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Context-dependent functions of pattern recognition receptors in cancer

Nature Reviews Cancer volume 22, pages 397–413 (2022)Cite this article

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Abstract

The immune system plays a critical role in shaping all facets of cancer, from the early initiation stage through to metastatic disease and resistance to therapy. Our understanding of the importance of the adaptive arm of the immune system in antitumour immunity has led to the implementation of immunotherapy with immune checkpoint inhibitors in numerous cancers, albeit with differing efficacy. By contrast, the clinical utility of innate immunity in cancer has not been exploited, despite dysregulated innate immunity being a feature of at least one-third of all cancers associated with tumour-promoting chronic inflammation. The past two decades have seen innate immune pattern recognition receptors (PRRs) emerge as critical regulators of the immune response to microbial infection and host tissue damage. More recently, it has become apparent that in many cancer types, PRRs play a central role in modulating a vast array of tumour-inhibiting and tumour-promoting cellular responses both in immune cells within the tumour microenvironment and directly in cancer cells. Herein, we provide a comprehensive overview of the fast-evolving field of PRRs in cancer, and discuss the potential to target PRRs for drug development and biomarker discovery in a wide range of oncology settings.

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Fig. 1: Pattern recognition receptors orchestrate diverse cellular processes relevant to cancer development and progression.
Fig. 2: Pattern recognition receptors induce tumour-promoting activities in immune cells.
Fig. 3: Pattern recognition receptors induce tumour-inhibitory activities in immune cells.
Fig. 4: Pattern recognition receptors induce tumour-promoting activities in non-immune cells.
Fig. 5: Pattern recognition receptors induce tumour-inhibitory activities in non-immune cells.

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References

  1. Lin, W. W. & Karin, M. A cytokine-mediated link between innate immunity, inflammation, and cancer. J. Clin. Invest. 117, 1175–1183 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Greten, F. R. & Grivennikov, S. I. Inflammation and cancer: triggers, mechanisms, and consequences. Immunity 51, 27–41 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011).

    CAS  PubMed  Google Scholar 

  4. van Elsland, D. & Neefjes, J. Bacterial infections and cancer. EMBO Rep. 19, e46632 (2018).

    PubMed  PubMed Central  Google Scholar 

  5. Krump, N. A. & You, J. Molecular mechanisms of viral oncogenesis in humans. Nat. Rev. Microbiol. 16, 684–698 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Pushalkar, S. et al. The pancreatic cancer microbiome promotes oncogenesis by induction of innate and adaptive immune suppression. Cancer Discov. 8, 403–416 (2018). This study demonstrates that enrichment of distinct microorganisms in pancreatic tumours activates TLR2 and TLR5 to induce innate and adaptive immunosuppression. The TLR-mediated immunosuppressive effects are elicited by macrophages, whose reprogramming towards MDSCs by microbiota–TLR engagement leads to T cell anergy and a favourable protumorigenic microenvironment.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Peterson, E. E. & Barry, K. C. The natural killer-dendritic cell immune axis in anti-cancer immunity and immunotherapy. Front. Immunol. 11, 621254 (2020).

    CAS  PubMed  Google Scholar 

  8. Meric-Bernstam, F., Larkin, J., Tabernero, J. & Bonini, C. Enhancing anti-tumour efficacy with immunotherapy combinations. Lancet 397, 1010–1022 (2021).

    CAS  PubMed  Google Scholar 

  9. Cao, X. Self-regulation and cross-regulation of pattern-recognition receptor signalling in health and disease. Nat. Rev. Immunol. 16, 35–50 (2016).

    CAS  PubMed  Google Scholar 

  10. Smith, S. & Jefferies, C. Role of DNA/RNA sensors and contribution to autoimmunity. Cytokine Growth Factor. Rev. 25, 745–757 (2014).

    CAS  PubMed  Google Scholar 

  11. Saxena, M. & Yeretssian, G. NOD-like receptors: master regulators of inflammation and cancer. Front. Immunol. 5, 327 (2014).

    PubMed  PubMed Central  Google Scholar 

  12. O’Neill, L. A., Golenbock, D. & Bowie, A. G. The history of Toll-like receptors - redefining innate immunity. Nat. Rev. Immunol. 13, 453–460 (2013).

    PubMed  Google Scholar 

  13. Sharma, B. R., Karki, R. & Kanneganti, T. D. Role of AIM2 inflammasome in inflammatory diseases, cancer and infection. Eur. J. Immunol. 49, 1998–2011 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Rehwinkel, J. & Gack, M. U. RIG-I-like receptors: their regulation and roles in RNA sensing. Nat. Rev. Immunol. 20, 537–551 (2020).

    CAS  PubMed  Google Scholar 

  15. Drouin, M., Saenz, J. & Chiffoleau, E. C-type lectin-like receptors: head or tail in cell death immunity. Front. Immunol. 11, 251 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Paludan, S. R. & Bowie, A. G. Immune sensing of DNA. Immunity 38, 870–880 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. West, A. C. & Jenkins, B. J. Inflammatory and non-inflammatory roles for Toll-like receptors in gastrointestinal cancer. Curr. Pharm. Des. 21, 2968–2977 (2015).

    CAS  PubMed  Google Scholar 

  18. Javaid, N. & Choi, S. Toll-like receptors from the perspective of cancer treatment. Cancers 12, 297 (2020).

    PubMed Central  Google Scholar 

  19. Karki, R. & Kanneganti, T. D. Diverging inflammasome signals in tumorigenesis and potential targeting. Nat. Rev. Cancer 19, 197–214 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Sun, J. et al. Sequence variants in Toll-like receptor gene cluster (TLR6-TLR1-TLR10) and prostate cancer risk. J. Natl Cancer Inst. 97, 525–532 (2005).

    CAS  PubMed  Google Scholar 

  21. Zheng, S. L. et al. Sequence variants of toll-like receptor 4 are associated with prostate cancer risk: results from the CAncer Prostate in Sweden Study. Cancer Res. 64, 2918–2922 (2004). This clinical study is among the first to suggest an association between PRRs and human cancer by identifying a link between a single-nucleotide polymorphism in the 3′ untranslated region of the TLR4 gene and significantly increased prostate cancer risk.

    CAS  PubMed  Google Scholar 

  22. Ou, T., Lilly, M. & Jiang, W. The pathologic role of toll-like receptor 4 in prostate cancer. Front. Immunol. 9, 1188 (2018).

    PubMed  PubMed Central  Google Scholar 

  23. Wang, D. & DuBois, R. N. Immunosuppression associated with chronic inflammation in the tumor microenvironment. Carcinogenesis 36, 1085–1093 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Castano-Rodriguez, N., Kaakoush, N. O. & Mitchell, H. M. Pattern-recognition receptors and gastric cancer. Front. Immunol. 5, 336 (2014).

    PubMed  PubMed Central  Google Scholar 

  25. Neamatallah, M. et al. Impact of Toll-like receptors 2(TLR2) and TLR 4 gene variations on HCV susceptibility, response to treatment and development of hepatocellular carcinoma in cirrhotic HCV patients. Immunol. Invest. 49, 462–476 (2020).

