Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Targeting cancer-promoting inflammation — have anti-inflammatory therapies come of age?

Nature Reviews Clinical Oncology volume 18, pages 261–279 (2021)Cite this article

Subjects

Abstract

The immune system has crucial roles in cancer development and treatment. Whereas adaptive immunity can prevent or constrain cancer through immunosurveillance, innate immunity and inflammation often promote tumorigenesis and malignant progression of nascent cancer. The past decade has witnessed the translation of knowledge derived from preclinical studies of antitumour immunity into clinically effective, approved immunotherapies for cancer. By contrast, the successful implementation of treatments that target cancer-associated inflammation is still awaited. Anti-inflammatory agents have the potential to not only prevent or delay cancer onset but also to improve the efficacy of conventional therapeutics and next-generation immunotherapies. Herein, we review the current clinical advances and experimental findings supporting the utility of an anti-inflammatory approach to the treatment of solid malignancies. Gaining a better mechanistic understanding of the mode of action of anti-inflammatory agents and designing more effective treatment combinations would advance the clinical application of this therapeutic approach.

Key points

  • Inflammation-related biological processes influence all stages of cancer development and treatment; environmental risk factors and both tumour-extrinsic and tumour-intrinsic inflammatory processes have been linked to tumour initiation, promotion and progression.

  • Several conventional drugs with anti-inflammatory properties have demonstrated protective effects against cancer but are yet to be deployed in at-risk populations and properly evaluated for therapeutic applicability.

  • Cytokine-specific agents with anti-inflammatory activities have antitumour efficacy in preclinical studies but evidence demonstrating activity against solid tumours in clinical trials is scarce.

  • Preclinical studies have revealed that anti-inflammatory drugs can suppress cancer development through multiple mechanisms.

  • Monotherapy with anti-inflammatory agents can elicit cell adaptability and/or affect tumour evolution in heterogeneous cancer types, leading to therapy resistance or even accelerated disease progression.

  • Overcoming current obstacles to the clinical introduction of anti-inflammatory therapy will require the development of effective combination regimens and the identification of reliable response biomarkers.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Evidence grading for anti-inflammatory agents in cancer prevention.
Fig. 2: Impact of anti-inflammatory agents on oncogenic pathways.
Fig. 3: Approaches to resolving cancer-associated inflammation and normalizing antitumour immunity.
Fig. 4: Potential perils of anti-IL-1β therapy for cancer.

Similar content being viewed by others

References

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

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Grivennikov, S. I., Greten, F. R. & Karin, M. Immunity, inflammation, and cancer. Cell 140, 883–899 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Balkwill, F. & Mantovani, A. Inflammation and cancer: back to Virchow? Lancet 357, 539–545 (2001).

    CAS  PubMed  Google Scholar 

  4. Diakos, C. I., Charles, K. A., McMillan, D. C. & Clarke, S. J. Cancer-related inflammation and treatment effectiveness. Lancet Oncol. 15, e493–e503 (2014).

    PubMed  Google Scholar 

  5. Yang, J. D. et al. A global view of hepatocellular carcinoma: trends, risk, prevention and management. Nat. Rev. Gastroenterol. Hepatol. 16, 589–604 (2019).

    PubMed  PubMed Central  Google Scholar 

  6. Brisson, M. et al. Impact of HPV vaccination and cervical screening on cervical cancer elimination: a comparative modelling analysis in 78 low-income and lower-middle-income countries. Lancet 395, 575–590 (2020).

    PubMed  PubMed Central  Google Scholar 

  7. Bosetti, C., Santucci, C., Gallus, S., Martinetti, M. & La Vecchia, C. Aspirin and the risk of colorectal and other digestive tract cancers: an updated meta-analysis through 2019. Ann. Oncol. 31, 558–568 (2020).

    CAS  PubMed  Google Scholar 

  8. Chapelle, N., Martel, M., Toes-Zoutendijk, E., Barkun, A. N. & Bardou, M. Recent advances in clinical practice: colorectal cancer chemoprevention in the average-risk population. Gut 69, 2244–2255 (2020).

    CAS  PubMed  Google Scholar 

  9. Shi, Y. et al. Targeting LIF-mediated paracrine interaction for pancreatic cancer therapy and monitoring. Nature 569, 131–135 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Calcinotto, A. et al. IL-23 secreted by myeloid cells drives castration-resistant prostate cancer. Nature 559, 363–369 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Ahern, E., Smyth, M. J., Dougall, W. C. & Teng, M. W. L. Roles of the RANKL-RANK axis in antitumour immunity - implications for therapy. Nat. Rev. Clin. Oncol. 15, 676–693 (2018).

    PubMed  Google Scholar 

  12. Quail, D. F. et al. The tumor microenvironment underlies acquired resistance to CSF-1R inhibition in gliomas. Science 352, aad3018 (2016).

    PubMed  PubMed Central  Google Scholar 

  13. Zhang, L. et al. Single-cell analyses inform mechanisms of myeloid-targeted therapies in colon cancer. Cell 181, 442–459.e29 (2020).

    CAS  PubMed  Google Scholar 

  14. Galon, J. & Bruni, D. Tumor immunology and tumor evolution: intertwined histories. Immunity 52, 55–81 (2020).

    CAS  PubMed  Google Scholar 

  15. Shalapour, S. & Karin, M. Pas de deux: control of anti-tumor immunity by cancer-associated inflammation. Immunity 51, 15–26 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  17. Elinav, E. et al. Inflammation-induced cancer: crosstalk between tumours, immune cells and microorganisms. Nat. Rev. Cancer 13, 759–771 (2013).

    CAS  PubMed  Google Scholar 

  18. Fridman, W. H., Zitvogel, L., Sautes-Fridman, C. & Kroemer, G. The immune contexture in cancer prognosis and treatment. Nat. Rev. Clin. Oncol. 14, 717–734 (2017).

    CAS  PubMed  Google Scholar 

  19. Ho, W. J., Jaffee, E. M. & Zheng, L. The tumour microenvironment in pancreatic cancer - clinical challenges and opportunities. Nat. Rev. Clin. Oncol. 17, 527–540 (2020).

    PubMed  PubMed Central  Google Scholar 

  20. Zhong, Z., Sanchez-Lopez, E. & Karin, M. Autophagy, inflammation, and immunity: a troika governing cancer and its treatment. Cell 166, 288–298 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Bruni, D., Angell, H. K. & Galon, J. The immune contexture and Immunoscore in cancer prognosis and therapeutic efficacy. Nat. Rev. Cancer 20, 662–680 (2020).

    CAS  PubMed  Google Scholar 

  22. Cancer Genome Atlas Research Network. Comprehensive and integrative genomic characterization of hepatocellular carcinoma. Cell 169, 1327–1341.e23 (2017).

    Google Scholar 

  23. Chang, M. H. et al. Long-term effects of hepatitis B immunization of infants in preventing liver cancer. Gastroenterology 151, 472–480.e1 (2016).

    CAS  PubMed  Google Scholar 

  24. Yin, J. et al. Effect of antiviral treatment with nucleotide/nucleoside analogs on postoperative prognosis of hepatitis B virus-related hepatocellular carcinoma: a two-stage longitudinal clinical study. J. Clin. Oncol. l31, 3647–3655 (2013).

    Google Scholar 

  25. Huang, G. et al. Antiviral therapy improves postoperative survival in patients with hepatocellular carcinoma: a randomized controlled trial. Ann. Surg. 261, 56–66 (2015).

