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Evolving therapeutic landscape of advanced hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) is one of the most common solid malignancies worldwide. A large proportion of patients with HCC are diagnosed at advanced stages and are only amenable to systemic therapies. We have witnessed the evolution of systemic therapies from single-agent targeted therapy (sorafenib and lenvatinib) to the combination of a checkpoint inhibitor plus targeted therapy (atezolizumab plus bevacizumab therapy). Despite remarkable advances, only a small subset of patients can obtain durable clinical benefit, and therefore substantial therapeutic challenges remain. In the past few years, emerging systemic therapies, including new molecular-targeted monotherapies (for example, donafenib), new immuno-oncology monotherapies (for example, durvalumab) and new combination therapies (for example, durvalumab plus tremelimumab), have shown encouraging results in clinical trials. In addition, many novel therapeutic approaches with the potential to offer improved treatment effects in patients with advanced HCC, such as sequential combination targeted therapy and next-generation adoptive cell therapy, have also been proposed and developed. In this Review, we summarize the latest clinical advances in the treatment of advanced HCC and discuss future perspectives that might inform the development of more effective therapeutics for advanced HCC.

Key points

  • Therapeutic advances have dramatically changed the systemic treatment landscape of advanced hepatocellular carcinoma (HCC).

  • Many molecular-targeted or immuno-oncology agents are being investigated as stand-alone therapies with potential predictive biomarkers for advanced HCC.

  • Combination therapies have become the current focus of treatment investigation in advanced HCC, and show remarkable therapeutic potential.

  • There has been an urgent need to develop effective biomarkers to select patients who would be most likely to benefit from well-established therapies for advanced HCC.

  • A number of innovative therapeutic approaches have been proposed, including some fascinating combination strategies involving targeted therapies and immunotherapies that provide new treatment opportunities for HCC.

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Fig. 1: Evolving systemic therapeutics for advanced HCC.
Fig. 2: Classifications of combination approaches in HCC.
Fig. 3: Immunomodulatory effects of molecular-targeted agents.
Fig. 4: Emerging targeted therapy-based strategies with therapeutic potential in HCC.
Fig. 5: Emerging immunotherapy-based strategies with therapeutic potential in HCC.

References

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

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  3. Akinyemiju, T. et al. The burden of primary liver cancer and underlying etiologies from 1990 to 2015 at the global, regional, and national level: results from the global burden of disease study 2015. JAMA Oncol. 3, 1683–1691 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  4. 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 

  5. Park, J. W. et al. Global patterns of hepatocellular carcinoma management from diagnosis to death: the BRIDGE Study. Liver Int. 35, 2155–2166 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  6. Lai, C. L., Wu, P. C., Chan, G. C., Lok, A. S. & Lin, H. J. Doxorubicin versus no antitumor therapy in inoperable hepatocellular carcinoma. A prospective randomized trial. Cancer 62, 479–483 (1988).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  8. Cheng, A. L. et al. Sunitinib versus sorafenib in advanced hepatocellular cancer: results of a randomized phase III trial. J. Clin. Oncol. 31, 4067–4075 (2013).

    Article  CAS  PubMed  Google Scholar 

  9. Johnson, P. J. et al. Brivanib versus sorafenib as first-line therapy in patients with unresectable, advanced hepatocellular carcinoma: results from the randomized phase III BRISK-FL study. J. Clin. Oncol. 31, 3517–3524 (2013).

    Article  CAS  PubMed  Google Scholar 

  10. Cainap, C. et al. Linifanib versus sorafenib in patients with advanced hepatocellular carcinoma: results of a randomized phase III trial. J. Clin. Oncol. 33, 172–179 (2015).

    Article  CAS  PubMed  Google Scholar 

  11. 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 

  12. 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 

  13. 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 

  14. 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 

  15. 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 

  16. Cheng, A. L. et al. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol. 10, 25–34 (2009).

    Article  CAS  PubMed  Google Scholar 

  17. 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 

  18. Haber, P. K. et al. Molecular markers of response to anti-PD1 therapy in advanced hepatocellular carcinoma. J. Clin. Oncol. 39, 4100–4100 (2021).