    CAS  PubMed  Google Scholar 

  26. Li, G. & Zheng, Z. Toll-like receptor 3 genetic variants and susceptibility to hepatocellular carcinoma and HBV-related hepatocellular carcinoma. Tumour Biol. 34, 1589–1594 (2013).

    CAS  PubMed  Google Scholar 

  27. Zhu, J. et al. Toll like receptor7 polymorphisms in relation to disease susceptibility and progression in Chinese patients with chronic HBV infection. Sci. Rep. 7, 12417 (2017).

    PubMed  PubMed Central  Google Scholar 

  28. Pandey, N. O. et al. Association of TLR4 and TLR9 polymorphisms and haplotypes with cervical cancer susceptibility. Sci. Rep. 9, 9729 (2019).

    PubMed  PubMed Central  Google Scholar 

  29. Messaritakis, I. et al. Evaluation of the detection of Toll-like receptors (TLRs) in cancer development and progression in patients with colorectal cancer. PLoS ONE 13, e0197327 (2018).

    PubMed  PubMed Central  Google Scholar 

  30. Nischalke, H. D. et al. The toll-like receptor 2 (TLR2) -196 to -174 del/ins polymorphism affects viral loads and susceptibility to hepatocellular carcinoma in chronic hepatitis C. Int. J. Cancer 130, 1470–1475 (2012).

    CAS  PubMed  Google Scholar 

  31. Lundy, J. et al. TLR2 activation promotes tumour growth and associates with patient survival and chemotherapy response in pancreatic ductal adenocarcinoma. Oncogene 40, 6007–6022 (2021).

    CAS  PubMed  Google Scholar 

  32. Tye, H. et al. STAT3-driven upregulation of TLR2 promotes gastric tumorigenesis independent of tumor inflammation. Cancer Cell 22, 466–478 (2012). This is the original report of TLR2 promoting gastric tumorigenesis, independent of inflammation, in a cancer cell-intrinsic mechanism by augmenting proliferation and suppressing apoptosis. This work also reveals that TLR2 is transcriptionally upregulated in the gastric epithelium by the oncogenic transcription factor STAT3, thus linking cytokine signalling and PRR networks in cancer.

    CAS  PubMed  Google Scholar 

  33. West, A. C. et al. Identification of a TLR2-regulated gene signature associated with tumor cell growth in gastric cancer. Oncogene 36, 5134–5144 (2017).

    CAS  PubMed  Google Scholar 

  34. Shehab, M., Sherri, N., Hussein, H., Salloum, N. & Rahal, E. A. Endosomal Toll-like receptors mediate enhancement of interleukin-17A production triggered by Epstein-Barr virus DNA in mice. J. Virol. 93, e00987–19 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Gaudreault, E., Fiola, S., Olivier, M. & Gosselin, J. Epstein-Barr virus induces MCP-1 secretion by human monocytes via TLR2. J. Virol. 81, 8016–8024 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Melit, L. E., Marginean, C. O., Marginean, C. D. & Marginean, M. O. The relationship between toll-like receptors and helicobacter pylori-related gastropathies: still a controversial topic. J. Immunol. Res. 2019, 8197048 (2019).

    PubMed  PubMed Central  Google Scholar 

  37. Ma, Z., Cao, Q., Xiong, Y., Zhang, E. & Lu, M. Interaction between hepatitis B virus and toll-like receptors: current status and potential therapeutic use for chronic hepatitis B. Vaccines 6, 6 (2018).

    PubMed Central  Google Scholar 

  38. Hasan, U. A. et al. The human papillomavirus type 16 E7 oncoprotein induces a transcriptional repressor complex on the Toll-like receptor 9 promoter. J. Exp. Med. 210, 1369–1387 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Dejea, C. M. et al. Patients with familial adenomatous polyposis harbor colonic biofilms containing tumorigenic bacteria. Science 359, 592–597 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Round, J. L. et al. The Toll-like receptor 2 pathway establishes colonization by a commensal of the human microbiota. Science 332, 974–977 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Li, K. et al. Activation of chemokine and inflammatory cytokine response in hepatitis C virus-infected hepatocytes depends on Toll-like receptor 3 sensing of hepatitis C virus double-stranded RNA intermediates. Hepatology 55, 666–675 (2012).

    CAS  PubMed  Google Scholar 

  42. Hishida, A. et al. No associations of Toll-like receptor 2 (TLR2) -196 to -174del polymorphism with the risk of Helicobacter pylori seropositivity, gastric atrophy, and gastric cancer in Japanese. Gastric Cancer 13, 251–257 (2010).

    CAS  PubMed  Google Scholar 

  43. Lourenco, C. M. et al. Characterization and strong risk association of TLR2 del -196 to -174 polymorphism and Helicobacter pylori and their influence on mRNA expression in gastric cancer. World J. Gastrointest. Oncol. 12, 535–548 (2020).

    PubMed  PubMed Central  Google Scholar 

  44. Fels Elliott, D. R. et al. Impact of mutations in Toll-like receptor pathway genes on esophageal carcinogenesis. PLoS Genet. 13, e1006808 (2017).

    PubMed  PubMed Central  Google Scholar 

  45. Holtorf, A., Conrad, A., Holzmann, B. & Janssen, K. P. Cell-type specific MyD88 signaling is required for intestinal tumor initiation and progression to malignancy. Oncoimmunology 7, e1466770 (2018).

    PubMed  PubMed Central  Google Scholar 

  46. Hennessy, C. & McKernan, D. P. Epigenetics and innate immunity: the ‘unTolld’ story. Immunol. Cell Biol. 94, 631–639 (2016).

    CAS  PubMed  Google Scholar 

  47. Cao, D. et al. 18beta-glycyrrhetinic acid inhibited mitochondrial energy metabolism and gastric carcinogenesis through methylation-regulated TLR2 signaling pathway. Carcinogenesis 40, 234–245 (2019).

    CAS  PubMed  Google Scholar 

  48. Kim, T. W. et al. Epigenetic modification of TLR4 promotes activation of NF-kappaB by regulating methyl-CpG-binding domain protein 2 and Sp1 in gastric cancer. Oncotarget 7, 4195–4209 (2016).

    PubMed  Google Scholar 

  49. Kutikhin, A. G. Role of NOD1/CARD4 and NOD2/CARD15 gene polymorphisms in cancer etiology. Hum. Immunol. 72, 955–968 (2011).

    CAS  PubMed  Google Scholar 

  50. Liu, J., He, C., Xu, Q., Xing, C. & Yuan, Y. NOD2 polymorphisms associated with cancer risk: a meta-analysis. PLoS ONE 9, e89340 (2014).

    PubMed  PubMed Central  Google Scholar 

  51. Fernandes, F. P., Leal, V. N. C., Souza de Lima, D., Reis, E. C. & Pontillo, A. Inflammasome genetics and complex diseases: a comprehensive review. Eur. J. Hum. Genet. 28, 1307–1321 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Cambui, R. A. G. et al. Double-edged sword of inflammasome genetics in colorectal cancer prognosis. Clin. Immunol. 213, 108373 (2020).