    PubMed  Google Scholar 

  26. Okamura, Y. et al. The achievement of a sustained virological response either before or after hepatectomy improves the prognosis of patients with primary hepatitis C virus-related hepatocellular carcinoma. Ann. Surg. Oncol. 26, 4566–4575 (2019).

    PubMed  Google Scholar 

  27. Kanwal, F. et al. Risk of hepatocellular cancer in HCV patients treated with direct-acting antiviral agents. Gastroenterology 153, 996–1005.e1 (2017).

    CAS  PubMed  Google Scholar 

  28. Yip, T. C. et al. Impact of age and gender on risk of hepatocellular carcinoma after hepatitis B surface antigen seroclearance. J. Hepatol. 67, 902–908 (2017).

    CAS  PubMed  Google Scholar 

  29. Nahon, P. et al. Incidence of hepatocellular carcinoma after direct antiviral therapy for HCV in patients with cirrhosis included in surveillance programs. Gastroenterology 155, 1436–1450.e6 (2018).

    PubMed  Google Scholar 

  30. Papatheodoridis, G. V. et al. Hepatocellular carcinoma prediction beyond year 5 of oral therapy in a large cohort of Caucasian patients with chronic hepatitis B. J. Hepatol. 72, 1088–1096 (2020).

    CAS  PubMed  Google Scholar 

  31. de Sanjose, S. et al. Human papillomavirus genotype attribution in invasive cervical cancer: a retrospective cross-sectional worldwide study. Lancet Oncol. 11, 1048–1056 (2010).

    PubMed  Google Scholar 

  32. Drolet, M., Benard, E., Perez, N., Brisson, M. & HPV Vaccination Impact Study Group. Population-level impact and herd effects following the introduction of human papillomavirus vaccination programmes: updated systematic review and meta-analysis. Lancet 394, 497–509 (2019).

    PubMed  PubMed Central  Google Scholar 

  33. Lei, J. et al. HPV vaccination and the risk of invasive cervical cancer. N. Engl. J. Med. 383, 1340–1348 (2020).

    CAS  PubMed  Google Scholar 

  34. Munz, C. Latency and lytic replication in Epstein-Barr virus-associated oncogenesis. Nat. Rev. Microbiol. 17, 691–700 (2019).

    CAS  PubMed  Google Scholar 

  35. Choi, I. J. et al. Helicobacter pylori therapy for the prevention of metachronous gastric cancer. N. Engl. J. Med. 378, 1085–1095 (2018).

    CAS  PubMed  Google Scholar 

  36. Wong, B. C. et al. Helicobacter pylori eradication to prevent gastric cancer in a high-risk region of China: a randomized controlled trial. JAMA 291, 187–194 (2004).

    CAS  PubMed  Google Scholar 

  37. Ford, A. C., Forman, D., Hunt, R. H., Yuan, Y. & Moayyedi, P. Helicobacter pylori eradication therapy to prevent gastric cancer in healthy asymptomatic infected individuals: systematic review and meta-analysis of randomised controlled trials. BMJ 348, g3174 (2014).

    PubMed  PubMed Central  Google Scholar 

  38. Li, W. Q. et al. Effects of Helicobacter pylori treatment and vitamin and garlic supplementation on gastric cancer incidence and mortality: follow-up of a randomized intervention trial. BMJ 366, l5016 (2019).

    PubMed  PubMed Central  Google Scholar 

  39. Mima, K. et al. Fusobacterium nucleatum and T cells in colorectal carcinoma. JAMA Oncol. 1, 653–661 (2015).

    PubMed  PubMed Central  Google Scholar 

  40. Yu, T. et al. Fusobacterium nucleatum promotes chemoresistance to colorectal cancer by modulating autophagy. Cell 170, 548–563.e16 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Bullman, S. et al. Analysis of fusobacterium persistence and antibiotic response in colorectal cancer. Science 358, 1443–1448 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Mima, K. et al. Fusobacterium nucleatum in colorectal carcinoma tissue and patient prognosis. Gut 65, 1973–1980 (2016).

    CAS  PubMed  Google Scholar 

  43. Poore, G. D. et al. Microbiome analyses of blood and tissues suggest cancer diagnostic approach. Nature 579, 567–574 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Schulz, M. D. et al. High-fat-diet-mediated dysbiosis promotes intestinal carcinogenesis independently of obesity. Nature 514, 508–512 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Ma, C. et al. Gut microbiome-mediated bile acid metabolism regulates liver cancer via NKT cells. Science 360, eaan5931 (2018).

    PubMed  PubMed Central  Google Scholar 

  46. Helmink, B. A., Khan, M. A. W., Hermann, A., Gopalakrishnan, V. & Wargo, J. A. The microbiome, cancer, and cancer therapy. Nat. Med. 25, 377–388 (2019).

    CAS  PubMed  Google Scholar 

  47. Dong, X. et al. Bioinorganic hybrid bacteriophage for modulation of intestinal microbiota to remodel tumor-immune microenvironment against colorectal cancer. Sci. Adv. 6, eaba1590 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Zhu, F. et al. Autoreactive T cells and chronic fungal infection drive esophageal carcinogenesis. Cell Host Microbe 21, 478–493.e7 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Bibbins-Domingo, K. & U.S. Preventive Services Task Force. Aspirin use for the primary prevention of cardiovascular disease and colorectal cancer: U.S. preventive services task force recommendation statement. Ann. Intern. Med. 164, 836–845 (2016).

    PubMed  Google Scholar 

  50. Khalaf, N. et al. Regular use of aspirin or non-aspirin nonsteroidal anti-inflammatory drugs is not associated with risk of incident pancreatic cancer in two large cohort studies. Gastroenterology 154, 1380–1390.e5 (2018).

    CAS  PubMed  Google Scholar 

  51. Simon, T. G. et al. Association of aspirin with hepatocellular carcinoma and liver-related mortality. N. Engl. J. Med. 382, 1018–1028 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Lee, T. Y. et al. Association of daily aspirin therapy with risk of hepatocellular carcinoma in patients with chronic hepatitis B. JAMA Intern. Med. 179, 633–640 (2019).

    PubMed  PubMed Central  Google Scholar 

  53. Burn, J. et al. Cancer prevention with aspirin in hereditary colorectal cancer (Lynch syndrome), 10-year follow-up and registry-based 20-year data in the CAPP2 study: a double-blind, randomised, placebo-controlled trial. Lancet 395, 1855–1863 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Cao, Y. et al. Population-wide Impact of long-term use of aspirin and the risk for cancer. JAMA Oncol. 2, 762–769 (2016).

    PubMed  PubMed Central  Google Scholar 

  55. Rothwell, P. M. et al. Effect of daily aspirin on risk of cancer metastasis: a study of incident cancers during randomised controlled trials. Lancet 379, 1591–1601 (2012).

    CAS  PubMed  Google Scholar 

  56. Frouws, M. A. et al. Effect of low-dose aspirin use on survival of patients with gastrointestinal malignancies; an observational study. Br. J. Cancer 116, 405–413 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Liao, X. et al. Aspirin use, tumor PIK3CA mutation, and colorectal-cancer survival. N. Engl. J. Med. 367, 1596–1606 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Hamada, T. et al. Aspirin use and colorectal cancer survival according to tumor CD274 (programmed cell death 1 ligand 1) expression status. J. Clin. Oncol. 35, 1836–1844 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Joharatnam-Hogan, N. et al. Aspirin as an adjuvant treatment for cancer: feasibility results from the Add-Aspirin randomised trial. Lancet Gastroenterol. Hepatol. 4, 854–862 (2019).

