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The complexity of immune evasion mechanisms throughout the metastatic cascade

  • Review Article
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From Nature Immunology

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Abstract

Metastasis, the spread of cancer from a primary site to distant organs, is an important challenge in oncology. This Review explores the complexities of immune escape mechanisms used throughout the metastatic cascade to promote tumor cell dissemination and affect organotropism. Specifically, we focus on adaptive plasticity of disseminated epithelial tumor cells to understand how they undergo phenotypic transitions to survive microenvironmental conditions encountered during metastasis. The interaction of tumor cells and their microenvironment is analyzed, highlighting the local and systemic effects that innate and adaptive immune systems have in shaping an immunosuppressive milieu to foster aggressive metastatic tumors. Effectively managing metastatic disease demands a multipronged approach to target the parallel and sequential mechanisms that suppress anti-tumor immunity. This management necessitates a deep understanding of the complex interplay between tumor cells, their microenvironment and immune responses that we provide with this Review.

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Fig. 1: Immune evasion mechanisms used by circulating tumor cells.
Fig. 2: Inflammatory mediators of metastatic colonization.
Fig. 3: Tumor-extrinsic and tumor-intrinsic regulation of dormancy.
Fig. 4: The pros and cons of tumor-intrinsic type 1 IFN signaling.

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References

  1. Gao, Y. et al. Metastasis organotropism: redefining the congenial soil. Dev. Cell 49, 375–391 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Conod, A., Silvano, M. & Ruiz, I. A. A. On the origin of metastases: induction of pro-metastatic states after impending cell death via ER stress, reprogramming, and a cytokine storm. Cell Rep. 38, 110490 (2022).

    Article  CAS  PubMed  Google Scholar 

  3. Deng, J. & Fleming, J. B. Inflammation and myeloid cells in cancer progression and metastasis. Front. Cell Dev. Biol. 9, 759691 (2021).

    Article  PubMed  Google Scholar 

  4. Phan, T. G. & Croucher, P. I. The dormant cancer cell life cycle. Nat. Rev. Cancer 20, 398–411 (2020).

    Article  CAS  PubMed  Google Scholar 

  5. Heerboth, S. et al. EMT and tumor metastasis. Clin. Transl. Med. 4, 6 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  6. 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 

  7. Peinado, H., Olmeda, D. & Cano, A. Snail, Zeb and bHLH factors in tumour progression: an alliance against the epithelial phenotype? Nat. Rev. Cancer 7, 415–428 (2007).

    Article  CAS  PubMed  Google Scholar 

  8. Eckert, M. A. et al. Twist1-induced invadopodia formation promotes tumor metastasis. Cancer Cell 19, 372–386 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Krebs, A. M. et al. The EMT-activator Zeb1 is a key factor for cell plasticity and promotes metastasis in pancreatic cancer. Nat. Cell Biol. 19, 518–529 (2017).

    Article  CAS  PubMed  Google Scholar 

  10. Tang, X., Sui, X., Weng, L. & Liu, Y. SNAIL1: linking tumor metastasis to immune evasion. Front. Immunol. 12, 724200 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Fazilaty, H. et al. A gene regulatory network to control EMT programs in development and disease. Nat. Commun. 10, 5115 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  12. Thiery, J. P., Acloque, H., Huang, R. Y. & Nieto, M. A. Epithelial–mesenchymal transitions in development and disease. Cell 139, 871–890 (2009).

    Article  CAS  PubMed  Google Scholar 

  13. Xiao, G. Y. et al. EMT activates exocytotic Rabs to coordinate invasion and immunosuppression in lung cancer. Proc. Natl Acad. Sci. USA 120, e2220276120 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Taki, M. et al. Tumor immune microenvironment during epithelial–mesenchymal transition. Clin. Cancer Res. 27, 4669–4679 (2021).

    Article  CAS  PubMed  Google Scholar 

  15. Dongre, A. et al. Epithelial-to-mesenchymal transition contributes to immunosuppression in breast carcinomas. Cancer Res. 77, 3982–3989 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Song, W., Mazzieri, R., Yang, T. & Gobe, G. C. Translational significance for tumor metastasis of tumor-associated macrophages and epithelial–mesenchymal transition. Front. Immunol. 8, 1106 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  17. Grigoriev, I. et al. Rab6 regulates transport and targeting of exocytotic carriers. Dev. Cell 13, 305–314 (2007).