    CAS  PubMed  Google Scholar 

  53. Huhn, S. et al. Coding variants in NOD-like receptors: an association study on risk and survival of colorectal cancer. PLoS ONE 13, e0199350 (2018).

    PubMed  PubMed Central  Google Scholar 

  54. Ungerback, J. et al. Genetic variation and alterations of genes involved in NFkappaB/TNFAIP3- and NLRP3-inflammasome signaling affect susceptibility and outcome of colorectal cancer. Carcinogenesis 33, 2126–2134 (2012).

    PubMed  Google Scholar 

  55. Verma, D. et al. The Q705K polymorphism in NLRP3 is a gain-of-function alteration leading to excessive interleukin-1beta and IL-18 production. PLoS ONE 7, e34977 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Verma, D. et al. Inflammasome polymorphisms confer susceptibility to sporadic malignant melanoma. Pigment. Cell Melanoma Res. 25, 506–513 (2012).

    CAS  PubMed  Google Scholar 

  57. Shi, F. et al. Low NLRP3 expression predicts a better prognosis of colorectal cancer. Biosci. Rep. 41, BSR20210280 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Xue, Y. et al. Correlation between the NLRP3 inflammasome and the prognosis of patients with LSCC. Front. Oncol. 9, 588 (2019).

    PubMed  PubMed Central  Google Scholar 

  59. Rebe, C. & Ghiringhelli, F. Interleukin-1beta and cancer. Cancers 12, 1791 (2020).

    CAS  PubMed Central  Google Scholar 

  60. Yang, X. et al. Association of interleukin-18 gene promoter -607 C>A and -137G>C polymorphisms with cancer risk: a meta-analysis of 26 studies. PLoS ONE 8, e73671 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Protti, M. P. & De Monte, L. Dual role of inflammasome adaptor ASC in cancer. Front. Cell Dev. Biol. 8, 40 (2020).

    PubMed  PubMed Central  Google Scholar 

  62. Dihlmann, S. et al. Lack of absent in melanoma 2 (AIM2) expression in tumor cells is closely associated with poor survival in colorectal cancer patients. Int. J. Cancer 135, 2387–2396 (2014).

    CAS  PubMed  Google Scholar 

  63. Woerner, S. M. et al. The putative tumor suppressor AIM2 is frequently affected by different genetic alterations in microsatellite unstable colon cancers. Genes Chromosomes Cancer 46, 1080–1089 (2007).

    CAS  PubMed  Google Scholar 

  64. Kondo, Y. et al. Overexpression of the DNA sensor proteins, absent in melanoma 2 and interferon-inducible 16, contributes to tumorigenesis of oral squamous cell carcinoma with p53 inactivation. Cancer Sci. 103, 782–790 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Nakamura, Y. et al. Overexpression of absent in melanoma 2 in oral squamous cell carcinoma contributes to tumor progression. Biochem. Biophys. Res. Commun. 509, 82–88 (2019).

    CAS  PubMed  Google Scholar 

  66. Dawson, R. E. et al. STAT3-mediated upregulation of the AIM2 DNA sensor links innate immunity with cell migration to promote epithelial tumourigenesis. Gut https://doi.org/10.1136/gutjnl-2020-323916 (2021). This study reports the discovery of a tumour-promoting cell-intrinsic role for AIM2 in gastric cancer, independent of inflammasomes, whereby AIM2 acts as a molecular bridge linking cytokine-mediated STAT3 signalling, innate immunity and epithelial cell migration via the microtubule regulatory protein end-binding protein 1.

    Article  PubMed  Google Scholar 

  67. Riva, G., Biolatti, M., Pecorari, G., Dell’Oste, V. & Landolfo, S. PYHIN proteins and HPV: role in the pathogenesis of head and neck squamous cell carcinoma. Microorganisms 8, 14 (2019).

    PubMed Central  Google Scholar 

  68. Torii, Y. et al. Epstein-Barr virus infection-induced inflammasome activation in human monocytes. PLoS ONE 12, e0175053 (2017).

    PubMed  PubMed Central  Google Scholar 

  69. Dutta, D. et al. BRCA1 Regulates IFI16 mediated nuclear innate sensing of herpes Viral DNA and subsequent induction of the innate inflammasome and interferon-beta responses. PLoS Pathog. 11, e1005030 (2015).

    PubMed  PubMed Central  Google Scholar 

  70. Kwon, J. & Bakhoum, S. F. The cytosolic DNA-sensing cGAS-STING pathway in cancer. Cancer Discov. 10, 26–391 (2020).

    CAS  PubMed  Google Scholar 

  71. Li, T. & Chen, Z. J. The cGAS-cGAMP-STING pathway connects DNA damage to inflammation, senescence, and cancer. J. Exp. Med. 215, 1287–1299 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Msaouel, P. et al. Comprehensive molecular characterization identifies distinct genomic and immune hallmarks of renal medullary carcinoma. Cancer Cell 37, 720–734 e713 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Lubbers, J. M. et al. Association of homozygous variants of STING1 with outcome in human cervical cancer. Cancer Sci. 112, 61–71 (2021).

    CAS  PubMed  Google Scholar 

  75. Bu, Y., Liu, F., Jia, Q. A. & Yu, S. N. Decreased expression of TMEM173 predicts poor prognosis in patients with hepatocellular carcinoma. PLoS ONE 11, e0165681 (2016).

    PubMed  PubMed Central  Google Scholar 

  76. Song, S. et al. Decreased expression of STING predicts poor prognosis in patients with gastric cancer. Sci. Rep. 7, 39858 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Jia, J., Ren, J., Yan, D., Xiao, L. & Sun, R. Association between the XRCC6 polymorphisms and cancer risks: a systematic review and meta-analysis. Medicine 94, e283 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Cornell, L. et al. DNA-PK–a candidate driver of hepatocarcinogenesis and tissue biomarker that predicts response to treatment and survival. Clin. Cancer Res. 21, 925–933 (2015).

    CAS  PubMed  Google Scholar 

  79. Polprasert, C. et al. Inherited and somatic defects in DDX41 in myeloid neoplasms. Cancer Cell 27, 658–670 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Qi, Z. et al. Identification of prognostic biomarkers and correlations with immune infiltrates among cGAS-STING in hepatocellular carcinoma. Biosci. Rep. 40, BSR20202603 (2020).

    PubMed  PubMed Central  Google Scholar 

  81. Brown, G. D., Willment, J. A. & Whitehead, L. C-type lectins in immunity and homeostasis. Nat. Rev. Immunol. 18, 374–389 (2018).

    CAS  PubMed  Google Scholar 

  82. Yan, H., Kamiya, T., Suabjakyong, P. & Tsuji, N. M. Targeting C-type lectin receptors for cancer immunity. Front. Immunol. 6, 408 (2015).