    PubMed  Google Scholar 

  60. McNeil, J. J. et al. Effect of aspirin on cancer incidence and mortality in older adults. J Natl Cancer Inst. https://doi.org/10.1093/jnci/djaa114 (2020).

    Article  PubMed Central  Google Scholar 

  61. Mahady, S. E. et al. Major GI bleeding in older persons using aspirin: incidence and risk factors in the ASPREE randomised controlled trial. Gut https://doi.org/10.1136/gutjnl-2020-321585 (2020).

    Article  PubMed  Google Scholar 

  62. McNeil, J. J. et al. Effect of aspirin on all-cause mortality in the healthy elderly. N. Engl. J. Med. 379, 1519–1528 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Bertagnolli, M. M. et al. Celecoxib for the prevention of sporadic colorectal adenomas. N. Engl. J. Med. 355, 873–884 (2006).

    CAS  PubMed  Google Scholar 

  64. Arber, N. et al. Celecoxib for the prevention of colorectal adenomatous polyps. N. Engl. J. Med 355, 885–895 (2006).

    CAS  PubMed  Google Scholar 

  65. Baron, J. A. et al. A randomized trial of rofecoxib for the chemoprevention of colorectal adenomas. Gastroenterology 131, 1674–1682 (2006).

    CAS  PubMed  Google Scholar 

  66. Bi, N. et al. Effect of concurrent chemoradiation with celecoxib vs concurrent chemoradiation alone on survival among patients with non-small cell lung cancer with and without cyclooxygenase 2 genetic variants: a phase 2 randomized clinical trial. JAMA Netw. Open 2, e1918070 (2019).

    PubMed  PubMed Central  Google Scholar 

  67. Chalabi, M. et al. Neoadjuvant immunotherapy leads to pathological responses in MMR-proficient and MMR-deficient early-stage colon cancers. Nat. Med. 26, 566–576 (2020).

    CAS  PubMed  Google Scholar 

  68. Zelenay, S. et al. Cyclooxygenase-dependent tumor growth through evasion of immunity. Cell 162, 1257–1270 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Desmedt, C. et al. Potential benefit of intra-operative administration of ketorolac on breast cancer recurrence according to the patient’s body mass index. J. Natl Cancer Inst. 110, 1115–1122 (2018).

    PubMed  Google Scholar 

  70. Felix, A. S. et al. Relationships of tubal ligation to endometrial carcinoma stage and mortality in the NRG oncology/gynecologic oncology group 210 trial. J. Natl Cancer Inst. 107, djv158 (2015).

    PubMed  PubMed Central  Google Scholar 

  71. Chan, A. O. et al. Prevalence of colorectal neoplasm among patients with newly diagnosed coronary artery disease. JAMA 298, 1412–1419 (2007).

    CAS  PubMed  Google Scholar 

  72. Poynter, J. N. et al. Statins and the risk of colorectal cancer. N. Engl. J. Med. 352, 2184–2192 (2005).

    CAS  PubMed  Google Scholar 

  73. Cheung, K. S. et al. Statins reduce the progression of non-advanced adenomas to colorectal cancer: a postcolonoscopy study in 187 897 patients. Gut 68, 1979–1985 (2019).

    CAS  PubMed  Google Scholar 

  74. Bonovas, S., Filioussi, K., Tsavaris, N. & Sitaras, N. M. Statins and cancer risk: a literature-based meta-analysis and meta-regression analysis of 35 randomized controlled trials. J. Clin. Oncol. 24, 4808–4817 (2006).

    CAS  PubMed  Google Scholar 

  75. Dale, K. M., Coleman, C. I., Henyan, N. N., Kluger, J. & White, C. M. Statins and cancer risk: a meta-analysis. JAMA 295, 74–80 (2006).

    CAS  PubMed  Google Scholar 

  76. Bardou, M., Barkun, A. & Martel, M. Effect of statin therapy on colorectal cancer. Gut 59, 1572–1585 (2010).

    CAS  PubMed  Google Scholar 

  77. Cardwell, C. R., Hicks, B. M., Hughes, C. & Murray, L. J. Statin use after colorectal cancer diagnosis and survival: a population-based cohort study. J. Clin. Oncol. 32, 3177–3183 (2014).

    PubMed  Google Scholar 

  78. Hoffmeister, M. et al. Statin use and survival after colorectal cancer: the importance of comprehensive confounder adjustment. J. Natl Cancer Inst. 107, djv045 (2015).

    PubMed  Google Scholar 

  79. Emilsson, L. et al. Examining bias in studies of statin treatment and survival in patients with cancer. JAMA Oncol. 4, 63–70 (2018).

    PubMed  Google Scholar 

  80. El-Serag, H. B., Johnson, M. L., Hachem, C. & Morgana, R. O. Statins are associated with a reduced risk of hepatocellular carcinoma in a large cohort of patients with diabetes. Gastroenterology 136, 1601–1608 (2009).

    CAS  PubMed  Google Scholar 

  81. Tsan, Y. T., Lee, C. H., Wang, J. D. & Chen, P. C. Statins and the risk of hepatocellular carcinoma in patients with hepatitis B virus infection. J. Clin. Oncol. 30, 623–630 (2012).

    PubMed  Google Scholar 

  82. Singh, S., Singh, P. P., Singh, A. G., Murad, M. H. & Sanchez, W. Statins are associated with a reduced risk of hepatocellular cancer: a systematic review and meta-analysis. Gastroenterology 144, 323–332 (2013).

    CAS  PubMed  Google Scholar 

  83. Tsan, Y. T. et al. Statins and the risk of hepatocellular carcinoma in patients with hepatitis C virus infection. J. Clin. Oncol. 31, 1514–1521 (2013).

    PubMed  Google Scholar 

  84. Bonovas, S., Nikolopoulos, G. & Sitaras, N. M. Statins and reduced risk of hepatocellular carcinoma in patients with hepatitis C virus infection: further evidence is warranted. J. Clin. Oncol. 31, 4160 (2013).

    PubMed  Google Scholar 

  85. Simon, T. G., Bonilla, H., Yan, P., Chung, R. T. & Butt, A. A. Atorvastatin and fluvastatin are associated with dose-dependent reductions in cirrhosis and hepatocellular carcinoma, among patients with hepatitis C virus: Results from ERCHIVES. Hepatology 64, 47–57 (2016).

    CAS  PubMed  Google Scholar 

  86. Kim, G., Jang, S. Y., Nam, C. M. & Kang, E. S. Statin use and the risk of hepatocellular carcinoma in patients at high risk: a nationwide nested case-control study. J. Hepatol. 68, 476–484 (2018).

    CAS  PubMed  Google Scholar 

  87. Simon, T. G. et al. Lipophilic Statins and risk for hepatocellular carcinoma and death in patients with chronic viral hepatitis: results from a nationwide Swedish population. Ann. Intern. Med. 171, 318–327 (2019).

    PubMed  PubMed Central  Google Scholar 

  88. Singh, P. P. & Singh, S. Statins are associated with reduced risk of gastric cancer: a systematic review and meta-analysis. Ann. Oncol. 24, 1721–1730 (2013).

    CAS  PubMed  Google Scholar 

  89. Shlomai, G., Neel, B., LeRoith, D. & Gallagher, E. J. Type 2 diabetes mellitus and cancer: the role of pharmacotherapy. J. Clin. Oncol. 34, 4264–4269 (2016).