    Article  CAS  PubMed  Google Scholar 

  18. Kudo-Saito, C., Shirako, H., Takeuchi, T. & Kawakami, Y. Cancer metastasis is accelerated through immunosuppression during Snail-induced EMT of cancer cells. Cancer Cell 15, 195–206 (2009).

    Article  CAS  PubMed  Google Scholar 

  19. Bates, M. et al. Circulating tumour cells: the good, the bad and the ugly. Biochim. Biophys. Acta Rev. Cancer 1878, 188863 (2023).

    Article  CAS  PubMed  Google Scholar 

  20. Mullins, R. D. Z., Pal, A., Barrett, T. F., Heft Neal, M. E. & Puram, S. V. Epithelial–mesenchymal plasticity in tumor immune evasion. Cancer Res. 82, 2329–2343 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Aiello, N. M. et al. EMT subtype influences epithelial plasticity and mode of cell migration. Dev. Cell 45, 681–695 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Pastushenko, I. et al. Identification of the tumour transition states occurring during EMT. Nature 556, 463–468 (2018).

    Article  CAS  PubMed  Google Scholar 

  23. Li, W. & Kang, Y. Probing the fifty shades of EMT in metastasis. Trends Cancer 2, 65–67 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  24. Wang, G. et al. The pan-cancer landscape of crosstalk between epithelial–mesenchymal transition and immune evasion relevant to prognosis and immunotherapy response. NPJ Precis. Oncol. 5, 56 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  25. Subhadarshini, S., Markus, J., Sahoo, S. & Jolly, M. K. Dynamics of epithelial–mesenchymal plasticity: what have single-cell investigations elucidated so far? ACS Omega 8, 11665–11673 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Parodi, M. et al. Hybrid epithelial–mesenchymal status of lung cancer dictates metastatic success through differential interaction with NK cells. J. Immunother. Cancer 12, e007895 (2024).

    Article  PubMed  PubMed Central  Google Scholar 

  27. Getu, A. A. et al. New frontiers in immune checkpoint B7-H3 (CD276) research and drug development. Mol. Cancer 22, 43 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Kroger, C. et al. Acquisition of a hybrid E/M state is essential for tumorigenicity of basal breast cancer cells. Proc. Natl Acad. Sci. USA 116, 7353–7362 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  30. Yamamoto, A., Doak, A. E. & Cheung, K. J. Orchestration of collective migration and metastasis by tumor cell clusters. Annu. Rev. Pathol. 18, 231–256 (2023).

    Article  CAS  PubMed  Google Scholar 

  31. Lo, H. C. et al. Resistance to natural killer cell immunosurveillance confers a selective advantage to polyclonal metastasis. Nat. Cancer 1, 709–722 (2020).

    Article  CAS  PubMed  Google Scholar 

  32. Chockley, P. J. et al. Epithelial–mesenchymal transition leads to NK cell-mediated metastasis-specific immunosurveillance in lung cancer. J. Clin. Invest. 128, 1384–1396 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  33. Lopez-Soto, A. et al. Epithelial–mesenchymal transition induces an antitumor immune response mediated by NKG2D receptor. J. Immunol. 190, 4408–4419 (2013).

    Article  CAS  PubMed  Google Scholar 

  34. Boya, M. et al. High throughput, label-free isolation of circulating tumor cell clusters in meshed microwells. Nat. Commun. 13, 3385 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Chen, Q. et al. A narrative review of circulating tumor cells clusters: a key morphology of cancer cells in circulation promote hematogenous metastasis. Front. Oncol. 12, 944487 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Lin, D. et al. Circulating tumor cells: biology and clinical significance. Signal Transduct. Target. Ther. 6, 404 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Chen, M. B. et al. Inflamed neutrophils sequestered at entrapped tumor cells via chemotactic confinement promote tumor cell extravasation. Proc. Natl Acad. Sci. USA 115, 7022–7027 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Najmeh, S. et al. Neutrophil extracellular traps sequester circulating tumor cells via β1-integrin mediated interactions. Int. J. Cancer 140, 2321–2330 (2017).