    PubMed  PubMed Central  Google Scholar 

  83. Qian, J. et al. TLR2 promotes glioma immune evasion by downregulating MHC class II molecules in microglia. Cancer Immunol. Res. 6, 1220–1233 (2018).

    CAS  PubMed  Google Scholar 

  84. McCoy, M. G. et al. Endothelial TLR2 promotes proangiogenic immune cell recruitment and tumor angiogenesis. Sci. Signal. 14, eabc5371 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Liu, Y. et al. Tumor exosomal rnas promote lung pre-metastatic niche formation by activating alveolar epithelial TLR3 to recruit neutrophils. Cancer Cell 30, 243–256 (2016).

    PubMed  Google Scholar 

  87. Li, B. et al. TLR2 deficiency enhances susceptibility to oral carcinogenesis by promoting an inflammatory environment. Am. J. Cancer Res. 9, 2599–2617 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Lowe, E. L. et al. Toll-like receptor 2 signaling protects mice from tumor development in a mouse model of colitis-induced cancer. PLoS ONE 5, e13027 (2010).

    PubMed  PubMed Central  Google Scholar 

  89. Li, S., Sun, R., Chen, Y., Wei, H. & Tian, Z. TLR2 limits development of hepatocellular carcinoma by reducing IL18-mediated immunosuppression. Cancer Res. 75, 986–995 (2015).

    CAS  PubMed  Google Scholar 

  90. Lin, H. et al. Loss of immunity-supported senescence enhances susceptibility to hepatocellular carcinogenesis and progression in Toll-like receptor 2-deficient mice. Hepatology 57, 171–182 (2013).

    CAS  PubMed  Google Scholar 

  91. Ochi, A. et al. MyD88 inhibition amplifies dendritic cell capacity to promote pancreatic carcinogenesis via Th2 cells. J. Exp. Med. 209, 1671–1687 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Ochi, A. et al. Toll-like receptor 7 regulates pancreatic carcinogenesis in mice and humans. J. Clin. Invest. 122, 4118–4129 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Zhan, Y., Seregin, S. S., Chen, J. & Chen, G. Y. Nod1 limits colitis-associated tumorigenesis by regulating IFN-gamma production. J. Immunol. 196, 5121–5129 (2016).

    CAS  PubMed  Google Scholar 

  94. Maisonneuve, C. et al. Nod1 promotes colorectal carcinogenesis by regulating the immunosuppressive functions of tumor-infiltrating myeloid cells. Cell Rep. 34, 108677 (2021).

    CAS  PubMed  Google Scholar 

  95. Suarez, G. et al. Nod1 imprints inflammatory and carcinogenic responses toward the gastric pathogen helicobacter pylori. Cancer Res. 79, 1600–1611 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Chen, G. Y., Liu, M., Wang, F., Bertin, J. & Nunez, G. A functional role for Nlrp6 in intestinal inflammation and tumorigenesis. J. Immunol. 186, 7187–7194 (2011).

    CAS  PubMed  Google Scholar 

  97. Allen, I. C. et al. The NLRP3 inflammasome functions as a negative regulator of tumorigenesis during colitis-associated cancer. J. Exp. Med. 207, 1045–1056 (2010). This study demonstrates that the inflammasome is linked to attenuation of the development of cancer by identifying that NLRP3 activation in haematopoietic cells contributes to the inhibition of CRC.

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Yao, X. et al. Remodelling of the gut microbiota by hyperactive NLRP3 induces regulatory T cells to maintain homeostasis. Nat. Commun. 8, 1896 (2017).

    PubMed  PubMed Central  Google Scholar 

  99. Hu, B. et al. Inflammation-induced tumorigenesis in the colon is regulated by caspase-1 and NLRC4. Proc. Natl Acad. Sci. USA 107, 21635–21640 (2010).

    PubMed  PubMed Central  Google Scholar 

  100. Tengesdal, I. W. et al. Targeting tumor-derived NLRP3 reduces melanoma progression by limiting MDSCs expansion. Proc. Natl Acad. Sci. USA 118, e2000915118 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Chow, M. T. et al. NLRP3 suppresses NK cell-mediated responses to carcinogen-induced tumors and metastases. Cancer Res. 72, 5721–5732 (2012).

    CAS  PubMed  Google Scholar 

  102. Kolb, R. et al. Obesity-associated NLRC4 inflammasome activation drives breast cancer progression. Nat. Commun. 7, 13007 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Martinez-Cardona, C. et al. AIM2 deficiency reduces the development of hepatocellular carcinoma in mice. Int. J. Cancer 143, 2997–3007 (2018).

    CAS  PubMed  Google Scholar 

  104. Woo, S. R. et al. STING-dependent cytosolic DNA sensing mediates innate immune recognition of immunogenic tumors. Immunity 41, 830–842 (2014). This study demonstes that the sensing of cytosolic DNA by STING contributes to antitumour immunity. It provides a mechanism by which type I interferons are produced in myeloid cells, which subsequently orchestrate tumour killing by NK cells and/or T cells.

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Marcus, A. et al. Tumor-derived cGAMP triggers a STING-mediated interferon response in non-tumor cells to activate the NK cell response. Immunity 49, 754–763 e754 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Thomsen, M. K. et al. The cGAS-STING pathway is a therapeutic target in a preclinical model of hepatocellular carcinoma. Oncogene 39, 1652–1664 (2020).

    CAS  PubMed  Google Scholar 

  107. Ahn, J. et al. Inflammation-driven carcinogenesis is mediated through STING. Nat. Commun. 5, 5166 (2014).

    CAS  PubMed  Google Scholar 

  108. Jones, S. A. & Jenkins, B. J. Recent insights into targeting the IL-6 cytokine family in inflammatory diseases and cancer. Nat. Rev. Immunol. 18, 773–789 (2018).

    CAS  PubMed  Google Scholar 

  109. Balkwill, F. Tumour necrosis factor and cancer. Nat. Rev. Cancer 9, 361–371 (2009).

    CAS  PubMed  Google Scholar 

  110. Faget, D. V., Ren, Q. & Stewart, S. A. Unmasking senescence: context-dependent effects of SASP in cancer. Nat. Rev. Cancer 19, 439–453 (2019).

    CAS  PubMed  Google Scholar 

  111. Fukata, M. et al. Toll-like receptor-4 promotes the development of colitis-associated colorectal tumors. Gastroenterology 133, 1869–1881 (2007).

    CAS  PubMed  Google Scholar 

  112. Fukata, M. et al. Innate immune signaling by Toll-like receptor-4 (TLR4) shapes the inflammatory microenvironment in colitis-associated tumors. Inflamm. Bowel Dis. 15, 997–1006 (2009).

    PubMed  Google Scholar 

  113. Fukata, M. et al. Constitutive activation of epithelial TLR4 augments inflammatory responses to mucosal injury and drives colitis-associated tumorigenesis. Inflamm. Bowel Dis. 17, 1464–1473 (2011).