    Google Scholar 

  90. Singh, S., Singh, P. P., Singh, A. G., Murad, M. H. & Sanchez, W. Anti-diabetic medications and the risk of hepatocellular cancer: a systematic review and meta-analysis. Am. J. Gastroenterol. 108, 881–891 (2013).

    CAS  PubMed  Google Scholar 

  91. Singh, S., Singh, P. P., Roberts, L. R. & Sanchez, W. Chemopreventive strategies in hepatocellular carcinoma. Nat. Rev. Gastroenterol. Hepatol. 11, 45–54 (2014).

    CAS  PubMed  Google Scholar 

  92. Llovet, J. M. et al. Hepatocellular carcinoma. Nat. Rev. Dis. Primers 2, 16018 (2016).

    PubMed  Google Scholar 

  93. Higurashi, T. et al. Metformin for chemoprevention of metachronous colorectal adenoma or polyps in post-polypectomy patients without diabetes: a multicentre double-blind, placebo-controlled, randomised phase 3 trial. Lancet Oncol. 17, 475–483 (2016).

    CAS  PubMed  Google Scholar 

  94. Foretz, M., Guigas, B. & Viollet, B. Understanding the glucoregulatory mechanisms of metformin in type 2 diabetes mellitus. Nat. Rev. Endocrinol. 15, 569–589 (2019).

    CAS  PubMed  Google Scholar 

  95. Vancura, A., Bu, P., Bhagwat, M., Zeng, J. & Vancurova, I. Metformin as an anticancer agent. Trends Pharmacol. Sci. 39, 867–878 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Petrera, M. et al. The ASAMET trial: a randomized, phase II, double-blind, placebo-controlled, multicenter, 2×2 factorial biomarker study of tertiary prevention with low-dose aspirin and metformin in stage I-III colorectal cancer patients. BMC Cancer 18, 1210 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Arrieta, O. et al. Effect of metformin plus tyrosine kinase inhibitors compared with tyrosine kinase inhibitors alone in patients with epidermal growth factor receptor-mutated lung adenocarcinoma: a phase 2 randomized clinical trial. JAMA Oncol. 5, e192553 (2019).

    PubMed Central  PubMed  Google Scholar 

  98. 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 

  99. Hong, D. S. et al. MABp1, a first-in-class true human antibody targeting interleukin-1alpha in refractory cancers: an open-label, phase 1 dose-escalation and expansion study. Lancet Oncol. 15, 656–666 (2014).

    CAS  PubMed  Google Scholar 

  100. Hickish, T. et al. MABp1 as a novel antibody treatment for advanced colorectal cancer: a randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol. 18, 192–201 (2017).

    CAS  PubMed  Google Scholar 

  101. Madhusudan, S. et al. Study of etanercept, a tumor necrosis factor-alpha inhibitor, in recurrent ovarian cancer. J. Clin. Oncol. 23, 5950–5959 (2005).

    CAS  PubMed  Google Scholar 

  102. Monk, J. P. et al. Assessment of tumor necrosis factor alpha blockade as an intervention to improve tolerability of dose-intensive chemotherapy in cancer patients. J. Clin. Oncol. 24, 1852–1859 (2006).

    CAS  PubMed  Google Scholar 

  103. Harrison, M. L. et al. Tumor necrosis factor alpha as a new target for renal cell carcinoma: two sequential phase II trials of infliximab at standard and high dose. J. Clin. Oncol. 25, 4542–4549 (2007).

    CAS  PubMed  Google Scholar 

  104. Larkin, J. M. et al. A phase I/II trial of sorafenib and infliximab in advanced renal cell carcinoma. Br. J. Cancer 103, 1149–1153 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Brown, E. R. et al. A clinical study assessing the tolerability and biological effects of infliximab, a TNF-alpha inhibitor, in patients with advanced cancer. Ann. Oncol. 19, 1340–1346 (2008).

    CAS  PubMed  Google Scholar 

  106. Postow, M. A., Sidlow, R. & Hellmann, M. D. Immune-related adverse events associated with immune checkpoint blockade. N. Engl. J. Med. 378, 158–168 (2018).

    CAS  PubMed  Google Scholar 

  107. Brahmer, J. R. et al. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: american society of clinical oncology clinical practice guideline. J. Clin. Oncol. 36, 1714–1768 (2018).

    CAS  PubMed  Google Scholar 

  108. Perez-Ruiz, E. et al. Prophylactic TNF blockade uncouples efficacy and toxicity in dual CTLA-4 and PD-1 immunotherapy. Nature 569, 428–432 (2019).

    CAS  PubMed  Google Scholar 

  109. 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 

  110. Johnson, D. E., O’Keefe, R. A. & Grandis, J. R. Targeting the IL-6/JAK/STAT3 signalling axis in cancer. Nat. Rev. Clin. Oncol. 15, 234–248 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Kang, S., Tanaka, T., Narazaki, M. & Kishimoto, T. Targeting interleukin-6 signaling in clinic. Immunity 50, 1007–1023 (2019).

    CAS  PubMed  Google Scholar 

  112. Shah, N. N. & Fry, T. J. Mechanisms of resistance to CAR T cell therapy. Nat. Rev. Clin. Oncol. 16, 372–385 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Rodon, J. et al. First-in-human dose study of the novel transforming growth factor-beta receptor I kinase inhibitor LY2157299 monohydrate in patients with advanced cancer and glioma. Clin. Cancer Res. 21, 553–560 (2015).

    CAS  PubMed  Google Scholar 

  114. Melisi, D. et al. Galunisertib plus gemcitabine vs. gemcitabine for first-line treatment of patients with unresectable pancreatic cancer. Br. J. Cancer 119, 1208–1214 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Kelley, R. K. et al. A phase 2 study of galunisertib (TGF-beta1 receptor type i inhibitor) and sorafenib in patients with advanced hepatocellular carcinoma. Clin. Transl. Gastroenterol. 10, e00056 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Batlle, E. & Massagué, J. Transforming growth factor-beta signaling in immunity and cancer. Immunity 50, 924–940 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Papadopoulos, K. P. et al. First-in-human study of AMG 820, a monoclonal anti-colony-stimulating factor 1 receptor antibody, in patients with advanced solid tumors. Clin. Cancer Res. 23, 5703–5710 (2017).

    CAS  PubMed  Google Scholar 

  118. Gomez-Roca, C. A. et al. Phase I study of emactuzumab single agent or in combination with paclitaxel in patients with advanced/metastatic solid tumors reveals depletion of immunosuppressive M2-like macrophages. Ann. Onco l30, 1381–1392 (2019).

    Google Scholar 

  119. Nywening, T. M. et al. Targeting tumour-associated macrophages with CCR2 inhibition in combination with FOLFIRINOX in patients with borderline resectable and locally advanced pancreatic cancer: a single-centre, open-label, dose-finding, non-randomised, phase 1b trial. Lancet Oncol. 17, 651–662 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Halama, N. et al. Tumoral immune cell exploitation in colorectal cancer metastases can be targeted effectively by Anti-CCR5 therapy in cancer patients. Cancer Cell 29, 587–601 (2016).

    CAS  PubMed  Google Scholar 

  121. DeNardo, D. G. & Ruffell, B. Macrophages as regulators of tumour immunity and immunotherapy. Nat. Rev. Immunol. 19, 369–382 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. Bockorny, B. et al. BL-8040, a CXCR4 antagonist, in combination with pembrolizumab and chemotherapy for pancreatic cancer: the COMBAT trial. Nat. Med. 26, 878–885 (2020).