    Article  CAS  PubMed  Google Scholar 

  39. Cools-Lartigue, J. et al. Neutrophil extracellular traps sequester circulating tumor cells and promote metastasis. J. Clin. Invest. 123, 3446–3458 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Li, J., Chen, J., Sun, J. & Li, K. The formation of NETs and their mechanism of promoting tumor metastasis. J. Oncol. 2023, 7022337 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  41. Liu, Q., Liao, Q. & Zhao, Y. Myeloid-derived suppressor cells (MDSC) facilitate distant metastasis of malignancies by shielding circulating tumor cells (CTC) from immune surveillance. Med. Hypotheses 87, 34–39 (2016).

    Article  CAS  PubMed  Google Scholar 

  42. Sugino, T. et al. Sinusoidal tumor angiogenesis is a key component in hepatocellular carcinoma metastasis. Clin. Exp. Metastasis 25, 835–841 (2008).

    Google Scholar 

  43. Fang, J. H. et al. A novel vascular pattern promotes metastasis of hepatocellular carcinoma in an epithelial–mesenchymal transition-independent manner. Hepatology 62, 452–465 (2015).

    Article  CAS  PubMed  Google Scholar 

  44. Renne, S. L. et al. Vessels encapsulating tumor clusters (VETC) is a powerful predictor of aggressive hepatocellular carcinoma. Hepatology 71, 183–195 (2020).

    Article  CAS  PubMed  Google Scholar 

  45. Duda, D. G. et al. Malignant cells facilitate lung metastasis by bringing their own soil. Proc. Natl Acad. Sci. USA 107, 21677–21682 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Xiong, G. et al. Hsp47 promotes cancer metastasis by enhancing collagen-dependent cancer cell–platelet interaction. Proc. Natl Acad. Sci. USA 117, 3748–3758 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Hapeman, J. D., Carneiro, C. S. & Nedelcu, A. M. A model for the dissemination of circulating tumour cell clusters involving platelet recruitment and a plastic switch between cooperative and individual behaviours. BMC Ecol. Evol. 23, 39 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Deng, X. & Terunuma, H. Harnessing NK cells to control metastasis. Vaccines 10, 2018 (2022).

  49. Liu, X. et al. Immune checkpoint HLA-E:CD94–NKG2A mediates evasion of circulating tumor cells from NK cell surveillance. Cancer Cell 41, 272–287 (2023).

    Article  CAS  PubMed  Google Scholar 

  50. Liu, X. et al. Immune checkpoints HLA-E:CD94–NKG2A and HLA-C:KIR2DL1 complementarily shield circulating tumor cells from NK-mediated immune surveillance. Cell Discov. 10, 16 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Massague, J. & Obenauf, A. C. Metastatic colonization by circulating tumour cells. Nature 529, 298–306 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Lyden, D. et al. Impaired recruitment of bone-marrow-derived endothelial and hematopoietic precursor cells blocks tumor angiogenesis and growth. Nat. Med. 7, 1194–1201 (2001).

    Article  CAS  PubMed  Google Scholar 

  53. Kaplan, R. N. et al. VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature 438, 820–827 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Gong, Z. et al. Lung fibroblasts facilitate pre-metastatic niche formation by remodeling the local immune microenvironment. Immunity 55, 1483–1500 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Wong, C. C. et al. Hypoxia-inducible factor 1 is a master regulator of breast cancer metastatic niche formation. Proc. Natl Acad. Sci. USA 108, 16369–16374 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Tyagi, A. et al. Nicotine promotes breast cancer metastasis by stimulating N2 neutrophils and generating pre-metastatic niche in lung. Nat. Commun. 12, 474 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Qi, Z., Qi, S., Ling, L., Lv, J. & Feng, Z. Salidroside attenuates inflammatory response via suppressing JAK2–STAT3 pathway activation and preventing STAT3 transfer into nucleus. Int. Immunopharmacol. 35, 265–271 (2016).

    Article  CAS  PubMed  Google Scholar 

  58. Yao, D., Dai, C. & Peng, S. Mechanism of the mesenchymal–epithelial transition and its relationship with metastatic tumor formation. Mol. Cancer Res. 9, 1608–1620 (2011).

