

    Zhihao Tu, Yuelin Chen & Zhimi Zhang

  2. Department of Head and Neck Oncology, West China Hospital of Stomatology, State Key Laboratory of Oral Diseases, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Sichuan University, Chengdu, China

    Wanrong Meng

  3. Department of Stomatology, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, University of Electronic Science and Technology of China, Chengdu, China

    Ling Li

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MWR and LL designed the concept. TZH, CYL, and ZZM searched the literatures. TZH, MWR, ZZM, and CYL wrote the manuscript. TZH and MWR created the figures and tables. MWR and LL revised the manuscript. LL provided the funding acquisition. All authors read and approved the final manuscript.

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Tu, Z., Chen, Y., Zhang, Z. et al. Barriers and solutions for CAR-T therapy in solid tumors. Cancer Gene Ther 32, 923–934 (2025). https://doi.org/10.1038/s41417-025-00931-7

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