    CAS  PubMed  Google Scholar 

  123. Ngo, B., Van Riper, J. M., Cantley, L. C. & Yun, J. Targeting cancer vulnerabilities with high-dose vitamin C. Nat. Rev. Cancer 19, 271–282 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  124. Zitvogel, L., Pietrocola, F. & Kroemer, G. Nutrition, inflammation and cancer. Nat. Immunol. 18, 843–850 (2017).

    CAS  PubMed  Google Scholar 

  125. Feldman, D., Krishnan, A. V., Swami, S., Giovannucci, E. & Feldman, B. J. The role of vitamin D in reducing cancer risk and progression. Nat. Rev. Cancer 14, 342–357 (2014).

    CAS  PubMed  Google Scholar 

  126. Shui, I. M. et al. Vitamin D-related genetic variation, plasma vitamin D, and risk of lethal prostate cancer: a prospective nested case-control study. J. Natl Cancer Inst. 104, 690–699 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. Ma, Y. et al. Association between vitamin D and risk of colorectal cancer: a systematic review of prospective studies. J. Clin. Oncol. 29, 3775–3782 (2011).

    CAS  PubMed  Google Scholar 

  128. Yuan, C. et al. Plasma 25-hydroxyvitamin D levels and survival in patients with advanced or metastatic colorectal cancer: findings from CALGB/SWOG 80405 (Alliance). Clin. Cancer Res. 25, 7497–7505 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  129. Borchmann, S. et al. Pretreatment vitamin D deficiency is associated with impaired progression-free and overall survival in Hodgkin lymphoma. J. Clin. Oncol. 37, 3528–3537 (2019).

    CAS  PubMed  Google Scholar 

  130. Lappe, J. et al. Effect of vitamin D and calcium supplementation on cancer incidence in older women: a randomized clinical trial. JAMA 317, 1234–1243 (2017).

    CAS  PubMed  Google Scholar 

  131. Manson, J. E. et al. Vitamin D supplements and prevention of cancer and cardiovascular disease. N. Engl. J. Med. 380, 33–44 (2019).

    CAS  PubMed  Google Scholar 

  132. Zhang, Y. et al. Association between vitamin D supplementation and mortality: systematic review and meta-analysis. BMJ 366, l4673 (2019).

    PubMed  PubMed Central  Google Scholar 

  133. Ng, K. et al. Effect of high-dose vs standard-dose vitamin D3 supplementation on progression-free survival among patients with advanced or metastatic colorectal cancer: the SUNSHINE randomized clinical trial. JAMA 321, 1370–1379 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. Urashima, M. et al. Effect of vitamin D supplementation on relapse-free survival among patients with digestive tract cancers: the AMATERASU randomized clinical trial. JAMA 321, 1361–1369 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  135. Grover, S. et al. Vitamin D intake is associated with decreased risk of immune checkpoint inhibitor-induced colitis. Cancer 126, 3758–3767 (2020).

    CAS  PubMed  Google Scholar 

  136. Manson, J. E. et al. Marine n-3 fatty acids and prevention of cardiovascular disease and cancer. N. Engl. J. Med. 380, 23–32 (2019).

    CAS  PubMed  Google Scholar 

  137. Song, M. et al. Effect of supplementation with marine omega-3 fatty acid on risk of colorectal adenomas and serrated polyps in the US general population: a prespecified ancillary study of a randomized clinical trial. JAMA Oncol. 6, 108–115 (2019).

    PubMed Central  Google Scholar 

  138. Hull, M. A. et al. Eicosapentaenoic acid and aspirin, alone and in combination, for the prevention of colorectal adenomas (seAFOod Polyp Prevention trial): a multicentre, randomised, double-blind, placebo-controlled, 2×2 factorial trial. Lancet 392, 2583–2594 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  139. Ebbing, M. et al. Cancer incidence and mortality after treatment with folic acid and vitamin B12. JAMA 302, 2119–2126 (2009).

    CAS  PubMed  Google Scholar 

  140. Martinez, M. E., Jacobs, E. T., Baron, J. A., Marshall, J. R. & Byers, T. Dietary supplements and cancer prevention: balancing potential benefits against proven harms. J. Natl Cancer Inst. 104, 732–739 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  141. Vollset, S. E. et al. Effects of folic acid supplementation on overall and site-specific cancer incidence during the randomised trials: meta-analyses of data on 50,000 individuals. Lancet 381, 1029–1036 (2013).

    CAS  PubMed  Google Scholar 

  142. Fortmann, S. P., Burda, B. U., Senger, C. A., Lin, J. S. & Whitlock, E. P. Vitamin and mineral supplements in the primary prevention of cardiovascular disease and cancer: an updated systematic evidence review for the U.S. Preventive Services Task Force. Ann. Intern. Med. 159, 824–834 (2013).

    PubMed  Google Scholar 

  143. Ambrosone, C. B. et al. Dietary supplement use during chemotherapy and survival outcomes of patients with breast cancer enrolled in a cooperative group clinical trial (SWOG S0221). J. Clin. Oncol. 38, 804–814 (2020).

    CAS  PubMed  Google Scholar 

  144. Chen, Y. X. et al. Berberine versus placebo for the prevention of recurrence of colorectal adenoma: a multicentre, double-blinded, randomised controlled study. Lancet Gastroenterol. Hepatol. 5, 267–275 (2020).

    PubMed  Google Scholar 

  145. Kern, M. A. et al. Proapoptotic and antiproliferative potential of selective cyclooxygenase-2 inhibitors in human liver tumor cells. Hepatology 36, 885–894 (2002).

    CAS  PubMed  Google Scholar 

  146. Xia, D., Wang, D., Kim, S. H., Katoh, H. & DuBois, R. N. Prostaglandin E2 promotes intestinal tumor growth via DNA methylation. Nat. Med. 18, 224–226 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  147. Pribluda, A. et al. A senescence-inflammatory switch from cancer-inhibitory to cancer-promoting mechanism. Cancer Cell 24, 242–256 (2013).

    CAS  PubMed  Google Scholar 

  148. Kim, H. B. et al. Prostaglandin E2 Activates YAP and a positive-signaling loop to promote colon regeneration after colitis but also carcinogenesis in mice. Gastroenterology 152, 616–630 (2017).

    CAS  PubMed  Google Scholar 

  149. Sutter, A. P. et al. Cell cycle arrest and apoptosis induction in hepatocellular carcinoma cells by HMG-CoA reductase inhibitors. Synergistic antiproliferative action with ligands of the peripheral benzodiazepine receptor. J. Hepatol. 43, 808–816 (2005).

    CAS  PubMed  Google Scholar 

  150. Yang, P. M. et al. Inhibition of autophagy enhances anticancer effects of atorvastatin in digestive malignancies. Cancer Res. 70, 7699–7709 (2010).

    CAS  PubMed  Google Scholar 

  151. Cao, Z. et al. MYC phosphorylation, activation, and tumorigenic potential in hepatocellular carcinoma are regulated by HMG-CoA reductase. Cancer Res. 71, 2286–2297 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  152. Miao, Z. F. et al. A metformin-responsive metabolic pathway controls distinct steps in gastric progenitor fate decisions and maturation. Cell Stem Cell 26, 910–925.e6 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  153. Ben Sahra, I. et al. The antidiabetic drug metformin exerts an antitumoral effect in vitro and in vivo through a decrease of cyclin D1 level. Oncogene 27, 3576–3586 (2008).

    PubMed  Google Scholar 

  154. Hirsch, H. A., Iliopoulos, D. & Struhl, K. Metformin inhibits the inflammatory response associated with cellular transformation and cancer stem cell growth. Proc. Natl Acad. Sci. USA 110, 972–977 (2013).