    Article  Google Scholar 

  19. Gok Yavuz, B. et al. Current landscape and future directions of biomarkers for immunotherapy in hepatocellular carcinoma. J. Hepatocell. Carcinoma 8, 1195–1207 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  20. 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 

  21. Llovet, J. M. et al. Trial design and endpoints in hepatocellular carcinoma: AASLD consensus conference. Hepatology 73, 158–191 (2021).

    Article  PubMed  Google Scholar 

  22. Gordan, J. D. et al. Systemic therapy for advanced hepatocellular carcinoma: ASCO guideline. J. Clin. Oncol. 38, 4317–4345 (2020).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  24. Finn, R. S. et al. Results of KEYNOTE-240: phase 3 study of pembrolizumab (Pembro) vs best supportive care (BSC) for second line therapy in advanced hepatocellular carcinoma (HCC) [abstract]. J. Clin. Oncol. 37 (Suppl. 15), 4004 (2019).

    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. Vogel, A. & Martinelli, E. Updated treatment recommendations for hepatocellular carcinoma (HCC) from the ESMO clinical practice guidelines. Ann. Oncol. 32, 801–805 (2021).

    Article  CAS  PubMed  Google Scholar 

  27. Cabibbo, G. et al. First-line immune checkpoint inhibitor-based sequential therapies for advanced hepatocellular carcinoma: rationale for future trials. Liver Cancer 11, 75–84 (2022).

    Article  CAS  PubMed  Google Scholar 

  28. Aoki, T. et al. Exploratory analysis of lenvatinib therapy in patients with unresectable hepatocellular carcinoma who have failed prior PD-1/PD-L1 checkpoint blockade. Cancers 12, 3048 (2020).

    Article  CAS  PubMed Central  Google Scholar 

  29. Kudo, M. Sequential therapy for hepatocellular carcinoma after failure of atezolizumab plus bevacizumab combination therapy. Liver Cancer 10, 85–93 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  30. Kudo, M. et al. Updated efficacy and safety of KEYNOTE-224: a phase II study of pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib. Eur. J. Cancer 167, 1–12 (2022).

    Article  CAS  PubMed  Google Scholar 

  31. 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 

  32. Pinter, M., Scheiner, B. & Peck-Radosavljevic, M. Immunotherapy for advanced hepatocellular carcinoma: a focus on special subgroups. Gut 70, 204–214 (2021).

    Article  CAS  PubMed  Google Scholar 

  33. Pfister, D. et al. NASH limits anti-tumour surveillance in immunotherapy-treated HCC. Nature 592, 450–456 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Haber, P. K. et al. Evidence-based management of hepatocellular carcinoma: systematic review and meta-analysis of randomized controlled trials (2002–2020). Gastroenterology 161, 879–898 (2021).

    Article  CAS  PubMed  Google Scholar 

  35. Kudo, M. Selection of systemic treatment regimen for unresectable hepatocellular carcinoma: does etiology matter? Liver Cancer 11, 283–289 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  36. Kudo, M. et al. Pembrolizumab as second-line therapy for advanced hepatocellular carcinoma: a subgroup analysis of Asian patients in the phase 3 KEYNOTE-240 trial. Liver Cancer 10, 275–284 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. 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 (Suppl. 4), 383 (2022).

    Article  Google Scholar 

  38. Liu, G. et al. Case report: complete response of primary massive hepatocellular carcinoma to anti-programmed death ligand-1 antibody following progression on anti-programmed death-1 antibody. Front. Immunol. 12, 712351 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Sanduzzi Zamparelli, M. et al. Early nivolumab addition to regorafenib in patients with hepatocellular carcinoma progressing under first-line therapy (GOING trial), interim analysis and safety profile [abstract]. J. Clin. Oncol. 40 (Suppl. 4), 428 (2022).

    Article  Google Scholar 

  40. Li, X. et al. A phase I dose-escalation, pharmacokinetics and food-effect study of oral donafenib in patients with advanced solid tumours. Cancer Chemother. Pharmacol. 85, 593–604 (2020).

    Article  CAS  PubMed  Google Scholar 

  41. 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 

  42. 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 

  43. Giordano, S. & Columbano, A. Met as a therapeutic target in HCC: facts and hopes. J. Hepatol. 60, 442–452 (2014).

    Article  CAS  PubMed  Google Scholar 

  44. Wang, H. et al. The function of the HGF/c-Met axis in hepatocellular carcinoma. Front. Cell Dev. Biol. 8, 55 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Goyal, L., Muzumdar, M. D. & Zhu, A. X. Targeting the HGF/c-MET pathway in hepatocellular carcinoma. Clin. Cancer Res. 19, 2310–2318 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Bouattour, M. et al. Recent developments of c-Met as a therapeutic target in hepatocellular carcinoma. Hepatology 67, 1132–1149 (2018).

