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  • Review Article
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Biomarkers for immunotherapy of hepatocellular carcinoma

Abstract

Immune-checkpoint inhibitors (ICIs) are now widely used for the treatment of patients with advanced-stage hepatocellular carcinoma (HCC). Two different ICI-containing regimens, atezolizumab plus bevacizumab and tremelimumab plus durvalumab, are now approved standard-of-care first-line therapies in this setting. However, and despite substantial improvements in survival outcomes relative to sorafenib, most patients with advanced-stage HCC do not derive durable benefit from these regimens. Advances in genome sequencing including the use of single-cell RNA sequencing (both of tumour material and blood samples), as well as immune cell identification strategies and other techniques such as radiomics and analysis of the microbiota, have created considerable potential for the identification of novel predictive biomarkers enabling the accurate selection of patients who are most likely to derive benefit from ICIs. In this Review, we summarize data on the immunology of HCC and the outcomes in patients receiving ICIs for the treatment of this disease. We then provide an overview of current biomarker use and developments in the past 5 years, including gene signatures, circulating tumour cells, high-dimensional flow cytometry, single-cell RNA sequencing as well as approaches involving the microbiome, radiomics and clinical markers. Novel concepts for further biomarker development in HCC are then discussed including biomarker-driven trials, spatial transcriptomics and integrated ‘big data’ analysis approaches. These concepts all have the potential to better identify patients who are most likely to benefit from ICIs and to promote the development of new treatment approaches.

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Fig. 1: Materials needed for rigorous biomarker investigations.
Fig. 2: Overview of the sources of various biomarker candidates for immunotherapy of HCC.
Fig. 3: Trial design for biomarker identification studies.
Fig. 4: Trial designs for biomarker-driven clinical trials.

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References

  1. International Agency for Research on Cancer. Estimated number of new cases in 2020, World, both sexes, all ages (excl. NMSC). Cancer Today https://gco.iarc.fr/today/online-analysis-table?v=2020&mode=cancer&mode_population=continents&population=900&populations=900&key=asr&sex=0&cancer=39&type=0&statistic=5&prevalence=0&population_group=0&ages_group%5B%5D=0&ages_group%5B%5D=17&group_cancer=1&include_nmsc=0&include_nmsc_other=1 (2020).

  2. Siegel, R. L., Miller, K. D., Wagle, N. S. & Jemal, A. Cancer statistics, 2023. CA Cancer J. Clin. 73, 17–48 (2023).

    Article  PubMed  Google Scholar 

  3. Llovet, J. M. et al. Hepatocellular carcinoma. Nat. Rev. Dis. Prim. 7, 6 (2021).

    Article  PubMed  Google Scholar 

  4. Cheng, A. L. et al. Updated efficacy and safety data from IMbrave150: atezolizumab plus bevacizumab vs. sorafenib for unresectable hepatocellular carcinoma. J. Hepatol. 76, 862–873 (2022).

    Article  CAS  PubMed  Google Scholar 

  5. Llovet, J. M. et al. Sorafenib in advanced hepatocellular carcinoma. N. Engl. J. Med. 359, 378–390 (2008).

    Article  CAS  PubMed  Google Scholar 

  6. Greten, T. F. et al. Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immunotherapy for the treatment of hepatocellular carcinoma. J. Immunother. Cancer 9, e002794 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  7. Finn, R. S. et al. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N. Engl. J. Med. 382, 1894–1905 (2020).

    Article  CAS  PubMed  Google Scholar 

  8. Abou-Alfa, G. K. et al. Tremelimumab plus durvalumab in unresectable hepatocellular carcinoma. NEJM Evid. 1 (8), https://doi.org/10.1056/EVIDoa2100070 (2022).

  9. Yau, T. et al. Nivolumab versus sorafenib in advanced hepatocellular carcinoma (CheckMate 459): a randomised, multicentre, open-label, phase 3 trial. Lancet Oncol. 23, 77–90 (2022).

    Article  CAS  PubMed  Google Scholar 

  10. Finn, R. S. et al. Pembrolizumab as second-line therapy in patients with advanced hepatocellular carcinoma in KEYNOTE-240: a randomized, double-blind, phase III trial. J. Clin. Oncol. 38, 193–202 (2020).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Monge, C., Xie, C., Steinberg, S. M. & Greten, T. F. Clinical indicators for long-term survival with immune checkpoint therapy in advanced hepatocellular carcinoma. J. Hepatocell. Carcinoma 8, 507–512 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  13. Pinato, D. J. et al. Treatment-related toxicity and improved outcome from immunotherapy in hepatocellular cancer: evidence from an FDA pooled analysis of landmark clinical trials with validation from routine practice. Eur. J. Cancer 157, 140–152 (2021).

    Article  CAS  PubMed  Google Scholar 

  14. Huang, D. Q., El-Serag, H. B. & Loomba, R. Global epidemiology of NAFLD-related HCC: trends, predictions, risk factors and prevention. Nat. Rev. Gastroenterol. Hepatol. 18, 223–238 (2021).

    Article  PubMed  Google Scholar 

  15. Marrero, J. A. et al. Diagnosis, staging, and management of hepatocellular carcinoma: 2018 practice guidance by the American Association for the Study of Liver Diseases. Hepatology 68, 723–750 (2018).

    Article  PubMed  Google Scholar 

  16. Child, C. G. & Turcotte, J. G. Surgery and portal hypertension. Major. Probl. Clin. Surg. 1, 1–85 (1964).

    CAS  PubMed  Google Scholar 

  17. Reig, M. et al. BCLC strategy for prognosis prediction and treatment recommendation: the 2022 update. J. Hepatol. 76, 681–693 (2022).

