Abstract
Recent advances in immunotherapy have affirmed the curative potential of T cell-based approaches for treating relapsed and refractory cancers. However, the therapeutic efficacy is limited in part owing to the ability of cancers to evade immunosurveillance and adapt to immunological pressure. In this Review, we provide a brief overview of cancer-mediated immunosuppressive mechanisms with a specific focus on the repression of the surveillance and effector function of T cells. We discuss CD8+ T cell exhaustion and functional heterogeneity and describe strategies for targeting the molecular checkpoints that restrict T cell differentiation and effector function to bolster immunotherapeutic effects. We also delineate the emerging contributions of the tumor microenvironment to T cell metabolism and conclude by highlighting discovery-based approaches for developing future cellular therapies. Continued exploration of T cell biology and engineering hold great promise for advancing therapeutic interventions for cancer.
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Acknowledgements
This work was supported by the National Institutes of Health (NIH) (K08CA279926 to C.C.Z.; CA253188, CA281868, AI105887, AI131703, Al140761, AI150241 and AI150514 to H.C.), an Alex Lemonade Stand Young Investigator Grant (to C.C.Z.) and the American Lebanese Syrian Associated Charities (ALSAC to C.C.Z., S.G. and H.C.). D.Z. is supported by grants from the German Research Foundation (SFB1371, ZE 832/6-1 and ZE 832/8-1). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. We thank B. Youngblood for conceptual feedback and discussion and N. Chapman for scientific editing.
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C.C.Z., D.Z., S.G. and H.C. wrote the manuscript.
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C.C.Z. declares patents related to epigenetic biomarkers and methods for enhancing CAR T cell function. S.G. is co-inventor on patents or patent applications in the fields of T cell and gene therapy for cancer, is a member of the scientific advisory board of Be Biopharma and CARGO and the Data and Safety Monitoring Board of Immatics and has received honoraria from Tessa Therapeutics within the last year. H.C. is a co-inventor on patents or patent applications in the field of immunotherapy and consults or consulted for Kumquat Biosciences, Chugai Pharmaceuticals, Ono Pharmaceutical and TCura Bioscience. D.Z. does not declare any competing interests.
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Zebley, C.C., Zehn, D., Gottschalk, S. et al. T cell dysfunction and therapeutic intervention in cancer. Nat Immunol 25, 1344–1354 (2024). https://doi.org/10.1038/s41590-024-01896-9
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DOI: https://doi.org/10.1038/s41590-024-01896-9