    Article  PubMed  Google Scholar 

  47. Ryoo, B. Y. et al. Randomised phase 1b/2 trial of tepotinib vs sorafenib in Asian patients with advanced hepatocellular carcinoma with MET overexpression. Br. J. Cancer 125, 200–208 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Faivre, S. J. et al. Activity of tepotinib in hepatocellular carcinoma (HCC) with high-level MET amplification (METamp): preclinical and clinical evidence [abstract]. J. Clin. Oncol. 39 (Suppl. 3), 329 (2021).

    Article  Google Scholar 

  49. Qin, S. et al. A phase II study of the efficacy and safety of the MET inhibitor capmatinib (INC280) in patients with advanced hepatocellular carcinoma. Ther. Adv. Med. Oncol. 11, 1758835919889001 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Babina, I. S. & Turner, N. C. Advances and challenges in targeting FGFR signalling in cancer. Nat. Rev. Cancer 17, 318–332 (2017).

    Article  CAS  PubMed  Google Scholar 

  51. Lee, H. J. et al. Fibroblast growth factor receptor isotype expression and its association with overall survival in patients with hepatocellular carcinoma. Clin. Mol. Hepatol. 21, 60–70 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  52. Liu, Y. et al. Dissecting the role of the FGF19-FGFR4 signaling pathway in cancer development and progression. Front. Cell Dev. Biol. 8, 95 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  53. Wu, X. et al. FGF19-induced hepatocyte proliferation is mediated through FGFR4 activation. J. Biol. Chem. 285, 5165–5170 (2010).

    Article  CAS  PubMed  Google Scholar 

  54. Kim, R. D. et al. First-in-human phase I study of fisogatinib (BLU-554) validates aberrant FGF19 signaling as a driver event in hepatocellular carcinoma. Cancer Discov. 9, 1696–1707 (2019).

    Article  CAS  PubMed  Google Scholar 

  55. Kang, H. J. et al. Characterization of hepatocellular carcinoma patients with FGF19 amplification assessed by fluorescence in situ hybridization: a large cohort study. Liver Cancer 8, 12–23 (2019).

    Article  CAS  PubMed  Google Scholar 

  56. Pickup, M., Novitskiy, S. & Moses, H. L. The roles of TGFβ in the tumour microenvironment. Nat. Rev. Cancer 13, 788–799 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Faivre, S. et al. Novel transforming growth factor beta receptor I kinase inhibitor galunisertib (LY2157299) in advanced hepatocellular carcinoma. Liver Int. 39, 1468–1477 (2019).

    Article  CAS  PubMed  Google Scholar 

  58. Yamashita, T. et al. EpCAM and α-fetoprotein expression defines novel prognostic subtypes of hepatocellular carcinoma. Cancer Res. 68, 1451–1461 (2008).

    Article  CAS  PubMed  Google Scholar 

  59. Villanueva, A. et al. Pivotal role of mTOR signaling in hepatocellular carcinoma. Gastroenterology 135, 1972–1983 (2008).

    Article  CAS  PubMed  Google Scholar 

  60. Zhou, Q., Lui, V. W. & Yeo, W. Targeting the PI3K/Akt/mTOR pathway in hepatocellular carcinoma. Future Oncol. 7, 1149–1167 (2011).

    Article  CAS  PubMed  Google Scholar 

  61. Boyault, S. et al. Transcriptome classification of HCC is related to gene alterations and to new therapeutic targets. Hepatology 45, 42–52 (2007).

    Article  CAS  PubMed  Google Scholar 

  62. Sahin, F. et al. mTOR and P70 S6 kinase expression in primary liver neoplasms. Clin. Cancer Res. 10, 8421–8425 (2004).

    Article  CAS  PubMed  Google Scholar 

  63. Zhu, A. X. et al. Effect of everolimus on survival in advanced hepatocellular carcinoma after failure of sorafenib: the EVOLVE-1 randomized clinical trial. JAMA 312, 57–67 (2014).

