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Microenvironmental regulation of solid tumour resistance to CAR T cell therapy

Nature Reviews Immunology (2025)Cite this article

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Abstract

Chimeric antigen receptor (CAR) T cell therapy holds significant promise for the treatment of cancer; however, its efficacy in solid tumours is substantially hindered by the immunosuppressive tumour microenvironment (TME). Solid tumours can resist immunotherapy by impairing T cell trafficking, function and persistence. One of the initial obstacles that CAR T cells encounter is the abnormal tumour vasculature, which restricts efficient T cell infiltration, further compounded by a dense extracellular matrix. CAR T cells that do infiltrate the tumours are outnumbered by immunosuppressive cells such as regulatory T cells, myeloid-derived suppressor cells and tumour-associated macrophages. Additionally, tumour cells can contribute to CAR T cell resistance by upregulating immune checkpoint molecules, such as PDL1 and CTLA4, and engage in metabolic competition. In this Review, we discuss how cellular and non-cellular components of the TME impair CAR T cell therapy and consider potential strategies to improve CAR T cell therapies for solid tumours, either by reprogramming the TME or by engineering CAR T cells to resist the immunosuppressive effects of the TME.

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Fig. 1: Cellular and non-cellular components of the TME induce tumour resistance to CAR T cell therapy.
Fig. 2: The tumour vasculature inhibits CAR T cell activity.
Fig. 3: Therapeutic strategies targeted at the ECM.
Fig. 4: Hijacking TME cues to enhance CAR T cell efficacy and safety.
Fig. 5: The therapeutic index of CAR T cell therapy.

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Acknowledgements

This work was supported, in part, by National Institutes of Health (NIH) grants R01NS094533 (to Y.F.), R01NS106108 (to Y.F.), R01CA241501 (to Y.F.) and R01HL155198 (to Y.F.), and American Cancer Society Yosemite Award 24-1331395 (to Y.F.).

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Author notes

  1. These authors contributed equally: Zachary L. Lamplugh, Nils Wellhausen.

Authors and Affiliations

  1. Department of Radiation Oncology, University of Pennsylvania, Philadelphia, PA, USA

    Zachary L. Lamplugh & Yi Fan

  2. Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA, USA

    Zachary L. Lamplugh, Nils Wellhausen, Carl H. June & Yi Fan

  3. Translational Center of Excellence in Hematopoietic Stem Cell Engineering, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA

    Nils Wellhausen

  4. Division of Hematology–Oncology, Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Nils Wellhausen

  5. Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Carl H. June

  6. Parker Institute for Cancer Immunotherapy, University of Pennsylvania, Philadelphia, PA, USA

    Carl H. June

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Contributions

Z.L.L. and N.W. contributed equally to all aspects of the Review; generated all figures, boxes and table; and wrote the original version of the Review. C.H.J. and Y.F. edited the Review and provided supervision.

Corresponding authors

Correspondence to Carl H. June or Yi Fan.

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Competing interests

C.H.J. is an inventor of patents and/or patent applications licensed to Novartis Institutes of Biomedical Research and receives licence revenue from such licences; is an inventor on patents and/or patent applications licensed to Kite Pharma, Capstan Therapeutics, Dispatch Therapeutics and BlueWhale Bio; and is a member of the scientific advisory boards of AC Immune, BluesphereBio, BlueWhale Bio, Cabaletta, Carisma, Cartography, Cellares, Celldex, Decheng, Replay Bio, Verismo and WIRB-Copernicus. Y.F. is a co-founder of Radix Therapeutics. The other authors declare no competing interests.

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Lamplugh, Z.L., Wellhausen, N., June, C.H. et al. Microenvironmental regulation of solid tumour resistance to CAR T cell therapy. Nat Rev Immunol (2025). https://doi.org/10.1038/s41577-025-01229-3

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