    Article  CAS  PubMed  Google Scholar 

  59. Del Pozo Martin, Y. et al. Mesenchymal cancer cell–stroma crosstalk promotes niche activation, epithelial reversion, and metastatic colonization. Cell Rep. 13, 2456–2469 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  60. Ouzounova, M. et al. Monocytic and granulocytic myeloid derived suppressor cells differentially regulate spatiotemporal tumour plasticity during metastatic cascade. Nat. Commun. 8, 14979 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Sceneay, J. et al. Primary tumor hypoxia recruits CD11b+/Ly6Cmed/Ly6G+ immune suppressor cells and compromises NK cell cytotoxicity in the premetastatic niche. Cancer Res. 72, 3906–3911 (2012).

    Article  CAS  PubMed  Google Scholar 

  62. Strauss, L. et al. Targeted deletion of PD-1 in myeloid cells induces antitumor immunity. Sci. Immunol. 5, eaay1863 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Gao, D. et al. Myeloid progenitor cells in the premetastatic lung promote metastases by inducing mesenchymal to epithelial transition. Cancer Res. 72, 1384–1394 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Kim, S. et al. Carcinoma-produced factors activate myeloid cells through TLR2 to stimulate metastasis. Nature 457, 102–106 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Gabrilovich, D. I., Ostrand-Rosenberg, S. & Bronte, V. Coordinated regulation of myeloid cells by tumours. Nat. Rev. Immunol. 12, 253–268 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Bassler, K., Schulte-Schrepping, J., Warnat-Herresthal, S., Aschenbrenner, A. C. & Schultze, J. L. The myeloid cell compartment—cell by cell. Annu. Rev. Immunol. 37, 269–293 (2019).

    Article  CAS  PubMed  Google Scholar 

  67. LaMarche, N. M. et al. An IL-4 signalling axis in bone marrow drives pro-tumorigenic myelopoiesis. Nature 625, 166–174 (2024).

    Article  CAS  PubMed  Google Scholar 

  68. Millrud, C. R., Bergenfelz, C. & Leandersson, K. On the origin of myeloid-derived suppressor cells. Oncotarget 8, 3649–3665 (2017).

    Article  PubMed  Google Scholar 

  69. Cassetta, L. et al. Differential expansion of circulating human MDSC subsets in patients with cancer, infection and inflammation. J. Immunother. Cancer 8, e001223 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  70. Maier, B. et al. A conserved dendritic-cell regulatory program limits antitumour immunity. Nature 580, 257–262 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Rodriguez-Tirado, C. et al. Interleukin 4 controls the pro-tumoral role of macrophages in mammary cancer pulmonary metastasis in mice. Cancers 14, 4336 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Jin, Q. et al. IL4/IL4R signaling promotes the osteolysis in metastatic bone of CRC through regulating the proliferation of osteoclast precursors. Mol. Med. 27, 152 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Ma, R. Y. et al. Monocyte-derived macrophages promote breast cancer bone metastasis outgrowth. J. Exp. Med. 217, e20191820 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Luckett, T. et al. Mesothelin secretion by pancreatic cancer cells co-opts macrophages and promotes metastasis. Cancer Res. 84, 527–544 (2024).

    Article  CAS  PubMed  Google Scholar 

  75. Dangaj, D. et al. Mannose receptor (MR) engagement by mesothelin GPI anchor polarizes tumor-associated macrophages and is blocked by anti-MR human recombinant antibody. PLoS ONE 6, e28386 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Feng, Y., Hu, X., Zhang, Y. & Wang, Y. The role of microglia in brain metastases: mechanisms and strategies. Aging Dis. 15, 169–185 (2024).

    Article  PubMed  PubMed Central  Google Scholar 

  77. Simon, A. et al. Metastatic breast cancer cells induce altered microglial morphology and electrical excitability in vivo. J. Neuroinflammation 17, 87 (2020).

    CAS  Google Scholar 

  78. Wu, S. Y. et al. Tamoxifen suppresses brain metastasis of estrogen receptor-deficient breast cancer by skewing microglia polarization and enhancing their immune functions. Breast Cancer Res. 23, 35 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Xing, F. et al. Loss of XIST in breast cancer activates MSN–c-Met and reprograms microglia via exosomal miRNA to promote brain metastasis. Cancer Res. 78, 4316–4330 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Zhou, H., Zhao, C., Shao, R., Xu, Y. & Zhao, W. The functions and regulatory pathways of S100A8/A9 and its receptors in cancers. Front. Pharmacol. 14, 1187741 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Aleckovic, M. & Kang, Y. Welcoming treat: astrocyte-derived exosomes induce PTEN suppression to foster brain metastasis. Cancer Cell 28, 554–556 (2015).