    PubMed  Google Scholar 

  114. Dapito, D. H. et al. Promotion of hepatocellular carcinoma by the intestinal microbiota and TLR4. Cancer Cell 21, 504–516 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Yu, L. X. et al. Endotoxin accumulation prevents carcinogen-induced apoptosis and promotes liver tumorigenesis in rodents. Hepatology 52, 1322–1333 (2010).

    CAS  PubMed  Google Scholar 

  116. Zambirinis, C. P. et al. TLR9 ligation in pancreatic stellate cells promotes tumorigenesis. J. Exp. Med. 212, 2077–2094 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Rutkowski, M. R. et al. Microbially driven TLR5-dependent signaling governs distal malignant progression through tumor-promoting inflammation. Cancer Cell 27, 27–40 (2015).

    CAS  PubMed  Google Scholar 

  118. Diamond, M. S. et al. Type I interferon is selectively required by dendritic cells for immune rejection of tumors. J. Exp. Med. 208, 1989–2003 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Fuertes, M. B. et al. Host type I IFN signals are required for antitumor CD8+ T cell responses through CD8{alpha}+ dendritic cells. J. Exp. Med. 208, 2005–2016 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Chin, A. I. et al. Toll-like receptor 3-mediated suppression of TRAMP prostate cancer shows the critical role of type I interferons in tumor immune surveillance. Cancer Res. 70, 2595–2603 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Shmuel-Galia, L. et al. Dysbiosis exacerbates colitis by promoting ubiquitination and accumulation of the innate immune adaptor STING in myeloid cells. Immunity 54, 1137–1153 e1138 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. Zhu, Q. et al. Cutting edge: STING mediates protection against colorectal tumorigenesis by governing the magnitude of intestinal inflammation. J. Immunol. 193, 4779–4782 (2014).

    CAS  PubMed  Google Scholar 

  123. Dou, Z. et al. Cytoplasmic chromatin triggers inflammation in senescence and cancer. Nature 550, 402–406 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  124. Lemos, H. et al. STING promotes the growth of tumors characterized by low antigenicity via IDO activation. Cancer Res. 76, 2076–2081 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. Jenkins, B. J. et al. Hyperactivation of Stat3 in gp130 mutant mice promotes gastric hyperproliferation and desensitizes TGF-beta signaling. Nat. Med. 11, 845–852 (2005).

    CAS  PubMed  Google Scholar 

  126. Scheeren, F. A. et al. A cell-intrinsic role for TLR2-MYD88 in intestinal and breast epithelia and oncogenesis. Nat. Cell Biol. 16, 1238–1248 (2014).

    CAS  PubMed  Google Scholar 

  127. Echizen, K., Hirose, O., Maeda, Y. & Oshima, M. Inflammation in gastric cancer: Interplay of the COX-2/prostaglandin E2 and Toll-like receptor/MyD88 pathways. Cancer Sci. 107, 391–397 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  128. Monlish, D. A. et al. Loss of Toll-like receptor 2 results in accelerated leukemogenesis in the NUP98-HOXD13 mouse model of MDS. Blood 131, 1032–1035 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  129. Shi, Y. J. et al. Toll-like receptor 4 regulates spontaneous intestinal tumorigenesis by up-regulating IL-6 and GM-CSF. J. Cell Mol. Med. 24, 385–397 (2020).

    CAS  PubMed  Google Scholar 

  130. Fukata, M. et al. Cox-2 is regulated by Toll-like receptor-4 (TLR4) signaling: role in proliferation and apoptosis in the intestine. Gastroenterology 131, 862–877 (2006).

    CAS  PubMed  Google Scholar 

  131. Li, Y. et al. Constitutive TLR4 signalling in intestinal epithelium reduces tumor load by increasing apoptosis in APC(Min/+) mice. Oncogene 33, 369–377 (2014).

    PubMed  Google Scholar 

  132. Burgueno, J. F. et al. Epithelial TLR4 signaling activates DUOX2 to induce microbiota-driven tumorigenesis. Gastroenterology 160, 797–808 e796 (2021).

    CAS  PubMed  Google Scholar 

  133. Koliaraki, V. et al. Innate sensing through mesenchymal TLR4/MyD88 signals promotes spontaneous intestinal tumorigenesis. Cell Rep. 26, 536–545 e534 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. Chen, R., Alvero, A. B., Silasi, D. A., Steffensen, K. D. & Mor, G. Cancers take their Toll — the function and regulation of Toll-like receptors in cancer cells. Oncogene 27, 225–233 (2008).

    CAS  PubMed  Google Scholar 

  135. Cario, E., Gerken, G. & Podolsky, D. K. Toll-like receptor 2 controls mucosal inflammation by regulating epithelial barrier function. Gastroenterology 132, 1359–1374 (2007).

    CAS  PubMed  Google Scholar 

  136. Podolsky, D. K., Gerken, G., Eyking, A. & Cario, E. Colitis-associated variant of TLR2 causes impaired mucosal repair because of TFF3 deficiency. Gastroenterology 137, 209–220 (2009).

    CAS  PubMed  Google Scholar 

  137. Nighot, M. et al. Lipopolysaccharide-induced increase in intestinal epithelial tight permeability is mediated by toll-like receptor 4/myeloid differentiation primary response 88 (MyD88) activation of myosin light chain kinase expression. Am. J. Pathol. 187, 2698–2710 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  138. Schirbel, A. et al. Pro-angiogenic activity of TLRs and NLRs: a novel link between gut microbiota and intestinal angiogenesis. Gastroenterology 144, 613–623 e619 (2013).

    CAS  PubMed  Google Scholar 

  139. West, X. Z. et al. Oxidative stress induces angiogenesis by activating TLR2 with novel endogenous ligands. Nature 467, 972–976 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  140. Bald, T. et al. Ultraviolet-radiation-induced inflammation promotes angiotropism and metastasis in melanoma. Nature 507, 109–113 (2014).

    CAS  PubMed  Google Scholar 

  141. Andrejeva, G. & Rathmell, J. C. Similarities and distinctions of cancer and immune metabolism in inflammation and tumors. Cell Metab. 26, 49–70 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  142. Chang, C. H. et al. Metabolic competition in the tumor microenvironment is a driver of cancer progression. Cell 162, 1229–1241 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  143. Veyrat, M. et al. Stimulation of the toll-like receptor 3 promotes metabolic reprogramming in head and neck carcinoma cells. Oncotarget 7, 82580–82593 (2016).

    PubMed  PubMed Central  Google Scholar 

  144. Ye, J. et al. TLR8 signaling enhances tumor immunity by preventing tumor-induced T-cell senescence. EMBO Mol. Med. 6, 1294–1311 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  145. Chen, G. Y., Shaw, M. H., Redondo, G. & Nunez, G. The innate immune receptor Nod1 protects the intestine from inflammation-induced tumorigenesis. Cancer Res. 68, 10060–10067 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  146. Williams, T. M. et al. The NLRP1 inflammasome attenuates colitis and colitis-associated tumorigenesis. J. Immunol. 194, 3369–3380 (2015).