    Article  PubMed  Google Scholar 

  18. Bruix, J., Chan, S. L., Galle, P. R., Rimassa, L. & Sangro, B. Systemic treatment of hepatocellular carcinoma: an EASL position paper. J. Hepatol. 75, 960–974 (2021).

    Article  CAS  PubMed  Google Scholar 

  19. Kudo, M. et al. Management of hepatocellular carcinoma in Japan: JSH consensus statements and recommendations 2021 update. Liver Cancer 10, 181–223 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Zhou, J. et al. Guidelines for the diagnosis and treatment of hepatocellular carcinoma (2019 edition). Liver Cancer 9, 682–720 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  21. Vogel, A. et al. Hepatocellular carcinoma: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann. Oncol. 29, iv238–iv255 (2018).

    Article  CAS  PubMed  Google Scholar 

  22. Kudo, M. et al. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Lancet 391, 1163–1173 (2018).

    Article  CAS  PubMed  Google Scholar 

  23. Ren, Z. et al. Sintilimab plus a bevacizumab biosimilar (IBI305) versus sorafenib in unresectable hepatocellular carcinoma (ORIENT-32): a randomised, open-label, phase 2-3 study. Lancet Oncol. 22, 977–990 (2021).

    Article  CAS  PubMed  Google Scholar 

  24. Qin, S. et al. Pembrolizumab plus best supportive care versus placebo plus best supportive care as second-line therapy in patients in Asia with advanced hepatocellular carcinoma (HCC): phase 3 KEYNOTE-394 study [abstract]. J. Clin. Oncol. 40 (4 Suppl.), 383 (2022).

    Article  Google Scholar 

  25. Yau, T. et al. Efficacy and safety of nivolumab plus ipilimumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib: the checkmate 040 randomized clinical trial. JAMA Oncol. 6, e204564 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  26. Sangro, B. et al. Diagnosis and management of toxicities of immune checkpoint inhibitors in hepatocellular carcinoma. J. Hepatol. 72, 320–341 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Chow, P. et al. IMbrave050: phase 3 study of adjuvant atezolizumab + bevacizumab versus active surveillance in patients with hepatocellular carcinoma (HCC) at high risk of disease recurrence following resection or ablation [abstract]. Cancer Res. 83 (8 Suppl.), CT003 (2023).

    Article  Google Scholar 

  28. Kaseb, A. O. et al. Perioperative nivolumab monotherapy versus nivolumab plus ipilimumab in resectable hepatocellular carcinoma: a randomised, open-label, phase 2 trial. Lancet Gastroenterol. Hepatol. 7, 208–218 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  29. Ho, W. J. et al. Neoadjuvant cabozantinib and nivolumab converts locally advanced HCC into resectable disease with enhanced antitumor immunity. Nat. Cancer 2, 891–903 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Shu, D. H. et al. 12-chemokine gene signature identifies major pathologic response in patients with hepatocellular carcinoma treated with neoadjuvant nivolumab and cabozantinib [abstract]. Cancer Res. 82 (12 Suppl.), 1323 (2022).

    Article  Google Scholar 

  31. Marron, T. U. et al. Neoadjuvant cemiplimab for resectable hepatocellular carcinoma: a single-arm, open-label, phase 2 trial. Lancet Gastroenterol. Hepatol. 7, 219–229 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  32. Biomarkers Definitions Working Group Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clin. Pharmacol. Ther. 69, 89–95 (2001).

    Article  Google Scholar 

  33. McKean, W. B., Moser, J. C., Rimm, D. & Hu-Lieskovan, S. Biomarkers in precision cancer immunotherapy: promise and challenges. Am. Soc. Clin. Oncol. Educ. Book. 40, e275–e291 (2020).

    Article  PubMed  Google Scholar 

  34. Han, Y., Liu, D. & Li, L. PD-1/PD-L1 pathway: current researches in cancer. Am. J. Cancer Res. 10, 727–742 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Paver, E. C. et al. Programmed death ligand-1 (PD-L1) as a predictive marker for immunotherapy in solid tumours: a guide to immunohistochemistry implementation and interpretation. Pathology 53, 141–156 (2021).

    Article  CAS  PubMed  Google Scholar 

  36. El-Khoueiry, A. B. et al. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet 389, 2492–2502 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Zhu, A. X. et al. Molecular correlates of clinical response and resistance to atezolizumab in combination with bevacizumab in advanced hepatocellular carcinoma. Nat. Med. 28, 1599–1611 (2022).

    Article  CAS  PubMed  Google Scholar 

  38. Zhu, A. X. et al. Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a non-randomised, open-label phase 2 trial. Lancet Oncol. 19, 940–952 (2018).

    Article  PubMed  Google Scholar 

  39. Duffy, A. G. et al. Tremelimumab in combination with ablation in patients with advanced hepatocellular carcinoma. J. Hepatol. 66, 545–551 (2017).

    Article  CAS  PubMed  Google Scholar 

  40. Ng, H. H. M. et al. Immunohistochemical scoring of CD38 in the tumor microenvironment predicts responsiveness to anti-PD-1/PD-L1 immunotherapy in hepatocellular carcinoma. J. Immunother. Cancer 8, e000987 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  41. Ang, C. et al. Prevalence of established and emerging biomarkers of immune checkpoint inhibitor response in advanced hepatocellular carcinoma. Oncotarget 10, 4018–4025 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  42. Yarchoan, M., Hopkins, A. & Jaffee, E. M. Tumor mutational burden and response rate to PD-1 inhibition. N. Engl. J. Med. 377, 2500–2501 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  Google Scholar 

  45. Chaisaingmongkol, J. et al. Common molecular subtypes among Asian hepatocellular carcinoma and cholangiocarcinoma. Cancer Cell 32, 57–70.e3 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Hoshida, Y. et al. Integrative transcriptome analysis reveals common molecular subclasses of human hepatocellular carcinoma. Cancer Res. 69, 7385–7392 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Haber, P. K. et al. Molecular markers of response to anti-PD1 therapy in advanced hepatocellular carcinoma. Gastroenterology 164, 72–88.e18 (2023).