    Article  CAS  PubMed  Google Scholar 

  82. Ma, W. et al. Type I interferon response in astrocytes promotes brain metastasis by enhancing monocytic myeloid cell recruitment. Nat. Commun. 14, 2632 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Evans, K. T. et al. Microglia promote anti-tumour immunity and suppress breast cancer brain metastasis. Nat. Cell Biol. 25, 1848–1859 (2023).

    Article  CAS  PubMed  Google Scholar 

  84. Correia, A. L. Locally sourced: site-specific immune barriers to metastasis. Nat. Rev. Immunol. 23, 522–538 (2023).

    Article  CAS  PubMed  Google Scholar 

  85. Medaglia, C. et al. Spatial reconstruction of immune niches by combining photoactivatable reporters and scRNA-seq. Science 358, 1622–1626 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Xu, Y. et al. Technological advances in cancer immunity: from immunogenomics to single-cell analysis and artificial intelligence. Signal Transduct. Target. Ther. 6, 312 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  87. Aouad, P., Quinn, H. M., Berger, A. & Brisken, C. Tumor dormancy: EMT beyond invasion and metastasis. Genesis 62, e23552 (2023).

  88. Borriello, L. et al. Primary tumor associated macrophages activate programs of invasion and dormancy in disseminating tumor cells. Nat. Commun. 13, 626 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Sosa, M. S. et al. NR2F1 controls tumour cell dormancy via SOX9- and RARβ-driven quiescence programmes. Nat. Commun. 6, 6170 (2015).

    Article  CAS  PubMed  Google Scholar 

  90. Khalil, B. D. et al. An NR2F1-specific agonist suppresses metastasis by inducing cancer cell dormancy. J. Exp. Med. 219, e20210836 (2022).

    Article  CAS  PubMed  Google Scholar 

  91. Riethmuller, G. & Klein, C. A. Early cancer cell dissemination and late metastatic relapse: clinical reflections and biological approaches to the dormancy problem in patients. Semin. Cancer Biol. 11, 307–311 (2001).

    Article  CAS  PubMed  Google Scholar 

  92. Teng, M. W., Swann, J. B., Koebel, C. M., Schreiber, R. D. & Smyth, M. J. Immune-mediated dormancy: an equilibrium with cancer. J. Leukoc. Biol. 84, 988–993 (2008).

    Article  CAS  PubMed  Google Scholar 

  93. Malladi, S. et al. Metastatic latency and immune evasion through autocrine inhibition of WNT. Cell 165, 45–60 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Pantel, K. et al. Frequent down-regulation of major histocompatibility class I antigen expression on individual micrometastatic carcinoma cells. Cancer Res. 51, 4712–4715 (1991).

    CAS  PubMed  Google Scholar 

  95. Pommier, A. et al. Unresolved endoplasmic reticulum stress engenders immune-resistant, latent pancreatic cancer metastases. Science 360, eaao4908 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  96. Goddard, E. T. et al. Immune evasion of dormant disseminated tumor cells is due to their scarcity and can be overcome by T cell immunotherapies. Cancer Cell 42, 119–134 (2024).

    Article  CAS  PubMed  Google Scholar 

  97. Owen, K. L. et al. Prostate cancer cell-intrinsic interferon signaling regulates dormancy and metastatic outgrowth in bone. EMBO Rep. 21, e50162 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Bidwell, B. N. et al. Silencing of Irf7 pathways in breast cancer cells promotes bone metastasis through immune escape. Nat. Med. 18, 1224–1231 (2012).

    Article  CAS  PubMed  Google Scholar 

  99. Reticker-Flynn, N. E. et al. Lymph node colonization induces tumor-immune tolerance to promote distant metastasis. Cell 185, 1924–1942 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Olkhanud, P. B. et al. Tumor-evoked regulatory B cells promote breast cancer metastasis by converting resting CD4+ T cells to T-regulatory cells. Cancer Res. 71, 3505–3515 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Meyer, M. A. et al. Breast and pancreatic cancer interrupt IRF8-dependent dendritic cell development to overcome immune surveillance. Nat. Commun. 9, 1250 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  102. Gabrilovich, D. I. et al. Production of vascular endothelial growth factor by human tumors inhibits the functional maturation of dendritic cells. Nat. Med. 2, 1096–1103 (1996).