    Article  PubMed  Google Scholar 

  64. Yeo, W. et al. Phase I/II study of temsirolimus for patients with unresectable hepatocellular carcinoma (HCC) – a correlative study to explore potential biomarkers for response. BMC Cancer 15, 395 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  65. Crispe, I. N. The liver as a lymphoid organ. Annu. Rev. Immunol. 27, 147–163 (2009).

    Article  CAS  PubMed  Google Scholar 

  66. Sangro, B., Sarobe, P., Hervás-Stubbs, S. & Melero, I. Advances in immunotherapy for hepatocellular carcinoma. Nat. Rev. Gastroenterol. Hepatol. 18, 525–543 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  67. 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 

  68. 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 

  69. Sun, Y. et al. Single-cell landscape of the ecosystem in early-relapse hepatocellular carcinoma. Cell 184, 404–421.e16 (2021).

    Article  CAS  PubMed  Google Scholar 

  70. Iwai, Y. et al. Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade. Proc. Natl Acad. Sci. USA 99, 12293–12297 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Jiang, Y., Chen, M., Nie, H. & Yuan, Y. PD-1 and PD-L1 in cancer immunotherapy: clinical implications and future considerations. Hum. Vaccin. Immunother. 15, 1111–1122 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  72. Maker, A. V., Attia, P. & Rosenberg, S. A. Analysis of the cellular mechanism of antitumor responses and autoimmunity in patients treated with CTLA-4 blockade. J. Immunol. 175, 7746–7754 (2005).

    Article  CAS  PubMed  Google Scholar 

  73. Sharma, A. et al. Anti-CTLA-4 immunotherapy does not deplete FOXP3(+) regulatory T cells (Tregs) in human cancers. Clin. Cancer Res. 25, 1233–1238 (2019).

    Article  CAS  PubMed  Google Scholar 

  74. 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 

  75. 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 

  76. Qin, S. et al. Camrelizumab in patients with previously treated advanced hepatocellular carcinoma: a multicentre, open-label, parallel-group, randomised, phase 2 trial. Lancet Oncol. 21, 571–580 (2020).

    Article  CAS  PubMed  Google Scholar 

  77. Desai, J. et al. Phase IA/IB study of single-agent tislelizumab, an investigational anti-PD-1 antibody, in solid tumors. J. Immunother. Cancer 8, e000453 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  78. Lee, D. W. et al. Phase II study of avelumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib. Clin. Cancer Res. 27, 713–718 (2021).

    Article  CAS  PubMed  Google Scholar 

  79. 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 

  80. Lee, M. S. et al. Atezolizumab with or without bevacizumab in unresectable hepatocellular carcinoma (GO30140): an open-label, multicentre, phase 1b study. Lancet Oncol. 21, 808–820 (2020).

    Article  CAS  PubMed  Google Scholar 

  81. Qin, S. et al. RATIONALE 301 study: tislelizumab versus sorafenib as first-line treatment for unresectable hepatocellular carcinoma. Fut. Oncol. 15, 1811–1822 (2019).

    Article  CAS  Google Scholar 

  82. Wainberg, Z. A. et al. Safety and clinical activity of durvalumab monotherapy in patients with hepatocellular carcinoma (HCC) [abstract]. J. Clin. Oncol. 35 (Suppl. 15), 4071 (2017).

    Article  Google Scholar 

  83. Abou-Alfa Ghassan, K. et al. Tremelimumab plus durvalumab in unresectable hepatocellular carcinoma. NEJM Evid. 1, EVIDoa2100070 (2022).

    Google Scholar 

  84. Kraehenbuehl, L., Weng, C. H., Eghbali, S., Wolchok, J. D. & Merghoub, T. Enhancing immunotherapy in cancer by targeting emerging immunomodulatory pathways. Nat. Rev. Clin. Oncol. 19, 37–50 (2022).

    Article  CAS  PubMed  Google Scholar 

  85. Boshuizen, J. & Peeper, D. S. Rational cancer treatment combinations: an urgent clinical need. Mol. Cell 78, 1002–1018 (2020).

    Article  CAS  PubMed  Google Scholar 

  86. Zhu, A. X. et al. SEARCH: a phase III, randomized, double-blind, placebo-controlled trial of sorafenib plus erlotinib in patients with advanced hepatocellular carcinoma. J. Clin. Oncol. 33, 559–566 (2015).