    CAS  PubMed  Google Scholar 

  147. Normand, S. et al. Nod-like receptor pyrin domain-containing protein 6 (NLRP6) controls epithelial self-renewal and colorectal carcinogenesis upon injury. Proc. Natl Acad. Sci. USA 108, 9601–9606 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  148. Elinav, E. et al. NLRP6 inflammasome regulates colonic microbial ecology and risk for colitis. Cell 145, 745–757 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  149. Wlodarska, M. et al. NLRP6 inflammasome orchestrates the colonic host-microbial interface by regulating goblet cell mucus secretion. Cell 156, 1045–1059 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  150. Hu, B. et al. Microbiota-induced activation of epithelial IL-6 signaling links inflammasome-driven inflammation with transmissible cancer. Proc. Natl Acad. Sci. USA 110, 9862–98670 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  151. Sharma, D. et al. Pyrin inflammasome regulates tight junction integrity to restrict colitis and tumorigenesis. Gastroenterology 154, 948–964.e948 (2018).

    CAS  PubMed  Google Scholar 

  152. Man, S. M. & Kanneganti, T. D. Converging roles of caspases in inflammasome activation, cell death and innate immunity. Nat. Rev. Immunol. 16, 7–21 (2016).

    CAS  PubMed  Google Scholar 

  153. Deswaerte, V. et al. Inflammasome adaptor ASC suppresses apoptosis of gastric cancer cells by an IL18-mediated inflammation-independent mechanism. Cancer Res. 78, 1293–1307 (2018).

    CAS  PubMed  Google Scholar 

  154. Vajjhala, P. R. et al. The inflammasome adaptor ASC induces procaspase-8 death effector domain filaments. J. Biol. Chem. 290, 29217–29230 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  155. Man, S. M. et al. Salmonella infection induces recruitment of caspase-8 to the inflammasome to modulate IL-1beta production. J. Immunol. 191, 5239–5246 (2013).

    CAS  PubMed  Google Scholar 

  156. Gurung, P. et al. FADD and caspase-8 mediate priming and activation of the canonical and noncanonical Nlrp3 inflammasomes. J. Immunol. 192, 1835–1846 (2014).

    CAS  PubMed  Google Scholar 

  157. Karki, R. et al. NLRC3 is an inhibitory sensor of PI3K-mTOR pathways in cancer. Nature 540, 583–587 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  158. Li, X. et al. Viral DNA binding to NLRC3, an inhibitory nucleic acid sensor, unleashes STING, a cyclic dinucleotide receptor that activates type I interferon. Immunity 50, 591–599 e596 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  159. Man, S. M. et al. Critical role for the DNA sensor AIM2 in stem cell proliferation and cancer. Cell 162, 45–58 (2015). This study demonstrates that the AIM2 cytosolic DNA sensor protects against CRC in an inflammasome-independent manner. The antitumour functions of AIM2 involve suppressing the proliferation of tumour-initiating intestinal stem cells by dampening WNT signalling, and is also associated with gut dysbiosis.

    CAS  PubMed  PubMed Central  Google Scholar 

  160. Wilson, J. E. et al. Inflammasome-independent role of AIM2 in suppressing colon tumorigenesis via DNA-PK and Akt. Nat. Med. 21, 906–913 (2015). This study demonstrates that the AIM2 cytosolic DNA sensor protects against CRC in an inflammasome-independent manner. The antitumour functions of AIM2 require inhibition of DNA-dependent protein kinase and the AKT pathway.

    CAS  PubMed  PubMed Central  Google Scholar 

  161. Ahn, J., Konno, H. & Barber, G. N. Diverse roles of STING-dependent signaling on the development of cancer. Oncogene 34, 5302–5308 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  162. Gulen, M. F. et al. Signalling strength determines proapoptotic functions of STING. Nat. Commun. 8, 427 (2017).

    PubMed  PubMed Central  Google Scholar 

  163. Poeck, H. et al. 5′-Triphosphate-siRNA: turning gene silencing and Rig-I activation against melanoma. Nat. Med. 14, 1256–1263 (2008).

    CAS  PubMed  Google Scholar 

  164. Boehmer, D. F. R. et al. OAS1/RNase L executes RIG-I ligand-dependent tumor cell apoptosis. Sci. Immunol. 6, eabe2550 (2021).

    CAS  PubMed  Google Scholar 

  165. Karki, R. et al. Interferon regulatory factor 1 regulates PANoptosis to prevent colorectal cancer. JCI Insight 5, e136720 (2020).

    PubMed Central  Google Scholar 

  166. Karki, R. et al. ADAR1 restricts ZBP1-mediated immune response and PANoptosis to promote tumorigenesis. Cell Rep. 37, 109858 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  167. Malireddi, R. K. S. et al. Inflammatory cell death, panoptosis, mediated by cytokines in diverse cancer lineages inhibits tumor growth. Immunohorizons 5, 568–580 (2021).

    PubMed  Google Scholar 

  168. Farnebo, L. et al. Targeting Toll-like receptor 2 inhibits growth of head and neck squamous cell carcinoma. Oncotarget 6, 9897–9907 (2015).

    PubMed  PubMed Central  Google Scholar 

  169. Pastille, E. et al. Inhibition of TLR4 signaling impedes tumor growth in colitis-associated colon cancer. Front. Immunol. 12, 669747 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  170. Cardillo, F. et al. Bacillus Calmette-Guérin immunotherapy for cancer. Vaccines 9, 439 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  171. Li, J. K., Balic, J. J., Yu, L. & Jenkins, B. TLR agonists as adjuvants for cancer vaccines. Adv. Exp. Med. Biol. 1024, 195–212 (2017).

    CAS  PubMed  Google Scholar 

  172. Goldberg, M. S. Improving cancer immunotherapy through nanotechnology. Nat. Rev. Cancer 19, 587–602 (2019).

    CAS  PubMed  Google Scholar 

  173. Rodell, C. B. et al. TLR7/8-agonist-loaded nanoparticles promote the polarization of tumour- associated macrophages to enhance cancer immunotherapy. Nat. Biomed. Eng. 2, 578–588 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  174. Marquez-Rodas, I. et al. Intratumoral nanoplexed poly I:C BO-112 in combination with systemic anti-PD-1 for patients with anti-PD-1-refractory tumors. Sci. Transl. Med. 12, eabb0391 (2020).

    CAS  PubMed  Google Scholar 

  175. Coll, R. C. et al. MCC950 directly targets the NLRP3 ATP-hydrolysis motif for inflammasome inhibition. Nat. Chem. Biol. 15, 556–559 (2019).

    CAS  PubMed  Google Scholar 

  176. Coll, R. C. et al. A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases. Nat. Med. 21, 248–255 (2015). This is the original description of the development of a first-in-class selective, SMI of NLRP3, MCC950. It also demonstrates the in vivo efficacy of MCC950 in ameliorating disease severity in mouse models for NLRP3-associated autoimmune syndromes.