    Article  CAS  PubMed  Google Scholar 

  48. Sangro, B. et al. Association of inflammatory biomarkers with clinical outcomes in nivolumab-treated patients with advanced hepatocellular carcinoma. J. Hepatol. 73, 1460–1469 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Hong, J. Y. et al. Hepatocellular carcinoma patients with high circulating cytotoxic T cells and intra-tumoral immune signature benefit from pembrolizumab: results from a single-arm phase 2 trial. Genome Med. 14, 1 (2022).

    Article  CAS  PubMed Central  Google Scholar 

  50. Huang, M. et al. The influence of immune heterogeneity on the effectiveness of immune checkpoint inhibitors in multifocal hepatocellular carcinomas. Clin. Cancer Res. 26, 4947–4957 (2020).

    Article  CAS  PubMed  Google Scholar 

  51. Budhu, A. et al. Tumor biology and immune infiltration define primary liver cancer subsets linked to overall survival after immunotherapy. Cell Rep. Med. 4, 101052 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Vanhersecke, L. et al. Mature tertiary lymphoid structures predict immune checkpoint inhibitor efficacy in solid tumors independently of PD-L1 expression. Nat. Cancer 2, 794–802 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Fridman, W. H. et al. B cells and tertiary lymphoid structures as determinants of tumour immune contexture and clinical outcome. Nat. Rev. Clin. Oncol. 19, 441–457 (2022).

    Article  CAS  PubMed  Google Scholar 

  54. Yu, S. et al. Tumor-infiltrating immune cells in hepatocellular carcinoma: Tregs is correlated with poor overall survival. PLoS ONE 15, e0231003 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Montironi, C. et al. Inflamed and non-inflamed classes of HCC: a revised immunogenomic classification. Gut 72, 129–140 (2022).

    Article  PubMed  Google Scholar 

  56. Ge, P. L. et al. Prognostic values of immune scores and immune microenvironment-related genes for hepatocellular carcinoma. Aging 12, 5479–5499 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Martin-Serrano, M. A. et al. Novel microenvironment-based classification of intrahepatic cholangiocarcinoma with therapeutic implications. Gut 72, 736–748 (2023).

    Article  CAS  PubMed  Google Scholar 

  58. Ma, L. et al. Single-cell atlas of tumor cell evolution in response to therapy in hepatocellular carcinoma and intrahepatic cholangiocarcinoma. J. Hepatol. 75, 1397–1408 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Marusyk, A., Janiszewska, M. & Polyak, K. Intratumor heterogeneity: the Rosetta stone of therapy resistance. Cancer Cell 37, 471–484 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Zhang, Q. et al. Landscape and dynamics of single immune cells in hepatocellular carcinoma. Cell 179, 829–845.e20 (2019).

    Article  CAS  PubMed  Google Scholar 

  61. Zheng, L. et al. Pan-cancer single-cell landscape of tumor-infiltrating T cells. Science 374, abe6474 (2021).

    Article  PubMed  Google Scholar 

  62. Sade-Feldman, M. et al. Defining T cell states associated with response to checkpoint immunotherapy in melanoma. Cell 175, 998–1013.e20 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Ma, L. et al. Tumor cell biodiversity drives microenvironmental reprogramming in liver cancer. Cancer Cell 36, 418–430.e6 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Bian, J. et al. T lymphocytes in hepatocellular carcinoma immune microenvironment: insights into human immunology and immunotherapy. Am. J. Cancer Res. 10, 4585 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Llovet, J. M. et al. Immunotherapies for hepatocellular carcinoma. Nat. Rev. Clin. Oncol. 19, 151–172 (2022).

    Article  CAS  PubMed  Google Scholar 

  66. Havel, J. J., Chowell, D. & Chan, T. A. The evolving landscape of biomarkers for checkpoint inhibitor immunotherapy. Nat. Rev. Cancer 19, 133–150 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Ho, D. W. et al. Single-cell RNA sequencing shows the immunosuppressive landscape and tumor heterogeneity of HBV-associated hepatocellular carcinoma. Nat. Commun. 12, 3684 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Liu, Y. et al. Identification of a tumour immune barrier in the HCC microenvironment that determines the efficacy of immunotherapy. J. Hepatol. 78, 770–782 (2023).

    Article  CAS  PubMed  Google Scholar 

  69. Nguyen, P. H. D. et al. Trajectory of immune evasion and cancer progression in hepatocellular carcinoma. Nat. Commun. 13, 1441 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Hoechst, B. et al. A new population of myeloid-derived suppressor cells in hepatocellular carcinoma patients induces CD4+CD25+Foxp3+ T cells. Gastroenterology 135, 234–243 (2008).

    Article  CAS  PubMed  Google Scholar 

  71. Liu, M. et al. Targeting monocyte-intrinsic enhancer reprogramming improves immunotherapy efficacy in hepatocellular carcinoma. Gut 69, 365–379 (2020).

    Article  CAS  PubMed  Google Scholar 

  72. Xue, R. et al. Liver tumour immune microenvironment subtypes and neutrophil heterogeneity. Nature 612, 141–147 (2022).

    Article  CAS  PubMed  Google Scholar 

  73. Geh, D. et al. Neutrophils as potential therapeutic targets in hepatocellular carcinoma. Nat. Rev. Gastroenterol. Hepatol. 19, 257–273 (2022).