    CAS  PubMed  Google Scholar 

  155. Wu, D. et al. Glucose-regulated phosphorylation of TET2 by AMPK reveals a pathway linking diabetes to cancer. Nature 559, 637–641 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  156. Yuan, H. et al. SETD2 restricts prostate cancer metastasis by integrating EZH2 and AMPK signaling pathways. Cancer Cell 38, 350–365.e7 (2020).

    PubMed  Google Scholar 

  157. Elgendy, M. et al. Combination of hypoglycemia and metformin impairs tumor metabolic plasticity and growth by modulating the PP2A-GSK3beta-MCL-1 axis. Cancer Cell 35, 798–815.e5 (2019).

    CAS  PubMed  Google Scholar 

  158. Sakurai, T. et al. Hepatocyte necrosis induced by oxidative stress and IL-1 alpha release mediate carcinogen-induced compensatory proliferation and liver tumorigenesis. Cancer Cell 14, 156–165 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  159. Naugler, W. E. & Karin, M. The wolf in sheep’s clothing: the role of interleukin-6 in immunity, inflammation and cancer. Trends Mol. Med. 14, 109–119 (2008).

    CAS  PubMed  Google Scholar 

  160. Tan, W. et al. Tumour-infiltrating regulatory T cells stimulate mammary cancer metastasis through RANKL-RANK signalling. Nature 470, 548–553 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  161. Kuan, E. L. & Ziegler, S. F. A tumor-myeloid cell axis, mediated via the cytokines IL-1alpha and TSLP, promotes the progression of breast cancer. Nat. Immunol. 19, 366–374 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  162. Rubin, J. B. et al. A small-molecule antagonist of CXCR4 inhibits intracranial growth of primary brain tumors. Proc. Natl Acad. Sci. USA 100, 13513–13518 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  163. Klein, S. et al. CXCR4 promotes neuroblastoma growth and therapeutic resistance through miR-15a/16-1-mediated ERK and BCL2/cyclin D1 pathways. Cancer Res. 78, 1471–1483 (2018).

    CAS  PubMed  Google Scholar 

  164. Tong, M. et al. Efficacy of annexin A3 blockade in sensitizing hepatocellular carcinoma to sorafenib and regorafenib. J. Hepatol. 69, 826–839 (2018).

    CAS  PubMed  Google Scholar 

  165. Cooper, J. & Giancotti, F. G. Integrin signaling in cancer: mechanotransduction, stemness, epithelial plasticity, and therapeutic resistance. Cancer Cell 35, 347–367 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  166. Zhang, Z. et al. Tumor microenvironment-derived NRG1 promotes antiandrogen resistance in prostate cancer. Cancer Cell 38, 279–296.e9 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  167. Maeda, S., Kamata, H., Luo, J. L., Leffert, H. & Karin, M. IKKbeta couples hepatocyte death to cytokine-driven compensatory proliferation that promotes chemical hepatocarcinogenesis. Cell 121, 977–990 (2005).

    CAS  PubMed  Google Scholar 

  168. Yuan, D. et al. Kupffer cell-derived Tnf triggers cholangiocellular tumorigenesis through JNK due to chronic mitochondrial dysfunction and ROS. Cancer Cell 31, 771–789.e6 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  169. Ma, C. et al. NAFLD causes selective CD4+ T lymphocyte loss and promotes hepatocarcinogenesis. Nature 531, 253–257 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  170. Gomes, A. L. et al. Metabolic inflammation-associated IL-17A causes non-alcoholic steatohepatitis and hepatocellular carcinoma. Cancer Cell 30, 161–175 (2016).

    CAS  PubMed  Google Scholar 

  171. Ma, H. Y. et al. IL-17 signaling in steatotic hepatocytes and macrophages promotes hepatocellular carcinoma in alcohol-related liver disease. J. Hepatol. 72, 946–959 (2020).

    CAS  PubMed  Google Scholar 

  172. 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).

    CAS  PubMed  Google Scholar 

  173. Boire, A. et al. Complement component 3 adapts the cerebrospinal fluid for leptomeningeal metastasis. Cell 168, 1101–1113.e13 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  174. Jacobetz, M. A. et al. Hyaluronan impairs vascular function and drug delivery in a mouse model of pancreatic cancer. Gut 62, 112–120 (2013).

    CAS  PubMed  Google Scholar 

  175. Ramanathan, R. K. et al. Phase IB/II randomized study of FOLFIRINOX plus pegylated recombinant human hyaluronidase versus FOLFIRINOX alone in patients with metastatic pancreatic adenocarcinoma: SWOG S1313. J. Clin. Oncol. 37, 1062–1069 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  176. Mantovani, A., Marchesi, F., Malesci, A., Laghi, L. & Allavena, P. Tumour-associated macrophages as treatment targets in oncology. Nat. Rev. Clin. Oncol. 14, 399–416 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  177. Pyonteck, S. M. et al. CSF-1R inhibition alters macrophage polarization and blocks glioma progression. Nat. Med. 19, 1264–1272 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  178. Wu, S. Y. et al. Nicotine promotes brain metastasis by polarizing microglia and suppressing innate immune function. J. Exp. Med. 217, e20191131 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  179. Xu, J. et al. CSF1R signaling blockade stanches tumor-infiltrating myeloid cells and improves the efficacy of radiotherapy in prostate cancer. Cancer Res. 73, 2782–2794 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  180. Escamilla, J. et al. CSF1 receptor targeting in prostate cancer reverses macrophage-mediated resistance to androgen blockade therapy. Cancer Res. 75, 950–962 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  181. Salvagno, C. et al. Therapeutic targeting of macrophages enhances chemotherapy efficacy by unleashing type I interferon response. Nat. Cell Biol. 21, 511–521 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  182. Bonavita, E. et al. PTX3 is an extrinsic oncosuppressor regulating complement-dependent inflammation in cancer. Cell 160, 700–714 (2015).

    CAS  PubMed  Google Scholar 

  183. Singh, N. et al. Activation of Gpr109a, receptor for niacin and the commensal metabolite butyrate, suppresses colonic inflammation and carcinogenesis. Immunity 40, 128–139 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  184. Tuting, T. & de Visser, K. E. Cancer. How neutrophils promote metastasis. Science 352, 145–146 (2016).

    PubMed  Google Scholar 

  185. Jaillon, S. et al. Neutrophil diversity and plasticity in tumour progression and therapy. Nat. Rev. Cancer 20, 485–503 (2020).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  187. Coffelt, S. B. et al. IL-17-producing gammadelta T cells and neutrophils conspire to promote breast cancer metastasis. Nature 522, 345–348 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  188. Wculek, S. K. & Malanchi, I. Neutrophils support lung colonization of metastasis-initiating breast cancer cells. Nature 528, 413–417 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  189. Albrengues, J. et al. Neutrophil extracellular traps produced during inflammation awaken dormant cancer cells in mice. Science 361, eaao4227 (2018).

    PubMed  PubMed Central  Google Scholar 

  190. Yang, L. et al. DNA of neutrophil extracellular traps promotes cancer metastasis via CCDC25. Nature 583, 133–138 (2020).

    CAS  PubMed  Google Scholar 

  191. Chen, X. & Song, E. Turning foes to friends: targeting cancer-associated fibroblasts. Nat. Rev. Drug Discov. 18, 99–115 (2019).