    Article  CAS  PubMed  Google Scholar 

  103. Park, S. J. et al. IL-6 regulates in vivo dendritic cell differentiation through STAT3 activation. J. Immunol. 173, 3844–3854 (2004).

    Article  CAS  PubMed  Google Scholar 

  104. Zhao, L. et al. Late-stage tumors induce anemia and immunosuppressive extramedullary erythroid progenitor cells. Nat. Med. 24, 1536–1544 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Long, H. et al. Tumor-induced erythroid precursor-differentiated myeloid cells mediate immunosuppression and curtail anti-PD-1/PD-L1 treatment efficacy. Cancer Cell 40, 674–693 (2022).

    Article  CAS  PubMed  Google Scholar 

  106. Parker, B. S., Rautela, J. & Hertzog, P. J. Antitumour actions of interferons: implications for cancer therapy. Nat. Rev. Cancer 16, 131–144 (2016).

    Article  PubMed  Google Scholar 

  107. Yu, R., Zhu, B. & Chen, D. Type I interferon-mediated tumor immunity and its role in immunotherapy. Cell. Mol. Life Sci. 79, 191 (2022).

    Article  CAS  Google Scholar 

  108. Schoenborn, J. R. & Wilson, C. B. Regulation of interferon-γ during innate and adaptive immune responses. Adv. Immunol. 96, 41–101 (2007).

    Article  CAS  PubMed  Google Scholar 

  109. Lazear, H. M., Nice, T. J. & Diamond, M. S. Interferon-λ: immune functions at barrier surfaces and beyond. Immunity 43, 15–28 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Ye, L., Schnepf, D. & Staeheli, P. Interferon-λ orchestrates innate and adaptive mucosal immune responses. Nat. Rev. Immunol. 19, 614–625 (2019).

    Article  CAS  PubMed  Google Scholar 

  111. Kotenko, S. V., Rivera, A., Parker, D. & Durbin, J. E. Type III IFNs: beyond antiviral protection. Semin. Immunol. 43, 101303 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Taffoni, C. et al. DNA damage repair kinase DNA-PK and cGAS synergize to induce cancer-related inflammation in glioblastoma. EMBO J. 42, e111961 (2023).

    Article  CAS  PubMed  Google Scholar 

  113. Antonczyk, A. et al. Direct inhibition of IRF-dependent transcriptional regulatory mechanisms associated with disease. Front. Immunol. 10, 1176 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Ishikawa, H., Ma, Z. & Barber, G. N. STING regulates intracellular DNA-mediated, type I interferon-dependent innate immunity. Nature 461, 788–792 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Wang, R. W., Vigano, S., Ben-David, U., Amon, A. & Santaguida, S. Aneuploid senescent cells activate NF-κB to promote their immune clearance by NK cells. EMBO Rep. 22, e52032 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Wang, H. et al. cGAS is essential for the antitumor effect of immune checkpoint blockade. Proc. Natl Acad. Sci. USA 114, 1637–1642 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Hoevenaar, W. H. M. et al. Degree and site of chromosomal instability define its oncogenic potential. Nat. Commun. 11, 1501 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Liu, J. et al. Epigenetic priming improves salvage chemotherapy in diffuse large B-cell lymphoma via endogenous retrovirus-induced cGAS–STING activation. Clin. Epigenetics 15, 75 (2023).

    Google Scholar 

  119. Lanng, K. R. B., Lauridsen, E. L. & Jakobsen, M. R. The balance of STING signaling orchestrates immunity in cancer. Nat. Immunol. 25, 1144–1157 (2024).

    Article  CAS  PubMed  Google Scholar 

  120. Ni, J. et al. STING signaling activation modulates macrophage polarization via CCL2 in radiation-induced lung injury. J. Transl. Med. 21, 590 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Wang, Q. et al. STING agonism reprograms tumor-associated macrophages and overcomes resistance to PARP inhibition in BRCA1-deficient models of breast cancer. Nat. Commun. 13, 3022 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  122. Du, H., Xu, T. & Cui, M. cGAS–STING signaling in cancer immunity and immunotherapy. Biomed. Pharmacother. 133, 110972 (2021).

