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Optimizing CAR T cell therapy for solid tumours: a clinical perspective

Nature Reviews Clinical Oncology (2025)Cite this article

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Abstract

Chimeric antigen receptor (CAR) T cell therapy is revolutionizing the management of haematological malignancies but faces particular hurdles in the treatment of solid tumours. In this Review, we discuss important advances in refining CAR T cell therapy to provide practical clinical insights to address these challenges. We describe key strategies, including target antigen selection to enhance efficacy while minimizing on-target, off-tumour toxicities; early apheresis, rapid manufacturing and frontline application to preserve T cell fitness and ensure timely treatment; lymphodepletion to augment CAR T cell expansion; locoregional delivery to maximize local therapeutic concentrations and reduce systemic toxicity; and repeat infusions to prolong therapeutic effects. Furthermore, we discuss advanced response evaluation frameworks that will be essential for accurate assessment of the efficacy of CAR T cell therapies, and we highlight the need for robust toxicity management approaches to mitigate severe adverse events. By systematically addressing these multifaceted challenges, this Review provides a comprehensive guide for the optimization of CAR T cell therapy for solid tumours to enhance both efficacy and safety.

Key points

  • Chimeric antigen receptor (CAR) T cell therapy is effective for the treatment of haematological malignancies, although implementing this therapeutic modality in solid tumours faces substantial challenges.

  • Key hurdles include tumour heterogeneity, the immunosuppressive tumour microenvironment and a paucity of tumour-specific antigens.

  • Target selection should prioritize antigens with high tumour specificity, broad tumour coverage and stable expression to minimize on-target, off-tumour toxicity and ensure durable antitumour efficacy.

  • Strategies such as early apheresis, rapid manufacturing and frontline application of CAR T cell products aim to improve T cell fitness and expedite therapy, which will be crucial for patients with aggressive and/or rapidly progressing solid tumours.

  • Lymphodepletion and locoregional delivery methods can enhance CAR T cell expansion, trafficking and local efficacy, with the potential to reduce the risks of systemic adverse effects.

  • Novel approaches to efficacy evaluation (beyond RECIST) and proactive safety management protocols are essential for accurate assessment of response, distinguishing pseudoprogression and mitigating severe CAR T cell-related adverse events.

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Fig. 1: Clinically evaluated targets for CAR T cell therapy across different solid tumour types.

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Acknowledgements

The work of the authors is funded by the National Key Research and Development Program of China (No. 2022YFC2505006 and 2023YFC3403700 to L.S., and No. 2022YFA0912400 to C.Q.), the National Natural Science Foundation of China (No. 82522068 to C.Q. and No. U22A20327 to L.S.), the Beijing Natural Science Foundation (L232080 to C.Q.), the Beijing Hospitals Authority Youth Program (QMS20201101 to C.Q.), the Science Foundation of Peking University Cancer Hospital (JC202406 to C.Q.), the Clinical Medicine Plus X – Young Scholars Project of Peking University (to C.Q.), the Peking University Clinical Scientist Training Program (to C.Q.), and the Fundamental Research Funds for the Central Universities (to C.Q.).

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  1. These authors contributed equally: Jiarui Li, Chang Liu, Panpan Zhang.

Authors and Affiliations

  1. Beijing Key Laboratory of Cell and Gene Therapy for Solid Tumors, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Beijing, China

    Jiarui Li

  2. Beijing Key Laboratory of Cell and Gene Therapy for Solid Tumors, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Early Drug Development Centre, Peking University Cancer Hospital & Institute, Beijing, China

    Chang Liu & Panpan Zhang

  3. Beijing Key Laboratory of Cell and Gene Therapy for Solid Tumors, State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Beijing, China

    Lin Shen

  4. Beijing Key Laboratory of Cell and Gene Therapy for Solid Tumors, State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Department of Early Drug Development Centre, Peking University Cancer Hospital & Institute, Beijing, China

    Changsong Qi

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Competing interests

L.S. declares consulting or advisory roles for AstraZeneca, Boehringer Ingelheim, MSD, Servier and Transcenta Holding, and has received research funding (to the institution) from BeiGene and CARsgen. C.Q. declares consulting or advisory roles for AstraZeneca, Bayer, CARsgen, Imunopharm and Legend. The other authors declare no competing interests.

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Li, J., Liu, C., Zhang, P. et al. Optimizing CAR T cell therapy for solid tumours: a clinical perspective. Nat Rev Clin Oncol (2025). https://doi.org/10.1038/s41571-025-01075-1

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