    CAS  PubMed  Google Scholar 

  192. Yoshimoto, S. et al. Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome. Nature 499, 97–101 (2013).

    CAS  PubMed  Google Scholar 

  193. Stone, R. L. et al. Paraneoplastic thrombocytosis in ovarian cancer. N. Engl. J. Med. 366, 610–618 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  194. Sitia, G. et al. Antiplatelet therapy prevents hepatocellular carcinoma and improves survival in a mouse model of chronic hepatitis B. Proc. Natl Acad. Sci. USA 109, E2165–E2172 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  195. Malehmir, M. et al. Platelet GPIbα is a mediator and potential interventional target for NASH and subsequent liver cancer. Nat. Med. 25, 641–655 (2019).

    CAS  PubMed  Google Scholar 

  196. Bottcher, J. P. et al. NK cells stimulate recruitment of cdc1 into the tumor microenvironment promoting cancer immune control. Cell 172, 1022–1037.e14 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  197. Loo, T. M. et al. Gut microbiota promotes obesity-associated liver cancer through PGE2-mediated suppression of antitumor immunity. Cancer Discov. 7, 522–538 (2017).

    CAS  PubMed  Google Scholar 

  198. Larsson, K. et al. COX/mPGES-1/PGE2 pathway depicts an inflammatory-dependent high-risk neuroblastoma subset. Proc. Natl Acad. Sci. USA 112, 8070–8075 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  199. Li, L. et al. Metformin-induced reduction of CD39 and CD73 blocks myeloid-derived suppressor cell activity in patients with ovarian cancer. Cancer Res. 78, 1779–1791 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  200. Cha, J. H. et al. Metformin promotes antitumor immunity via endoplasmic-reticulum-associated degradation of PD-L1. Mol. Cell 71, 606–620.e7 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  201. Wang, S. et al. Low-dose metformin reprograms the tumor immune microenvironment in human esophageal cancer: results of a phase II clinical trial. Clin Cancer Res. 26, 4921–4932 (2020).

    CAS  PubMed  Google Scholar 

  202. Yang, W. et al. Potentiating the antitumour response of CD8+ T cells by modulating cholesterol metabolism. Nature 531, 651–655 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  203. Ma, X. et al. Cholesterol induces CD8+ T cell exhaustion in the tumor microenvironment. Cell Metab. 30, 143–156.e5 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  204. Rachidi, S. et al. Platelets subvert T cell immunity against cancer via GARP-TGFβ axis. Sci. Immunol. 2, eaai791 (2017).

    Google Scholar 

  205. Ries, C. H. et al. Targeting tumor-associated macrophages with anti-CSF-1R antibody reveals a strategy for cancer therapy. Cancer Cell 25, 846–859 (2014).

    CAS  PubMed  Google Scholar 

  206. Zhu, Y. et al. CSF1/CSF1R blockade reprograms tumor-infiltrating macrophages and improves response to T-cell checkpoint immunotherapy in pancreatic cancer models. Cancer Res. 74, 5057–5069 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  207. Marigo, I. et al. T cell cancer therapy requires CD40-CD40L activation of tumor necrosis factor and inducible nitric-oxide-synthase-producing dendritic cells. Cancer Cell 30, 377–390 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  208. Zhu, Y. et al. Disruption of tumour-associated macrophage trafficking by the osteopontin-induced colony-stimulating factor-1 signalling sensitises hepatocellular carcinoma to anti-PD-L1 blockade. Gut 68, 1653–1666 (2019).

    CAS  PubMed  Google Scholar 

  209. Su, S. et al. Immune checkpoint inhibition overcomes ADCP-induced immunosuppression by macrophages. Cell 175, 442–457.e23 (2018).

    CAS  PubMed  Google Scholar 

  210. Kaplanov, I. et al. Blocking IL-1beta reverses the immunosuppression in mouse breast cancer and synergizes with anti-PD-1 for tumor abrogation. Proc. Natl Acad. Sci. USA 116, 1361–1369 (2019).

    CAS  PubMed  Google Scholar 

  211. Lu, X. et al. Effective combinatorial immunotherapy for castration-resistant prostate cancer. Nature 543, 728–732 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  212. Liao, W. et al. KRAS-IRF2 axis drives immune suppression and immune therapy resistance in colorectal cancer. Cancer Cell 35, 559–572.e7 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  213. Highfill, S. L. et al. Disruption of CXCR2-mediated MDSC tumor trafficking enhances anti-PD1 efficacy. Sci. Transl. Med. 6, 237ra267 (2014).

    Google Scholar 

  214. Greene, S. et al. Inhibition of MDSC Trafficking with SX-682, a CXCR1/2 inhibitor, enhances NK-cell immunotherapy in head and neck cancer models. Clin. Cancer Res. 26, 1420–1431 (2020).

    CAS  PubMed  Google Scholar 

  215. 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 

  216. Wu, P. et al. γδT17 cells promote the accumulation and expansion of myeloid-derived suppressor cells in human colorectal cancer. Immunity 40, 785–800 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  217. Kortlever, R. M. et al. Myc cooperates with ras by programming inflammation and immune suppression. Cell 171, 1301–1315.e14 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  218. Markiewski, M. M. et al. Modulation of the antitumor immune response by complement. Nat. Immunol. 9, 1225–1235 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  219. Medler, T. R. et al. Complement C5a fosters squamous carcinogenesis and limits T cell response to chemotherapy. Cancer Cell 34, 561–578.e6 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  220. Ajona, D. et al. A combined PD-1/C5a blockade synergistically protects against lung cancer growth and metastasis. Cancer Discov. 7, 694–703 (2017).

    CAS  PubMed  Google Scholar 

  221. Reis, E. S., Mastellos, D. C., Ricklin, D., Mantovani, A. & Lambris, J. D. Complement in cancer: untangling an intricate relationship. Nat. Rev. Immunol. 18, 5–18 (2018).

    CAS  PubMed  Google Scholar 

  222. Feng, M. et al. Phagocytosis checkpoints as new targets for cancer immunotherapy. Nat. Rev. Cancer 19, 568–586 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  223. Shalapour, S. et al. Immunosuppressive plasma cells impede T-cell-dependent immunogenic chemotherapy. Nature 521, 94–98 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  224. Shalapour, S. et al. Inflammation-induced IgA+ cells dismantle anti-liver cancer immunity. Nature 551, 340–345 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  225. Daley, D. et al. γδ T cells support pancreatic oncogenesis by restraining alphabeta T cell activation. Cell 166, 1485–1499.e15 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  226. Gao, Y. et al. Tumor immunoevasion by the conversion of effector NK cells into type 1 innate lymphoid cells. Nat. Immunol. 18, 1004–1015 (2017).

    CAS  PubMed  Google Scholar 

  227. Yan, J. et al. MAIT cells promote tumor initiation, growth, and metastases via tumor MR1. Cancer Discov. 10, 124–141 (2020).

    CAS  PubMed  Google Scholar 

  228. Chen, Y. et al. CXCR4 inhibition in tumor microenvironment facilitates anti-programmed death receptor-1 immunotherapy in sorafenib-treated hepatocellular carcinoma in mice. Hepatology 61, 1591–1602 (2015).