    Article  CAS  PubMed  Google Scholar 

  123. Li, Q. et al. cGAS–STING, an important signaling pathway in diseases and their therapy. MedComm 5, e511 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Hu, J. et al. STING inhibits the reactivation of dormant metastasis in lung adenocarcinoma. Nature 616, 806–813 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Brockwell, N. K. et al. Neoadjuvant interferons: critical for effective PD-1-based immunotherapy in TNBC. Cancer Immunol. Res. 5, 871–884 (2017).

    Article  CAS  PubMed  Google Scholar 

  126. Rautela, J. et al. Loss of host type-I IFN signaling accelerates metastasis and impairs NK-cell antitumor function in multiple models of breast cancer. Cancer Immunol. Res. 3, 1207–1217 (2015).

    Article  CAS  PubMed  Google Scholar 

  127. Touati, N. et al. Correlation between severe infection and breast cancer metastases in the EORTC 10994/BIG 1-00 trial: investigating innate immunity as a tumour suppressor in breast cancer. Eur. J. Cancer 72, 95–102 (2017).

    Article  PubMed  Google Scholar 

  128. Marks, Z. R. C. et al. Interferon-ε is a tumour suppressor and restricts ovarian cancer. Nature 620, 1063–1070 (2023).

    Article  CAS  PubMed  Google Scholar 

  129. Fung, K. Y. et al. Interferon-ε protects the female reproductive tract from viral and bacterial infection. Science 339, 1088–1092 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Stifter, S. A. et al. Defining the distinct, intrinsic properties of the novel type I interferon, IFNϵ. J. Biol. Chem. 293, 3168–3179 (2018).

    Article  CAS  PubMed  Google Scholar 

  131. Bakhoum, S. F. et al. Chromosomal instability drives metastasis through a cytosolic DNA response. Nature 553, 467–472 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Li, J. et al. Non-cell-autonomous cancer progression from chromosomal instability. Nature 620, 1080–1088 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Qiu, J. et al. Cancer cells resistant to immune checkpoint blockade acquire interferon-associated epigenetic memory to sustain T cell dysfunction. Nat. Cancer 4, 43–61 (2023).

    CAS  PubMed  Google Scholar 

  134. Cole, K., Al-Kadhimi, Z. & Talmadge, J. E. Role of myeloid-derived suppressor cells in tumor recurrence. Cancer Metastasis Rev. 42, 113–142 (2023).

    CAS  Google Scholar 

  135. Yofe, I. et al. Spatial and temporal mapping of breast cancer lung metastases identify TREM2 macrophages as regulators of the metastatic boundary. Cancer Discov. 13, 2610–2631 (2023).

    Article  CAS  PubMed  Google Scholar 

  136. Park, M. D. et al. TREM2 macrophages drive NK cell paucity and dysfunction in lung cancer. Nat. Immunol. 24, 792–801 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Fabre, T. et al. Identification of a broadly fibrogenic macrophage subset induced by type 3 inflammation. Sci. Immunol. 8, eadd8945 (2023).

    Article  CAS  PubMed  Google Scholar 

  138. Cortese, N. et al. High-resolution analysis of mononuclear phagocytes reveals GPNMB as a prognostic marker in human colorectal liver metastasis. Cancer Immunol. Res. 11, 405–420 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Parvez, A. et al. PD-1 and PD-L1: architects of immune symphony and immunotherapy breakthroughs in cancer treatment. Front. Immunol. 14, 1296341 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Tarhini, A. A. et al. Tumor associated PD-L1 expression pattern in microscopically tumor positive sentinel lymph nodes in patients with melanoma. J. Transl. Med. 13, 319 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  141. Klement, J. D. et al. Tumor PD-L1 engages myeloid PD-1 to suppress type I interferon to impair cytotoxic T lymphocyte recruitment. Cancer Cell 41, 620–636 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Du, Z. et al. Inhibition of IFN-α signaling by a PKC- and protein tyrosine phosphatase SHP-2-dependent pathway. Proc. Natl Acad. Sci. USA 102, 10267–10272 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Zanker, D. J. et al. Intratumoral administration of the Toll-like receptor 7/8 agonist 3M-052 enhances interferon-driven tumor immunogenicity and suppresses metastatic spread in preclinical triple-negative breast cancer. Clin. Transl. Immunol. 9, e1177 (2020).

    Article  CAS  Google Scholar 

  144. Honda, K. et al. IRF-7 is the master regulator of type-I interferon-dependent immune responses. Nature 434, 772–777 (2005).