    CAS  PubMed  PubMed Central  Google Scholar 

  177. Huang, C. F. et al. NLRP3 inflammasome activation promotes inflammation-induced carcinogenesis in head and neck squamous cell carcinoma. J. Exp. Clin. Cancer Res. 36, 116 (2017).

    PubMed  PubMed Central  Google Scholar 

  178. Chen, L. et al. Blockage of the NLRP3 inflammasome by MCC950 improves anti-tumor immune responses in head and neck squamous cell carcinoma. Cell Mol. Life Sci. 75, 2045–2058 (2018).

    CAS  PubMed  Google Scholar 

  179. Hamarsheh, S. & Zeiser, R. NLRP3 inflammasome activation in cancer: a double-edged sword. Front. Immunol. 11, 1444 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  180. El-Sharkawy, L. Y., Brough, D. & Freeman, S. Inhibiting the NLRP3 Inflammasome. Molecules 25, 5533 (2020).

    CAS  PubMed Central  Google Scholar 

  181. Ghiringhelli, F. et al. Activation of the NLRP3 inflammasome in dendritic cells induces IL-1beta-dependent adaptive immunity against tumors. Nat. Med. 15, 1170–1178 (2009). This study demonstrates that in response to chemotherapy, dying tumour cells release ATP, which activates the NLRP3 inflammasome–IL-1β axis via P2X7 purinergic receptors in dendritic cells. The IL-1β released from dendritic cells primes IFNγ-producing cytotoxic CD8+ T cells to activate antitumour immunity, thus unveiling an NLRP3-associated bridge between innate and adaptive immune antitumorigenic responses.

    CAS  PubMed  Google Scholar 

  182. Ridker, P. M. et al. Effect of interleukin-1beta inhibition with canakinumab on incident lung cancer in patients with atherosclerosis: exploratory results from a randomised, double-blind, placebo-controlled trial. Lancet 390, 1833–1842 (2017).

    CAS  PubMed  Google Scholar 

  183. Garlanda, C. & Mantovani, A. Interleukin-1 in tumor progression, therapy, and prevention. Cancer Cell 39, 1023–1027 (2021).

    CAS  PubMed  Google Scholar 

  184. Girard-Guyonvarc’h, C., Harel, M. & Gabay, C. The role of interleukin 18/interleukin 18- binding protein in adult-onset still’s disease and systemic juvenile idiopathic arthritis. J. Clin. Med. 11, 430 (2022).

    PubMed  PubMed Central  Google Scholar 

  185. Geller, A., Shrestha, R. & Yan, J. Yeast-derived beta-glucan in cancer: novel uses of a traditional therapeutic. Int. J. Mol. Sci. 20, 3618 (2019).

    CAS  PubMed Central  Google Scholar 

  186. Su, Y., Chen, L., Yang, F. & Cheung, P. C. K. Beta-d-glucan-based drug delivery system and its potential application in targeting tumor associated macrophages. Carbohydr. Polym. 253, 117258 (2021).

    CAS  PubMed  Google Scholar 

  187. Kortylewski, M. & Moreira, D. Myeloid cells as a target for oligonucleotide therapeutics: turning obstacles into opportunities. Cancer Immunol. Immunother. 66, 979–9882 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  188. Schmidt, F. I. et al. A single domain antibody fragment that recognizes the adaptor ASC defines the role of ASC domains in inflammasome assembly. J. Exp. Med. 213, 771–790 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  189. Lee, S. H. et al. ERK activation drives intestinal tumorigenesis in Apc(min/+) mice. Nat. Med. 16, 665–670 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  190. Huang, L., Xu, H. & Peng, G. TLR-mediated metabolic reprogramming in the tumor microenvironment: potential novel strategies for cancer immunotherapy. Cell Mol. Immunol. 15, 428–437 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  191. Bruchard, M. et al. Chemotherapy-triggered cathepsin B release in myeloid-derived suppressor cells activates the Nlrp3 inflammasome and promotes tumor growth. Nat. Med. 19, 57–64 (2013). This study demonstrates that the chemotherapeutics gemcitabine and 5-fluorouracil activate the NLRP3 inflammasome in MDSCs via the release of cathepsin B from dying cells. The subsequent inflammasome-mediated upregulated production of IL-1β promotes tumour angiogenesis, which negates the antitumour effects of chemotherapy.

    CAS  PubMed  Google Scholar 

  192. Feng, X. et al. The role of NLRP3 inflammasome in 5-fluorouracil resistance of oral squamous cell carcinoma. J. Exp. Clin. Cancer Res. 36, 81 (2017).

    PubMed  PubMed Central  Google Scholar 

  193. Geller, L. T. et al. Potential role of intratumor bacteria in mediating tumor resistance to the chemotherapeutic drug gemcitabine. Science 357, 1156–1160 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  194. Yu, T. et al. Fusobacterium nucleatum promotes chemoresistance to colorectal cancer by modulating autophagy. Cell 170, 548–563 e516 (2017). This study demonstrates that the gut microorganism Fusobacterium nucleatum is abundant in CRC, and promotes resistance to 5-FU chemotherapy by engaging the innate immune TLR4–MyD88 signalling axis and specific microRNAs to activate autophagy in cancer cells.

    CAS  PubMed  PubMed Central  Google Scholar 

  195. Iida, N. et al. Commensal bacteria control cancer response to therapy by modulating the tumor microenvironment. Science 342, 967–970 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  196. Daillere, R. et al. Enterococcus hirae and Barnesiella intestinihominis facilitate cyclophosphamide-induced therapeutic immunomodulatory effects. Immunity 45, 931–943 (2016).

    CAS  PubMed  Google Scholar 

  197. Shiao, S. L. et al. Commensal bacteria and fungi differentially regulate tumor responses to radiation therapy. Cancer Cell 39, 1202–1213 e1206 (2021).

    CAS  PubMed  Google Scholar 

  198. Urban-Wojciuk, Z. et al. The role of TLRs in anti-cancer immunity and tumor rejection. Front. Immunol. 10, 2388 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  199. de Martel, C., Georges, D., Bray, F., Ferlay, J. & Clifford, G. M. Global burden of cancer attributable to infections in 2018: a worldwide incidence analysis. Lancet Glob. Health 8, e180–e190 (2020).

    PubMed  Google Scholar 

  200. Piconese, S., Cammarata, I. & Barnaba, V. Viral hepatitis, inflammation, and cancer: a lesson for autoimmunity. J. Autoimmun. 95, 58–68 (2018).

    CAS  PubMed  Google Scholar 

  201. Wong, S. H. & Yu, J. Gut microbiota in colorectal cancer: mechanisms of action and clinical applications. Nat. Rev. Gastroenterol. Hepatol. 16, 690–704 (2019).