    Article  CAS  PubMed  Google Scholar 

  74. Ma, L. et al. Multiregional single-cell dissection of tumor and immune cells reveals stable lock-and-key features in liver cancer. Nat. Commun. 13, 7533 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Murai, H. et al. Multiomics identifies the link between intratumor steatosis and the exhausted tumor immune microenvironment in hepatocellular carcinoma. Hepatology 1, 77–91 (2022).

    Google Scholar 

  76. Provine, N. M. & Klenerman, P. MAIT cells in health and disease. Annu. Rev. Immunol. 38, 203–228 (2020).

    Article  CAS  PubMed  Google Scholar 

  77. Ruf, B. et al. Tumor-associated macrophages trigger MAIT cell dysfunction at the HCC invasive margin. Cell 186, 3686–3705.e32 (2023).

    Article  CAS  PubMed  Google Scholar 

  78. Nguyen, P. H. D. et al. Intratumoural immune heterogeneity as a hallmark of tumour evolution and progression in hepatocellular carcinoma. Nat. Commun. 12, 227 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Zhang, S. et al. Spatial transcriptomics analysis of neoadjuvant cabozantinib and nivolumab in advanced hepatocellular carcinoma identifies independent mechanisms of resistance and recurrence. Preprint at bioRxiv https://www.biorxiv.org/content/10.1101/2023.01.10.523481v1 (2023).

  80. Slamon, D. J. et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N. Engl. J. Med. 344, 783–792 (2001).

    Article  CAS  PubMed  Google Scholar 

  81. Villanueva, A. Hepatocellular carcinoma. N. Engl. J. Med. 380, 1450–1462 (2019).

    Article  CAS  PubMed  Google Scholar 

  82. Hu, X., Chen, R., Wei, Q. & Xu, X. The landscape of alpha fetoprotein in hepatocellular carcinoma: where are we? Int. J. Biol. Sci. 18, 536–551 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Galle, P. R. et al. Biology and significance of alpha-fetoprotein in hepatocellular carcinoma. Liver Int. 39, 2214–2229 (2019).

    Article  PubMed  Google Scholar 

  84. Bruix, J. et al. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 389, 56–66 (2017).

    Article  CAS  PubMed  Google Scholar 

  85. Abou-Alfa, G. K. et al. Cabozantinib in patients with advanced and progressing hepatocellular carcinoma. N. Engl. J. Med. 379, 54–63 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Zhu, A. X. et al. Ramucirumab after sorafenib in patients with advanced hepatocellular carcinoma and increased α-fetoprotein concentrations (REACH-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 20, 282–296 (2019).

    Article  CAS  PubMed  Google Scholar 

  87. Zhu, A. X. et al. Alpha-fetoprotein as a potential surrogate biomarker for atezolizumab + bevacizumab treatment of hepatocellular carcinoma. Clin. Cancer Res. 28, 3537–3545 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Shao, Y. Y. et al. Early alpha-foetoprotein response associated with treatment efficacy of immune checkpoint inhibitors for advanced hepatocellular carcinoma. Liver Int. 39, 2184–2189 (2019).

    Article  CAS  PubMed  Google Scholar 

  89. Lee, P. C. et al. Predictors of response and survival in immune checkpoint inhibitor-treated unresectable hepatocellular carcinoma. Cancers 12, 182 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Spahn, S. et al. Clinical and genetic tumor characteristics of responding and non-responding patients to PD-1 inhibition in hepatocellular carcinoma. Cancers 12, 3830 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Scheiner, B. et al. Prognosis of patients with hepatocellular carcinoma treated with immunotherapy – development and validation of the CRAFITY score. J. Hepatol. 76, 353–363 (2022).

    Article  CAS  PubMed  Google Scholar 

  92. Hatanaka, T. et al. Prognostic impact of C-reactive protein and alpha-fetoprotein in immunotherapy score in hepatocellular carcinoma patients treated with atezolizumab plus bevacizumab: a multicenter retrospective study. Hepatol. Int. 16, 1150–1160 (2022).

    Article  PubMed  Google Scholar 

  93. Teng, W. et al. Combination of CRAFITY score with alpha-fetoprotein response predicts a favorable outcome of atezolizumab plus bevacizumab for unresectable hepatocellular carcinoma. Am. J. Cancer Res. 12, 1899–1911 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Sun, X. et al. Reductions in AFP and PIVKA-II can predict the efficiency of anti-PD-1 immunotherapy in HCC patients. BMC Cancer 21, 775 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Myojin, Y. et al. Interleukin-6 is a circulating prognostic biomarker for hepatocellular carcinoma patients treated with combined immunotherapy. Cancers 14, 883 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Yang, H. et al. High serum IL-6 correlates with reduced clinical benefit of atezolizumab and bevacizumab in unresectable hepatocellular carcinoma. JHEP Rep. 5, 100672 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  97. Feun, L. G. et al. Phase 2 study of pembrolizumab and circulating biomarkers to predict anticancer response in advanced, unresectable hepatocellular carcinoma. Cancer 125, 3603–3614 (2019).

    Article  CAS  PubMed  Google Scholar 

  98. Feun, L. G. et al. Circulating biomarkers to predict antitumor response to immunotherapy in advanced unresectable hepatoma [abstract]. Cancer Res. 82 (12 Suppl.), 2771 (2022).

    Article  Google Scholar 

  99. Li, X. S., Li, J. W., Li, H. & Jiang, T. Prognostic value of programmed cell death ligand 1 (PD-L1) for hepatocellular carcinoma: a meta-analysis. Biosci. Rep. 40, BSR20200459 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Wang, T., Denman, D., Bacot, S. M. & Feldman, G. M. Challenges and the evolving landscape of assessing blood-based PD-L1 expression as a biomarker for anti-PD-(L)1 immunotherapy. Biomedicines 10, 1181 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Lin, Z. F., Qin, L. X. & Chen, J. H. Biomarkers for response to immunotherapy in hepatobiliary malignancies. Hepatobiliary Pancreat. Dis. Int. 21, 413–419 (2022).