    Article  CAS  PubMed  Google Scholar 

  145. Boydell, E. et al. Neoadjuvant immunotherapy: a promising new standard of care. Int. J. Mol. Sci. 24, 11849 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Rosner, S., Reuss, J. E. & Forde, P. M. PD-1 blockade in early-stage lung cancer. Annu. Rev. Med. 70, 425–435 (2019).

    Article  CAS  PubMed  Google Scholar 

  147. Topalian, S. L., Taube, J. M. & Pardoll, D. M. Neoadjuvant checkpoint blockade for cancer immunotherapy. Science 367, eaax0182 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Graff, J. N. et al. A phase II single-arm study of pembrolizumab with enzalutamide in men with metastatic castration-resistant prostate cancer progressing on enzalutamide alone. J. Immunother. Cancer 8, e000642 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  149. Shah, A. N. et al. Phase II study of pembrolizumab and capecitabine for triple negative and hormone receptor-positive, HER2-negative endocrine-refractory metastatic breast cancer. J. Immunother. Cancer 8, e000173 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  150. Wolchok, J. D. et al. Long-term outcomes with nivolumab plus ipilimumab or nivolumab alone versus ipilimumab in patients with advanced melanoma. J. Clin. Oncol. 40, 127–137 (2022).

    Article  CAS  PubMed  Google Scholar 

  151. PD-1 blockade falls short (repeatedly) in prostate cancer. Cancer Discov. 13, 1032–1033 (2023).

  152. Walsh, L. A. & Quail, D. F. Decoding the tumor microenvironment with spatial technologies. Nat. Immunol. 24, 1982–1993 (2023).

    Article  CAS  PubMed  Google Scholar 

  153. Mullard, A. Tumour-infiltrating lymphocyte cancer therapy nears FDA finish line. Nat. Rev. Drug Discov. 23, 3–7 (2024).

    Article  CAS  PubMed  Google Scholar 

  154. Zebley, C. C., Zehn, D., Gottschalk, S. & Chi, H. T cell dysfunction and therapeutic intervention in cancer. Nat. Immunol. 25, 1344–1354 (2024).

    Article  CAS  PubMed  Google Scholar 

  155. Lickefett, B. et al. Lymphodepletion — an essential but undervalued part of the chimeric antigen receptor T-cell therapy cycle. Front. Immunol. 14, 1303935 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Koumprentziotis, I. A. et al. New emerging targets in cancer immunotherapy: the role of B7-H3. Vaccines 12, 54 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Tao, R. et al. Revolutionizing cancer treatment: enhancing CAR-T cell therapy with CRISPR/Cas9 gene editing technology. Front. Immunol. 15, 1354825 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Dagher, O. K. & Posey, A. D. Jr. Forks in the road for CAR T and CAR NK cell cancer therapies. Nat. Immunol. 24, 1994–2007 (2023).

    Article  CAS  PubMed  Google Scholar 

  159. Huang, Y., Wang, H., Yue, X. & Li, X. Bone serves as a transfer station for secondary dissemination of breast cancer. Bone Res. 11, 21 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This work was supported by National Health and Medical Research Council (NHMRC) investigator and ideas grants to B.S.P. (2018167, 2012943), and grant funding from the National Breast Cancer Foundation (IIRS-23-021).

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Authors and Affiliations

  1. Cancer Evolution and Metastasis Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia

    Nicole M. Haynes, Thomas B. Chadwick & Belinda S. Parker

  2. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia

    Nicole M. Haynes, Thomas B. Chadwick & Belinda S. Parker

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N.M.H. and B.S.P. conceptualized the manuscript. N.M.H. wrote the manuscript and contributed to the generation of the figures. T.B.C. conceptualized and generated the figures. B.S.P. supervised and contributed to the writing of the manuscript and the preparation of the figures. All authors edited and approved the final version of the manuscript.

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Correspondence to Belinda S. Parker.

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Nature Immunology thanks Dan Duda and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editor: Nick Bernard, in collaboration with the Nature Immunology team.

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Haynes, N.M., Chadwick, T.B. & Parker, B.S. The complexity of immune evasion mechanisms throughout the metastatic cascade. Nat Immunol (2024). https://doi.org/10.1038/s41590-024-01960-4

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