Nature | www.nature.com | 11 Article 12. Huang, Q. et al. The primordial differentiation of tumor-specific memory CD8 + T cells as bona fide responders to PD-1/PD-L1 blockade in draining lymph nodes. Cell 185 , 4049–4066 (2022). 13. Wang, G. et al. Antigen-specific profiling identifies T-bet + melanoma-specific CD8 + T cells associated with response to neoadjuvant PD-1 blockade. Cancer Cell 44 , 221–234 (2026). 14. Pai, J. A. et al. Lineage tracing reveals clonal progenitors and long-term persistence of tumor-specific T cells during immune checkpoint blockade. Cancer Cell 41 , 776–790 (2023). 15. Morad, G., Helmink, B. A., Sharma, P. & Wargo, J. A. Hallmarks of response, resistance, and toxicity to immune checkpoint blockade. Cell 184 , 5309–5337 (2021). 16. Memon, D. et al. Clinical and molecular features of acquired resistance to immunotherapy in non-small cell lung cancer. Cancer Cell 42 , 209–224 (2024). 17. van Krimpen, A. et al. Immune suppression in the tumor-draining lymph node corresponds with distant disease recurrence in patients with melanoma. Cancer Cell 40 , 798–799 (2022). 18. Núñez, N. G. et al. Tumor invasion in draining lymph nodes is associated with T reg accumulation in breast cancer patients. Nat. Commun. 11 , 3272 (2020). 19. Reticker-Flynn, N. E. et al. Lymph node colonization induces tumor-immune tolerance to promote distant metastasis. Cell 185 , 1924–1942 (2022). 20. Haist, M. et al. Lymph node colonization induces tissue remodeling via immunosuppressive fibroblast-myeloid cell niches supporting metastatic tolerance. Cancer Cell 44 , 604–623 (2026). 21. Maier, B. et al. A conserved dendritic-cell regulatory program limits antitumour immunity. Nature 580 , 257–262 (2020). 22. Coulton, A. et al. Using a pan-cancer atlas to investigate tumour associated macrophages as regulators of immunotherapy response. Nat. Commun. 15 , 5665 (2024). 23. Liu, B., Zhang, Y., Wang, D., Hu, X. & Zhang, Z. Single-cell meta-analyses reveal responses of tumor-reactive CXCL13 + T cells to immune-checkpoint blockade. Nat. Cancer 3 , 1123–1136 (2022). 24. Yoshitomi, H. et al. Human Sox4 facilitates the development of CXCL13-producing helper T cells in inflammatory environments. Nat. Commun. 9 , 3762 (2018). 25. Khan, O. et al. TOX transcriptionally and epigenetically programs CD8 + T cell exhaustion. Nature 571 , 211–218 (2019). 26. Man, K. et al. Transcription factor IRF4 promotes CD8 + T cell exhaustion and limits the development of memory-like T cells during chronic infection. Immunity 47 , 1129–1141 (2017). 27. Hirsch, T. et al. IRF4 impedes human CD8 T cell function and promotes cell proliferation and PD-1 expression. Cell Rep. 43 , 114401 (2024). 28. Liu, Y. et al. IL-2 regulates tumor-reactive CD8 + T cell exhaustion by activating the aryl hydrocarbon receptor. Nat. Immunol. 22 , 358–369 (2021). 29. Wu, J. E. et al. In vitro modeling of CD8 + T cell exhaustion enables CRISPR screening to reveal a role for BHLHE40. Sci. Immunol. 8 , eade3369 (2023). 30. van der Leun, A. M., Thommen, D. S. & Schumacher, T. N. CD8 + T cell states in human cancer: insights from single-cell analysis. Nat. Rev. Cancer 20 , 218–232 (2020). 31. Horton, B. L. et al. Lack of CD8 + T cell effector differentiation during priming mediates checkpoint blockade resistance in non-small cell lung cancer. Sci. Immunol. 6 , eabi8800 (2021). 32. Sekine, T. et al. TOX is expressed by exhausted and polyfunctional human effector memory CD8 + T cells. Sci. Immunol. 5 , eaba7918 (2020). 33. Zheng, L. et al. Pan-cancer single-cell landscape of tumor-infiltrating T cells. Science 374 , abe6474 (2021). 34. Burn, T. N. et al. Antigen reactivity defines tissue-resident memory and exhausted T cells in tumors. Nat. Immunol. 27 , 98–109 (2026). 35. Beltra, J. C. et al. Developmental relationships of four exhausted CD8 + T cell subsets reveals underlying transcriptional and epigenetic landscape control mechanisms. Immunity 52 , 825–841 (2020). 36. Miki, Y. et al. Dual roles of group IID phospholipase A2 in inflammation and cancer. J. Biol. Chem. 291 , 15588–15601 (2016). 37. Miki, Y. et al. Lymphoid tissue phospholipase A2 group IID resolves contact hypersensitivity by driving antiinflammatory lipid mediators. J. Exp. Med. 210 , 1217–1234 (2013). 38. Jing, H. et al. PLA2G2D promotes immune escape in non-small cell lung cancer by regulating T cell immune function through PD-L1-expressing extracellular vesicles. Scand. J. Immunol. 100 , e13393 (2024). 39. Wong, L. R. et al. Eicosanoid signalling blockade protects middle-aged mice from severe COVID-19. Nature 605 , 146–151 (2022). 40. von Allmen, C. E. et al. Secretory phospholipase A2-IID is an effector molecule of CD4 + CD25 + regulatory T cells. Proc. Natl Acad. Sci. USA 106 , 11673–11678 (2009). 41. Kim, N. et al. Single-cell RNA sequencing demonstrates the molecular and cellular reprogramming of metastatic lung adenocarcinoma. Nat. Commun. 11 , 2285 (2020). 42. Liu, T. et al. Single cell profiling of primary and paired metastatic lymph node tumors in breast cancer patients. Nat. Commun. 13 , 6823 (2022). 43. Baratin, M. et al. T cell zone resident macrophages silently dispose of apoptotic cells in the lymph node. Immunity 47 , 349–362 (2017). 44. Grant, S. M., Lou, M., Yao, L., Germain, R. N. & Radtke, A. J. The lymph node at a glance— how spatial organization optimizes the immune response. J. Cell Sci. 133 , jcs241828 (2020). 45. Vijay, R. et al. Critical role of phospholipase A2 group IID in age-related susceptibility to severe acute respiratory syndrome-CoV infection. J. Exp. Med. 212 , 1851–1868 (2015). 46. Liu, M. et al. Prostaglandin D2 axis impairs immunity against melanoma via dendritic cells and γδ T cells in middle-aged mice. J. Immunol. 215 , vkaf288 https://doi.org/10.1093/ jimmun/vkaf288 (2025). 47. Cindy Yang, S. Y. et al. Pan-cancer analysis of longitudinal metastatic tumors reveals genomic alterations and immune landscape dynamics associated with pembrolizumab sensitivity. Nat. Commun. 12 , 5137 (2021). Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. 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