    Article  PubMed  Google Scholar 

  102. Pallozzi, M. et al. Non-invasive biomarkers for immunotherapy in patients with hepatocellular carcinoma: current knowledge and future perspectives. Cancers 14, 4631 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Dharmapuri, S. et al. Predictive value of neutrophil to lymphocyte ratio and platelet to lymphocyte ratio in advanced hepatocellular carcinoma patients treated with anti-PD-1 therapy. Cancer Med. 9, 4962–4970 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Hung, H. C. et al. Response prediction in immune checkpoint inhibitor immunotherapy for advanced hepatocellular carcinoma. Cancers 13, 1607 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Muhammed, A. et al. The systemic inflammatory response identifies patients with adverse clinical outcome from immunotherapy in hepatocellular carcinoma. Cancers 14, 186 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  106. Mei, J. et al. Comparison of the prognostic value of inflammation-based scores in patients with hepatocellular carcinoma after anti-PD-1 therapy. J. Inflamm. Res. 14, 3879–3890 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  107. Wu, Y. L. et al. Neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios as prognostic biomarkers in unresectable hepatocellular carcinoma treated with atezolizumab plus bevacizumab. Cancers 14, 5834 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Kim, C. et al. Association of high levels of antidrug antibodies against atezolizumab with clinical outcomes and T-cell responses in patients with hepatocellular carcinoma. JAMA Oncol. 8, 1825–1829 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  109. Chew, V. et al. Delineation of an immunosuppressive gradient in hepatocellular carcinoma using high-dimensional proteomic and transcriptomic analyses. Proc. Natl Acad. Sci. USA 114, E5900–E5909 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Zheng, C. et al. Landscape of infiltrating T cells in liver cancer revealed by single-cell sequencing. Cell 169, 1342–1356.e16 (2017).

    Article  CAS  PubMed  Google Scholar 

  111. Sun, Y. et al. Single-cell landscape of the ecosystem in early-relapse hepatocellular carcinoma. Cell 184, 404–421 e416 (2021).

    Article  CAS  PubMed  Google Scholar 

  112. Heinrich, B. et al. The tumour microenvironment shapes innate lymphoid cells in patients with hepatocellular carcinoma. Gut 71, 1161–1175 (2022).

    Article  CAS  PubMed  Google Scholar 

  113. Spitzer, M. H. & Nolan, G. P. Mass cytometry: single cells, many features. Cell 165, 780–791 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Monge, C. et al. Phase I/II study of PexaVec in combination with immune checkpoint inhibition in refractory metastatic colorectal cancer. J. Immunother. Cancer 11, e005640 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  115. Gohil, S. H., Iorgulescu, J. B., Braun, D. A., Keskin, D. B. & Livak, K. J. Applying high-dimensional single-cell technologies to the analysis of cancer immunotherapy. Nat. Rev. Clin. Oncol. 18, 244–256 (2021).

    Article  PubMed  Google Scholar 

  116. Krieg, C. et al. High-dimensional single-cell analysis predicts response to anti-PD-1 immunotherapy. Nat. Med. 24, 144–153 (2018).

    Article  CAS  PubMed  Google Scholar 

  117. Agdashian, D. et al. The effect of anti-CTLA4 treatment on peripheral and intra-tumoral T cells in patients with hepatocellular carcinoma. Cancer Immunol. Immunother. 68, 599–608 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Hung, Y. P. et al. Potential of circulating immune cells as biomarkers of nivolumab treatment efficacy for advanced hepatocellular carcinoma. J. Chin. Med. Assoc. 84, 144–150 (2021).

    Article  CAS  PubMed  Google Scholar 

  119. Heinrich, B. et al. Checkpoint inhibitors modulate plasticity of innate lymphoid cells in peripheral blood of patients with hepatocellular carcinoma. Front. Immunol. 13, 849958 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Ruf, B., Heinrich, B. & Greten, T. F. Immunobiology and immunotherapy of HCC: spotlight on innate and innate-like immune cells. Cell Mol. Immunol. 18, 112–127 (2021).

    Article  CAS  PubMed  Google Scholar 

  121. Barsch, M. et al. T-cell exhaustion and residency dynamics inform clinical outcomes in hepatocellular carcinoma. J. Hepatol. 77, 397–409 (2022).

    Article  CAS  PubMed  Google Scholar 

  122. Chuah, S. et al. Uncoupling immune trajectories of response and adverse events from anti-PD-1 immunotherapy in hepatocellular carcinoma. J. Hepatol. 77, 683–694 (2022).

    Article  CAS  PubMed  Google Scholar 

  123. Sidiropoulos, D. N. et al. Integrated T cell cytometry metrics for immune-monitoring applications in immunotherapy clinical trials. JCI Insight 7, e160398 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  124. Alix-Panabieres, C. & Pantel, K. Liquid biopsy: from discovery to clinical application. Cancer Discov. 11, 858–873 (2021).

    Article  CAS  PubMed  Google Scholar 

  125. Schroers-Martin, J. G. et al. Molecular monitoring of lymphomas. Annu. Rev. Pathol. 18, 149–180 (2023).

    Article  PubMed  Google Scholar 

  126. von Felden, J., Garcia-Lezana, T., Schulze, K., Losic, B. & Villanueva, A. Liquid biopsy in the clinical management of hepatocellular carcinoma. Gut 69, 2025–2034 (2020).

    Article  Google Scholar 

  127. Klein, E. A. et al. Clinical validation of a targeted methylation-based multi-cancer early detection test using an independent validation set. Ann. Oncol. 32, 1167–1177 (2021).

    Article  CAS  PubMed  Google Scholar 

  128. Tran, N. H., Kisiel, J. & Roberts, L. R. Using cell-free DNA for HCC surveillance and prognosis. JHEP Rep. 3, 100304 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  129. Kaseb, A. O. et al. Molecular profiling of hepatocellular carcinoma using circulating cell-free DNA. Clin. Cancer Res. 25, 6107–6118 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. von Felden, J. et al. Mutations in circulating tumor DNA predict primary resistance to systemic therapies in advanced hepatocellular carcinoma. Oncogene 40, 140–151 (2021).

    Article  Google Scholar 

  131. Matsumae, T. et al. Circulating cell-free DNA profiling predicts the therapeutic outcome in advanced hepatocellular carcinoma patients treated with combination immunotherapy. Cancers 14, 3367 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Harding, J. J. et al. Prospective genotyping of hepatocellular carcinoma: clinical implications of next-generation sequencing for matching patients to targeted and immune therapies. Clin. Cancer Res. 25, 2116–2126 (2019).

    Article  CAS  PubMed  Google Scholar 

  133. An, H. J., Chon, H. J. & Kim, C. Peripheral blood-based biomarkers for immune checkpoint inhibitors. Int. J. Mol. Sci. 22, 9414 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Tamminga, M. et al. Circulating tumor cells in advanced non-small cell lung cancer patients are associated with worse tumor response to checkpoint inhibitors. J. Immunother. Cancer 7, 173 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  135. Winograd, P. et al. Hepatocellular carcinoma-circulating tumor cells expressing PD-L1 are prognostic and potentially associated with response to checkpoint inhibitors. Hepatol. Commun. 4, 1527–1540 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Budhu, A. et al. Integrated metabolite and gene expression profiles identify lipid biomarkers associated with progression of hepatocellular carcinoma and patient outcomes. Gastroenterology 144, 1066–1075.e1 (2013).

    Article  CAS  PubMed  Google Scholar 

  137. Pomyen, Y. et al. Tumor metabolism and associated serum metabolites define prognostic subtypes of Asian hepatocellular carcinoma. Sci. Rep. 11, 12097 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Breeur, M. et al. Pan-cancer analysis of pre-diagnostic blood metabolite concentrations in the European Prospective Investigation into Cancer and Nutrition. BMC Med. 20, 351 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Fujiwara, N. et al. A blood-based prognostic liver secretome signature and long-term hepatocellular carcinoma risk in advanced liver fibrosis. Med 2, 836–850.e10 (2021).

    Article  CAS  PubMed  Google Scholar 

  140. Hung, M. H. et al. Tumor methionine metabolism drives T-cell exhaustion in hepatocellular carcinoma. Nat. Commun. 12, 1455 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Wu, H. et al. Dynamic microbiome and metabolome analyses reveal the interaction between gut microbiota and anti-PD-1 based immunotherapy in hepatocellular carcinoma. Int. J. Cancer 151, 1321–1334 (2022).

    Article  CAS  PubMed  Google Scholar 

  142. Gong, X. Q. et al. Progress of MRI radiomics in hepatocellular carcinoma. Front. Oncol. 11, 698373 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  143. Dercle, L. et al. Artificial intelligence and radiomics: fundamentals, applications, and challenges in immunotherapy. J. Immunother. Cancer 10, e005292 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  144. Dercle, L. et al. Emerging and evolving concepts in cancer immunotherapy imaging. Radiology 306, 32–46 (2023).

    Article  PubMed  Google Scholar 

  145. Martinino, A. et al. Artificial intelligence in the diagnosis of hepatocellular carcinoma: a systematic review. J. Clin. Med. 11, 6368 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  146. Tao, Y. Y. et al. Radiomic analysis based on magnetic resonance imaging for predicting PD-L2 expression in hepatocellular carcinoma. Cancers (Basel) 15, 365 (2023).

    Article  CAS  PubMed  Google Scholar 

  147. Chen, S. et al. Pretreatment prediction of immunoscore in hepatocellular cancer: a radiomics-based clinical model based on Gd-EOB-DTPA-enhanced MRI imaging. Eur. Radiol. 29, 4177–4187 (2019).

    Article  PubMed  Google Scholar 

  148. Hectors, S. J. et al. MRI radiomics features predict immuno-oncological characteristics of hepatocellular carcinoma. Eur. Radiol. 30, 3759–3769 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  149. Yuan, G. et al. Development and validation of a contrast-enhanced CT-based radiomics nomogram for prediction of therapeutic efficacy of anti-PD-1 antibodies in advanced HCC patients. Front. Immunol. 11, 613946 (2020).

    Article  CAS  PubMed  Google Scholar 

  150. Castilla-Lievre, M. A. et al. Diagnostic value of combining 11C-choline and 18F-FDG PET/CT in hepatocellular carcinoma. Eur. J. Nucl. Med. Mol. Imaging 43, 852–859 (2016).

    Article  CAS  PubMed  Google Scholar 

  151. European Association for the Study of the Liver EASL clinical practice guidelines: management of hepatocellular carcinoma. J. Hepatol. 69, 182–236 (2018).

    Article  Google Scholar 

  152. Wei, W. et al. ImmunoPET: concept, design, and applications. Chem. Rev. 120, 3787–3851 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Bell, M., Turkbey, E. B. & Escorcia, F. E. Radiomics, radiogenomics, and next-generation molecular imaging to augment diagnosis of hepatocellular carcinoma. Cancer J. 26, 108–115 (2020).

    Article  CAS  PubMed  Google Scholar 

  154. Mena, E. et al. Functional imaging of liver cancer (FLIC): study protocol of a phase 2 trial of 18F-DCFPyL PET/CT imaging for patients with hepatocellular carcinoma. PLoS ONE 17, e0277407 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Rizzo, A. et al. PSMA radioligand uptake as a biomarker of neoangiogenesis in solid tumours: diagnostic or theragnostic factor? Cancers 14, 4309 (2022).

    Article  Google Scholar 

  156. Sepich-Poore, G. D. et al. The microbiome and human cancer. Science 371, eabc4552 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. McQuade, J. L., Daniel, C. R., Helmink, B. A. & Wargo, J. A. Modulating the microbiome to improve therapeutic response in cancer. Lancet Oncol. 20, e77–e91 (2019).

    Article  PubMed  Google Scholar 

  158. McCulloch, J. A. et al. Intestinal microbiota signatures of clinical response and immune-related adverse events in melanoma patients treated with anti-PD-1. Nat. Med. 28, 545–556 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Schwabe, R. F. & Greten, T. F. Gut microbiome in HCC – mechanisms, diagnosis and therapy. J. Hepatol. 72, 230–238 (2020).

    Article  CAS  PubMed  Google Scholar 

  160. Silveira, M. A. D., Bilodeau, S., Greten, T. F., Wang, X. W. & Trinchieri, G. The gut–liver axis: host microbiota interactions shape hepatocarcinogenesis. Trends Cancer 8, 583–597 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Myojin, Y. & Greten, T. F. The microbiome and liver cancer. Cancer J. 29, 57–60 (2023).

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  PubMed Central  Google Scholar 

  163. Zhang, L. et al. The association between antibiotic use and outcomes of HCC patients treated with immune checkpoint inhibitors. Front. Immunol. 13, 956533 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Fulgenzi, C. A. M. et al. Effect of early antibiotic exposure on survival of patients receiving atezolizumab plus bevacizumab but not sorafenib for unresectable HCC: a sub-analysis of the phase III IMbrave150 study. J. Clin. Oncol. 41, 597–597 (2023).

    Article  Google Scholar 

  165. Davar, D. et al. Fecal microbiota transplant overcomes resistance to anti-PD-1 therapy in melanoma patients. Science 371, 595–602 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. McDermott, D. F. et al. Clinical activity and molecular correlates of response to atezolizumab alone or in combination with bevacizumab versus sunitinib in renal cell carcinoma. Nat. Med. 24, 749–757 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Lee, W. S., Yang, H., Chon, H. J. & Kim, C. Combination of anti-angiogenic therapy and immune checkpoint blockade normalizes vascular–immune crosstalk to potentiate cancer immunity. Exp. Mol. Med. 52, 1475–1485 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Zhang, Y. et al. VEGFR2 activity on myeloid cells mediates immune suppression in the tumor microenvironment. JCI Insight 6, e150375 (2021).

    Article  Google Scholar 

  169. Kudo, M. Scientific rationale for combined immunotherapy with PD-1/PD-L1 antibodies and VEGF inhibitors in advanced hepatocellular carcinoma. Cancers 12, 1089 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Neely, J. et al. Genomic and transcriptomic analyses related to the clinical efficacy of first-line nivolumab in advanced hepatocellular carcinoma from the phase 3 CheckMate 459 trial [abstract]. Cancer Res. 82 (12 Suppl.), 2145 (2022).

    Article  Google Scholar 

  171. Ruiz de Galarreta, M. et al. β-Catenin activation promotes immune escape and resistance to anti-PD-1 therapy in hepatocellular carcinoma. Cancer Discov. 9, 1124–1141 (2019).

    Article  CAS  PubMed  Google Scholar 

  172. Kaseb, A. O. et al. Immunologic correlates of pathologic complete response to preoperative immunotherapy in hepatocellular carcinoma. Cancer Immunol. Res. 7, 1390–1395 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Jiang, P. et al. Big data in basic and translational cancer research. Nat. Rev. Cancer 22, 625–639 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Boehm, K. M., Khosravi, P., Vanguri, R., Gao, J. & Shah, S. P. Harnessing multimodal data integration to advance precision oncology. Nat. Rev. Cancer 22, 114–126 (2022).

    Article  CAS  PubMed  Google Scholar 

  175. Cohen, Y. C. et al. Identification of resistance pathways and therapeutic targets in relapsed multiple myeloma patients through single-cell sequencing. Nat. Med. 27, 491–503 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Echle, A. et al. Deep learning in cancer pathology: a new generation of clinical biomarkers. Br. J. Cancer 124, 686–696 (2021).

    Article  PubMed  Google Scholar 

  177. Kato, S. et al. Real-world data from a molecular tumor board demonstrates improved outcomes with a precision N-of-One strategy. Nat. Commun. 11, 4965 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Tamborero, D. et al. The molecular tumor board portal supports clinical decisions and automated reporting for precision oncology. Nat. Cancer 3, 251–261 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  179. Vanguri, R. S. et al. Multimodal integration of radiology, pathology and genomics for prediction of response to PD-(L)1 blockade in patients with non-small cell lung cancer. Nat. Cancer 3, 1151–1164 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Hoang, D.-T. et al. Synthetic lethality-based prediction of cancer treatment response from histopathology images. Cell 3, 2487–2502.e13 (2023).

    Google Scholar 

  181. Shi, A. et al. Plasma-derived extracellular vesicle analysis and deconvolution enable prediction and tracking of melanoma checkpoint blockade outcome. Sci. Adv. 6, eabb3461 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Cao, Y. et al. Predicting tumor immune microenvironment and checkpoint therapy response of head & neck cancer patients from blood immune single-cell transcriptomics. Preprint at bioRxiv https://www.biorxiv.org/content/10.1101/2023.01.17.524455v1 (2023).

  183. Singal, A. G. et al. International liver cancer association (ILCA) white paper on biomarker development for hepatocellular carcinoma. Gastroenterology 160, 2572–2584 (2021).

    Article  PubMed  Google Scholar 

  184. Liu, J. et al. A viral exposure signature defines early onset of hepatocellular carcinoma. Cell 182, 317–328.e10 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Lo, Y. M. D., Han, D. S. C., Jiang, P. & Chiu, R. W. K. Epigenetics, fragmentomics, and topology of cell-free DNA in liquid biopsies. Science 372, eaaw3616 (2021).

    Article  CAS  PubMed  Google Scholar 

  186. Foda, Z. H. et al. Detecting liver cancer using cell-free DNA fragmentomes. Cancer Discov. 13, 616–631 (2022).

    Article  PubMed Central  Google Scholar 

  187. Dudani, J. S., Ibrahim, M., Kirkpatrick, J., Warren, A. D. & Bhatia, S. N. Classification of prostate cancer using a protease activity nanosensor library. Proc. Natl Acad. Sci. USA 115, 8954–8959 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  188. Canady, T. D. et al. Digital-resolution detection of microRNA with single-base selectivity by photonic resonator absorption microscopy. Proc. Natl Acad. Sci. USA 116, 19362–19367 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. Zhao, B. et al. Digital-resolution and highly sensitive detection of multiple exosomal small RNAs by DNA toehold probe-based photonic resonator absorption microscopy. Talanta 241, 123256 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  190. Qin, S. et al. Final analysis of RATIONALE-301: randomized, phase III study of tislelizumab versus sorafenib as first-line treatment for unresectable hepatocellular carcinoma [abstract LBA36]. Ann. Oncol. 33 (Suppl. 7), S1402–S1403 (2022).

    Article  Google Scholar 

  191. Qin, S. et al. Camrelizumab (C) plus rivoceranib (R) vs. sorafenib (S) as first-line therapy for unresectable hepatocellular carcinoma (uHCC): a randomized, phase III trial [abstract LBA35]. Ann. Oncol. 33 (Suppl. 7), S1401–S1402 (2022).

    Article  Google Scholar 

  192. Kelley, R. K. et al. Cabozantinib plus atezolizumab versus sorafenib for advanced hepatocellular carcinoma (COSMIC-312): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 23, 995–1008 (2022).

    Article  CAS  PubMed  Google Scholar 

  193. Finn, R. S. et al. Primary results from the phase III LEAP-002 study: lenvatinib plus pembrolizumab versus lenvatinib as first-line (1L) therapy for advanced hepatocellular carcinoma (aHCC) [abstract LBA34]. Ann. Oncol. 33 (Suppl. 7), S1401 (2022).

    Article  Google Scholar 

  194. Qin, S. et al. Donafenib versus sorafenib in first-line treatment of unresectable or metastatic hepatocellular carcinoma: a randomized, open-label, parallel-controlled phase II-III trial. J. Clin. Oncol. 39, 3002–3011 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. Qin, S. et al. Apatinib as second-line or later therapy in patients with advanced hepatocellular carcinoma (AHELP): a multicentre, double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Gastroenterol. Hepatol. 6, 559–568 (2021).

    Article  PubMed  Google Scholar 

  196. Qin, S. et al. Pembrolizumab versus placebo as second-line therapy in patients from Asia with advanced hepatocellular carcinoma: a randomized, double-blind, phase III trial. J. Clin. Oncol. 41, 1434–1443 (2023).

    Article  CAS  PubMed  Google Scholar 

  197. Verset, G. et al. Pembrolizumab monotherapy for previously untreated advanced hepatocellular carcinoma: data from the open-label, phase II KEYNOTE-224 trial. Clin. Cancer Res. 28, 2547–2554 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  198. Yau, T. et al. Nivolumab plus cabozantinib with or without ipilimumab for advanced hepatocellular carcinoma: results from cohort 6 of the CheckMate 040 trial. J. Clin. Oncol. 41, 1747–1757 (2023).

    Article  CAS  PubMed  Google Scholar 

  199. Xu, J. et al. Camrelizumab in combination with apatinib in patients with advanced hepatocellular carcinoma (RESCUE): a nonrandomized, open-label, phase II trial. Clin. Cancer Res. 27, 1003–1011 (2021).

    Article  CAS  PubMed  Google Scholar 

  200. Finn, R. S. et al. Phase Ib study of lenvatinib plus pembrolizumab in patients with unresectable hepatocellular carcinoma. J. Clin. Oncol. 38, 2960–2970 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  201. Kelley, R. K. et al. Safety, efficacy, and pharmacodynamics of tremelimumab plus durvalumab for patients with unresectable hepatocellular carcinoma: randomized expansion of a phase I/II study. J. Clin. Oncol. 39, 2991–3001 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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A.V., F.K., M.Y., L.M., E.R. and X.W.W researched data for the manuscript and made a substantial contribution to discussions of content. All authors wrote the manuscript, and A.V., F.K., B.R. M.Y., L.M. and E.R. edited and/or reviewed the manuscript prior to submission.

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Correspondence to Tim F. Greten.

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A.V. has acted as a consultant and/or adviser for Astra Zeneca, BMS, Eisai, FirstWorld, Genentech, Natera, NGM Pharmaceuticals, Pioneering Medicine and Roche; has received research support from Eisai; has stock options from Espervita; and is listed as an inventor on a patent related to early detection of HCC (PCT/US20/61441). M.Y. has acted as a consultant and/or adviser for AstraZeneca, Eisai, Exelixis, Genentech, Hepion and Replimune; has received research funding from Bristol-Myers Squibb, Genentech and Incyte; and holds equity in Adventris Pharmaceuticals. The other authors declare no competing interests.

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Greten, T.F., Villanueva, A., Korangy, F. et al. Biomarkers for immunotherapy of hepatocellular carcinoma. Nat Rev Clin Oncol 20, 780–798 (2023). https://doi.org/10.1038/s41571-023-00816-4

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