    CAS  PubMed  Google Scholar 

  229. Jiang, H. et al. Targeting focal adhesion kinase renders pancreatic cancers responsive to checkpoint immunotherapy. Nat. Med. 22, 851–860 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  230. Xiao, Q. et al. DKK2 imparts tumor immunity evasion through beta-catenin-independent suppression of cytotoxic immune-cell activation. Nat. Med. 24, 262–270 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  231. Giavridis, T. et al. CAR T cell-induced cytokine release syndrome is mediated by macrophages and abated by IL-1 blockade. Nat. Med. 24, 731–738 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  232. Martin, M. J., Hayward, R., Viros, A. & Marais, R. Metformin accelerates the growth of BRAF V600E-driven melanoma by upregulating VEGF-A. Cancer Discov. 2, 344–355 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  233. Umemura, A. et al. Liver damage, inflammation, and enhanced tumorigenesis after persistent mTORC1 inhibition. Cell Metab. 20, 133–144 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  234. Coll, A. P. et al. GDF15 mediates the effects of metformin on body weight and energy balance. Nature 578, 444–448 (2020).

    CAS  PubMed  Google Scholar 

  235. Suriben, R. et al. Antibody-mediated inhibition of GDF15-GFRAL activity reverses cancer cachexia in mice. Nat. Med. 26, 1264–1270 (2020).

    PubMed  Google Scholar 

  236. Gabitova-Cornell, L. et al. Cholesterol pathway inhibition induces TGF-beta signaling to promote basal differentiation in pancreatic cancer. Cancer Cell 38, 567–583.e11 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  237. Obradovic, M. M. S. et al. Glucocorticoids promote breast cancer metastasis. Nature 567, 540–544 (2019).

    CAS  PubMed  Google Scholar 

  238. Wagenblast, E. et al. A model of breast cancer heterogeneity reveals vascular mimicry as a driver of metastasis. Nature 520, 358–362 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  239. 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).

    CAS  PubMed  Google Scholar 

  240. Vegran, F. et al. The transcription factor IRF1 dictates the IL-21-dependent anticancer functions of TH9 cells. Nat. Immunol. 15, 758–766 (2014).

    CAS  PubMed  Google Scholar 

  241. Dmitrieva-Posocco, O. et al. Cell-type-specific responses to interleukin-1 control microbial invasion and tumor-elicited inflammation in colorectal cancer. Immunity 50, 166–180.e7 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  242. Castano, Z. et al. IL-1beta inflammatory response driven by primary breast cancer prevents metastasis-initiating cell colonization. Nat. Cell Biol. 20, 1084–1097 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  243. Kumar, V. et al. Cancer-associated fibroblasts neutralize the anti-tumor effect of CSF1 receptor blockade by inducing PMN-MDSC infiltration of tumors. Cancer Cell 32, 654–668.e5 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  244. Bonapace, L. et al. Cessation of CCL2 inhibition accelerates breast cancer metastasis by promoting angiogenesis. Nature 515, 130–133 (2014).

    CAS  PubMed  Google Scholar 

  245. Singhal, S. et al. Origin and role of a subset of tumor-associated neutrophils with antigen-presenting cell features in early-stage human lung cancer. Cancer Cell 30, 120–135 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  246. Ponzetta, A. et al. Neutrophils driving unconventional T cells mediate resistance against murine sarcomas and selected human tumors. Cell 178, 346–360.e24 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  247. Roumenina, L. T., Daugan, M. V., Petitprez, F., Sautes-Fridman, C. & Fridman, W. H. Context-dependent roles of complement in cancer. Nat. Rev. Cancer 19, 698–715 (2019).

    CAS  PubMed  Google Scholar 

  248. Ozdemir, B. C. et al. Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival. Cancer Cell 25, 719–734 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  249. Sayin, V. I. et al. Antioxidants accelerate lung cancer progression in mice. Sci. Transl. Med. 6, 221ra215 (2014).

    Google Scholar 

  250. Le Gal, K. et al. Antioxidants can increase melanoma metastasis in mice. Sci. Transl. Med. 7, 308re8 (2015).

    PubMed  Google Scholar 

  251. Wiel, C. et al. BACH1 stabilization by antioxidants stimulates lung cancer metastasis. Cell 178, 330–345.e22 (2019).

    CAS  PubMed  Google Scholar 

  252. Piskounova, E. et al. Oxidative stress inhibits distant metastasis by human melanoma cells. Nature 527, 186–191 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  253. Lopez-Otin, C., Blasco, M. A., Partridge, L., Serrano, M. & Kroemer, G. The hallmarks of aging. Cell 153, 1194–1217 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  254. Biragyn, A. & Ferrucci, L. Gut dysbiosis: a potential link between increased cancer risk in ageing and inflammaging. Lancet Oncol. 19, e295–e304 (2018).

    PubMed  PubMed Central  Google Scholar 

  255. Finlay, B. B. et al. Can we harness the microbiota to enhance the efficacy of cancer immunotherapy? Nat. Rev. Immunol. 20, 522–528 (2020).

    CAS  PubMed  Google Scholar 

  256. Wargo, J. A. Modulating gut microbes. Science 369, 1302–1303 (2020).

    CAS  PubMed  Google Scholar 

  257. Chen, D. S. & Mellman, I. Elements of cancer immunity and the cancer-immune set point. Nature 541, 321–330 (2017).

    CAS  PubMed  Google Scholar 

  258. Elinav, E., Garrett, W. S., Trinchieri, G. & Wargo, J. The cancer microbiome. Nat. Rev. Cancer 19, 371–376 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  259. Gong, T., Liu, L., Jiang, W. & Zhou, R. DAMP-sensing receptors in sterile inflammation and inflammatory diseases. Nat. Rev. Immunol. 20, 95–112 (2020).

    CAS  PubMed  Google Scholar 

  260. McLaughlin, M. et al. Inflammatory microenvironment remodelling by tumour cells after radiotherapy. Nat. Rev. Cancer 20, 203–217 (2020).

    CAS  PubMed  Google Scholar 

  261. Chen, D. S. & Mellman, I. Oncology meets immunology: the cancer-immunity cycle. Immunity 39, 1–10 (2013).

    PubMed  Google Scholar 

  262. Palucka, A. K. & Coussens, L. M. The basis of oncoimmunology. Cell 164, 1233–1247 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The work of the authors is supported by grants from the National Key Research and Development Program of China (2016YFC0905900 to B.S.), the State Key Program of the National Natural Science Foundation (81930086 to B.S.; 81871970 and 81672801 to J.H.) and the US NIH (U01AA027681, R01CA211794, R01CA234128, P01CA128814, R01CA198103 and Tower Cancer Research Grant to M.K.). The work of J.H. is also supported by the Hundred Talent Program of Sun Yat-sen University. Figures in this review were drafted with the assistance of Dr Haiyan Zhang (Sun Yat-sen University Cancer Center).

Author information

Author notes

  1. Jiajie Hou

    Present address: Department of Liver Surgery, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China

Authors and Affiliations

  1. Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China

    Jiajie Hou & Beicheng Sun

  2. Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, University of California San Diego School of Medicine, La Jolla, CA, USA

    Michael Karin

Authors
  1. Jiajie Hou
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Michael Karin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Beicheng Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors contributed to all aspects of manuscript preparation.

Corresponding authors

Correspondence to Michael Karin or Beicheng Sun.

Ethics declarations

Competing interests

M.K. has received research support from Merck and Aduro Pharmaceuticals. J.H. and B.S. declare no competing interests.

Additional information

Peer review information

Nature Reviews Clinical Oncology thanks Andrew Chan and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hou, J., Karin, M. & Sun, B. Targeting cancer-promoting inflammation — have anti-inflammatory therapies come of age?. Nat Rev Clin Oncol 18, 261–279 (2021). https://doi.org/10.1038/s41571-020-00459-9

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41571-020-00459-9

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer