Larkin, J. et al. Five-year survival with combined nivolumab and ipilimumab in advanced melanoma. N. Engl. J. Med. 381, 1535–1546 (2019).

Article  CAS  PubMed  Google Scholar 

Gill, J. & Prasad, V. A reality check of the accelerated approval of immune-checkpoint inhibitors. Nat. Rev. Clin. Oncol. 16, 656–658 (2019).

Article  PubMed  Google Scholar 

Haslam, A. & Prasad, V. Estimation of the percentage of US patients with cancer who are eligible for and respond to checkpoint inhibitor immunotherapy drugs. JAMA Netw. Open 2, e192535 (2019).

Article  PubMed  PubMed Central  Google Scholar 

Yi, M. et al. Combination strategies with PD-1/PD-L1 blockade: current advances and future directions. Mol. Cancer 21, 28 (2022).

Article  PubMed  PubMed Central  Google Scholar 

Daly, R. J., Scott, A. M., Klein, O. & Ernst, M. Enhancing therapeutic anti-cancer responses by combining immune checkpoint and tyrosine kinase inhibition. Mol. Cancer 21, 189 (2022).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Schoenfeld, A. J. & Hellmann, M. D. Acquired resistance to immune checkpoint inhibitors. Cancer Cell 37, 443–455 (2020).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Finck, A. V., Blanchard, T., Roselle, C. P., Golinelli, G. & June, C. H. Engineered cellular immunotherapies in cancer and beyond. Nat. Med. 28, 678–689 (2022).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Waldman, A. D., Fritz, J. M. & Lenardo, M. J. A guide to cancer immunotherapy: from T cell basic science to clinical practice. Nat. Rev. Immunol. 20, 651–668 (2020).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Kalbasi, A. & Ribas, A. Tumour-intrinsic resistance to immune checkpoint blockade. Nat. Rev. Immunol. 20, 25–39 (2020).

Article  CAS  PubMed  Google Scholar 

Negi, N. & Das, B. K. CNS: not an immunoprivilaged site anymore but a virtual secondary lymphoid organ. Int. Rev. Immunol. 37, 57–68 (2018).

Article  PubMed  Google Scholar 

Griffith, T. S., Brunner, T., Fletcher, S. M., Green, D. R. & Ferguson, T. A. Fas ligand-induced apoptosis as a mechanism of immune privilege. Science 270, 1189–1192 (1995).

Article  CAS  PubMed  Google Scholar 

Engelhardt, B., Vajkoczy, P. & Weller, R. O. The movers and shapers in immune privilege of the CNS. Nat. Immunol. 18, 123–131 (2017).

Article  CAS  PubMed  Google Scholar 

Medawar, P. B. Immunity to homologous grafted skin; the fate of skin homografts transplanted to the brain, to subcutaneous tissue, and to the anterior chamber of the eye. Br. J. Exp. Pathol. 29, 58–69 (1948).

CAS  PubMed  PubMed Central  Google Scholar 

Joyce, J. A. & Fearon, D. T. T cell exclusion, immune privilege, and the tumor microenvironment. Science 348, 74–80 (2015).

Article  CAS  PubMed  Google Scholar 

Giles, J. R., Globig, A.-M., Kaech, S. M. & Wherry, E. J. CD8+ T cells in the cancer-immunity cycle. Immunity 56, 2231–2253 (2023).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Seo, W., Jerin, C. & Nishikawa, H. Transcriptional regulatory network for the establishment of CD8+ T cell exhaustion. Exp. Mol. Med. 53, 202–209 (2021).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Chopp, L., Redmond, C., O’Shea, J. J. & Schwartz, D. M. From thymus to tissues and tumors: a review of T-cell biology. J. Allergy Clin. Immunol. 151, 81–97 (2023).

Article  CAS  PubMed  Google Scholar 

Yuan, S., Almagro, J. & Fuchs, E. Beyond genetics: driving cancer with the tumour microenvironment behind the wheel. Nat. Rev. Cancer 24, 274–286 (2024).

Article  CAS  PubMed  PubMed Central  Google Scholar 

de Visser, K. E. & Joyce, J. A. The evolving tumor microenvironment: from cancer initiation to metastatic outgrowth. Cancer Cell 41, 374–403 (2023).

Article  PubMed  Google Scholar 

Jardim, D. L., Goodman, A., de Melo Gagliato, D. & Kurzrock, R. The challenges of tumor mutational burden as an immunotherapy biomarker. Cancer Cell 39, 154–173 (2021).

Article  CAS  PubMed  Google Scholar 

Spranger, S. et al. Density of immunogenic antigens does not explain the presence or absence of the T-cell-inflamed tumor microenvironment in melanoma. Proc. Natl Acad. Sci. USA 113, E7759–E7768 (2016). This study shows that neoantigens can be equally abundant in T cell-inflamed versus T cell-uninflamed melanoma tumours, implicating that the immunosuppressive TME, along with cancer cell-intrinsic mechanisms, has a key role in regulating T cell responses.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Leone, P. et al. MHC class I antigen processing and presenting machinery: organization, function, and defects in tumor cells. J. Natl Cancer Inst. 105, 1172–1187 (2013).

Article  CAS  PubMed  Google Scholar 

Kraemer, A. I. et al. The immunopeptidome landscape associated with T cell infiltration, inflammation and immune editing in lung cancer. Nat. Cancer 4, 608–628 (2023). In this study of lung cancer, neoantigen density does not correlate with T cell inflammation; instead, it is associated with immunoediting in non-inflamed tumours.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Schreiber, R. D., Old, L. J. & Smyth, M. J. Cancer immunoediting: integrating immunity’s roles in cancer suppression and promotion. Science 331, 1565–1570 (2011).

Article  CAS  PubMed  Google Scholar 

Kalluri, R. & Weinberg, R. A. The basics of epithelial–mesenchymal transition. J. Clin. Invest. 119, 1420–1428 (2009).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Dongre, A. et al. Direct and indirect regulators of epithelial-mesenchymal transition-mediated immunosuppression in breast carcinomas. Cancer Discov. 11, 1286–1305 (2021). This study in mouse breast cancer models illuminates and functionally validates signals-out that programme immunosuppression in the TME in the context of EMP.

Article  CAS  PubMed  Google Scholar 

Lüönd, F. et al. Distinct contributions of partial and full EMT to breast cancer malignancy. Dev. Cell 56, 3203–3221.e11 (2021).

Article  PubMed  Google Scholar 

Gu, Y., Zhang, Z. & Ten Dijke, P. Harnessing epithelial–mesenchymal plasticity to boost cancer immunotherapy. Cell Mol. Immunol. 20, 318–340 (2023).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Singh, D. & Siddique, H. R. Epithelial-to-mesenchymal transition in cancer progression: unraveling the immunosuppressive module driving therapy resistance. Cancer Metastasis Rev. 43, 155–173 (2024).

Article  PubMed  Google Scholar 

Chen, Z., Han, F., Du, Y., Shi, H. & Zhou, W. Hypoxic microenvironment in cancer: molecular mechanisms and therapeutic interventions. Signal Transduct. Target. Ther. 8, 70 (2023).

Article  PubMed  PubMed Central  Google Scholar 

Semenza, G. L. Targeting intratumoral hypoxia to enhance anti-tumor immunity. Semin. Cancer Biol. 96, 5–10 (2023).