    CAS  PubMed  Google Scholar 

  202. Drexler, S. K. et al. Tissue-specific opposing functions of the inflammasome adaptor ASC in the regulation of epithelial skin carcinogenesis. Proc. Natl Acad. Sci. USA 109, 18384–18389 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  203. Zaki, M. H. et al. The NLRP3 inflammasome protects against loss of epithelial integrity and mortality during experimental colitis. Immunity 32, 379–391 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  204. Dupaul-Chicoine, J. et al. The Nlrp3 inflammasome suppresses colorectal cancer metastatic growth in the liver by promoting natural killer cell tumoricidal activity. Immunity 43, 751–763 (2015).

    CAS  PubMed  Google Scholar 

  205. Zaki, M. H., Vogel, P., Body-Malapel, M., Lamkanfi, M. & Kanneganti, T. D. IL-18 production downstream of the Nlrp3 inflammasome confers protection against colorectal tumor formation. J. Immunol. 185, 4912–4920 (2010). This study demonstrates that the inflammasome is linked to attenuation of the development of cancer. Notably, activation of NLRP3 mediates protection against colitis-associated tumorigenesis via IL-18, a key cytokine which can induce antitumorigenic signalling via IFNγ and STAT1.

    CAS  PubMed  Google Scholar 

  206. Huber, S. et al. IL-22BP is regulated by the inflammasome and modulates tumorigenesis in the intestine. Nature 491, 259–263 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  207. Salcedo, R. et al. MyD88-mediated signaling prevents development of adenocarcinomas of the colon: role of interleukin 18. J. Exp. Med. 207, 1625–1636 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  208. Tu, S. et al. Overexpression of interleukin-1beta induces gastric inflammation and cancer and mobilizes myeloid-derived suppressor cells in mice. Cancer Cell 14, 408–419 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  209. Das, S., Shapiro, B., Vucic, E. A., Vogt, S. & Bar-Sagi, D. Tumor cell-derived IL1beta promotes desmoplasia and immune suppression in pancreatic cancer. Cancer Res. 80, 1088–1101 (2020). This study demonstrates that tumour cell-derived IL-1β promotes the activation and secretory phenotype of quiescent pancreatic stellate cells to establish a tumour-promoting immunosuppressive TME. Notably, IL-1β production is dependent on microbial-driven activation of TLR4 in pancreatic tumours, which subsequently engage the NLRP3 inflammasome, thus revealing crosstalk between TLR and NLR family members to promote immune evasion in cancer.

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors thank R. Smith (Hudson Institute of Medical Research, Melbourne, Australia) for editing the manuscript. B.J.J. is supported by a Senior Research Fellowship from the National Health and Medical Research Council of Australia. S.M.M. is supported by a CSL Centenary Fellowship.

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Authors and Affiliations

  1. Division of Immunity, Inflammation and Infection, The John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia

    Si Ming Man

  2. Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, VIC, Australia

    Brendan J. Jenkins

  3. Department of Molecular and Translational Science, School of Clinical Sciences, Monash University, Clayton, VIC, Australia

    Brendan J. Jenkins

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Glossary

Pattern recognition receptors

(PRRs). Protein receptors expressed on the cell surface or in intracellular compartments (cytosol, nucleus and endosomes) of immune and non-immune cells. They recognize conserved molecular structures in microorganisms (pathogen-associated molecular patterns) or host-derived molecules released by damaged or dying cells (damage-associated molecular patterns).

MyD88

Myeloid differentiation primary response protein 88, a key signalling adaptor protein of members of the Toll-like receptor (TLR) (except TLR3) and IL-1 receptor families.

NLRP3

Nucleotide-binding oligomerization domain (NOD), leucin-rich repeat and pyrin domain-containing 3 (NLRP3), the best characterized pattern recognition receptor protein among the NLRP subfamily of NOD-like receptors for its role in pyroptosis (programmed inflammatory cell death) and inflammation.

Inflammasome

A multiprotein signalling hub comprising absent in melanoma 2 (AIM2), pyrin or nucleotide-binding oligomerization domain-like receptors (NLRC4/NAIP, NLRP1B, NLRP3, NLRP6 and NLRP12) as a sensor, the adaptor protein ASC and the cysteine protease caspase 1, which controls the production of mature, biologically active cytokines IL-1β and IL-18.

cGAS–STING

Cyclic guanosine monophosphate (GMP)–adenosine monophosphate (AMP) synthase (cGAS) is a cytosolic sensor of microbial (viral) and host (nuclear or mitochondrial) DNA, and activates its downstream effector protein stimulator of interferon genes (STING) in immune and non-immune (for example, epithelial cancer) cells to facilitate innate and adaptive immune responses.

Chemical carcinogen

A genotoxic chemical used in mouse models to elicit carcinogenesis in specific tissues, such as azoxymethane in colorectal cancer, 7,12-dimethylbenz[a]anthracene/12-O-tetradecanoylphorbol 13-acetate in skin cancer and diethylnitrosamine in liver cancer. Azoxymethane used with dextran sodium sulfate also induces colitis-associated colorectal cancer.

M2 macrophages

Protumorigenic (alternatively activated) macrophages with activities including production of anti-inflammatory cytokines that create an immunosuppressive tumour microenvironment.

TRIF

TIR domain-containing adaptor protein inducing interferon-β (IFNβ), an adaptor protein of Toll-like receptor 3 (TLR3) and TLR4 that contributes to inducing the production of type I interferons.

M1 macrophage

Classically activated macrophage with antitumour functions, including microbicidal activity and facilitating a T helper 1-type response while simultaneously dampening T helper 2-type responses.

Type I interferon

Polypeptides (for example, interferon-α (IFNα) and IFNβ) secreted by immune and non-immune (for example, tumour) cells that have several functions, including antimicrobial responses, promotion of antigen presentation by innate immune cells and activation of adaptive immunity, incorporating T cell-mediated antitumour immunity.

Senescence-associated secretory phenotype

A network of secreted factors produced by senescent cells, including cytokines, chemokines, growth factors, secreted proteases and non-protein metabolites.

Hypoxia-inducible factor 1α

An evolutionarily conserved transcription factor whose expression increases during hypoxia (low-oxygen condition) and can induce the expression of genes supporting multiple cellular processes, such as cell proliferation, survival and glucose metabolism.

Bacillus Calmette–Guérin

(BCG). Named after its inventors Albert Calmette and Camille Guérin, a live attenuated strain of Mycobacterium bovis comprising Toll-like receptor 2 (TLR2)/TLR4-activating components (for example, peptidoglycans) that is used primarily as a vaccine against tuberculosis.

MCC950

Small-molecule chemical inhibitor (also known as CP-456,773 or CRID3) of NLRP3 that directly binds to the NLRP3 NACHT domain and blocks ATP hydrolysis, inhibiting NLRP3 inflammasome activation.

Canakinumab Anti-inflammatory Thrombosis Outcome Study

(CANTOS). A large, randomized, double-blind trial involving the administration of the IL-1β-blocking antibody canakinumab to patients with atherosclerosis.

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Man, S.M., Jenkins, B.J. Context-dependent functions of pattern recognition receptors in cancer. Nat Rev Cancer 22, 397–413 (2022). https://doi.org/10.1038/s41568-022-00462-5

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