    Article  CAS  PubMed  Google Scholar 

  87. Koeberle, D. et al. Sorafenib with or without everolimus in patients with advanced hepatocellular carcinoma (HCC): a randomized multicenter, multinational phase II trial (SAKK 77/08 and SASL 29). Ann. Oncol. 27, 856–861 (2016).

    Article  CAS  PubMed  Google Scholar 

  88. Ciuleanu, T. et al. A randomized, double-blind, placebo-controlled phase II study to assess the efficacy and safety of mapatumumab with sorafenib in patients with advanced hepatocellular carcinoma. Ann. Oncol. 27, 680–687 (2016).

    Article  CAS  PubMed  Google Scholar 

  89. Cheng, A. L. et al. Safety and efficacy of tigatuzumab plus sorafenib as first-line therapy in subjects with advanced hepatocellular carcinoma: a phase 2 randomized study. J. Hepatol. 63, 896–904 (2015).

    Article  CAS  PubMed  Google Scholar 

  90. Thomas, M. B. et al. A randomized phase II open-label multi-institution study of the combination of bevacizumab and erlotinib compared to sorafenib in the first-line treatment of patients with advanced hepatocellular carcinoma. Oncology 94, 329–339 (2018).

    Article  CAS  PubMed  Google Scholar 

  91. Kelley, R. K. et al. Phase II trial of the combination of temsirolimus and sorafenib in advanced hepatocellular carcinoma with tumor mutation profiling. Liver Cancer 10, 561–571 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Jin, H. et al. EGFR activation limits the response of liver cancer to lenvatinib. Nature 595, 730–734 (2021).

    Article  CAS  PubMed  Google Scholar 

  93. Komposch, K. & Sibilia, M. EGFR signaling in liver diseases. Int. J. Mol. Sci. 17, 30 (2015).

    Article  PubMed Central  Google Scholar 

  94. Lim, H. Y. et al. Phase II studies with refametinib or refametinib plus sorafenib in patients with RAS-mutated hepatocellular carcinoma. Clin. Cancer Res. 24, 4650–4661 (2018).

    Article  CAS  PubMed  Google Scholar 

  95. Patel, S. A. & Minn, A. J. Combination cancer therapy with immune checkpoint blockade: mechanisms and strategies. Immunity 48, 417–433 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Johnson, D. B., Sullivan, R. J. & Menzies, A. M. Immune checkpoint inhibitors in challenging populations. Cancer 123, 1904–1911 (2017).

    Article  PubMed  Google Scholar 

  97. 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 

  98. Kudo, M. Scientific rationale for combination immunotherapy of hepatocellular carcinoma with anti-PD-1/PD-L1 and anti-CTLA-4 antibodies. Liver Cancer 8, 413–426 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  99. Pelizzaro, F. et al. Capecitabine in advanced hepatocellular carcinoma: a multicenter experience. Dig. Liver Dis. 51, 1713–1719 (2019).

    Article  CAS  PubMed  Google Scholar 

  100. Paik, J. Nivolumab plus relatlimab: first approval. Drugs 82, 925–931 (2022).

    Article  CAS  PubMed  Google Scholar 

  101. Majidpoor, J. & Mortezaee, K. Angiogenesis as a hallmark of solid tumors – clinical perspectives. Cell. Oncol. 44, 715–737 (2021).

    Article  CAS  Google Scholar 

  102. Jain, R. K. Antiangiogenesis strategies revisited: from starving tumors to alleviating hypoxia. Cancer Cell 26, 605–622 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Ramjiawan, R. R., Griffioen, A. W. & Duda, D. G. Anti-angiogenesis for cancer revisited: is there a role for combinations with immunotherapy? Angiogenesis 20, 185–204 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  104. Shigeta, K. et al. Dual programmed death receptor-1 and vascular endothelial growth factor receptor-2 blockade promotes vascular normalization and enhances antitumor immune responses in hepatocellular carcinoma. Hepatology 71, 1247–1261 (2020).

    Article  CAS  PubMed  Google Scholar 

  105. Hansen, W. et al. Neuropilin 1 deficiency on CD4+Foxp3+ regulatory T cells impairs mouse melanoma growth. J. Exp. Med. 209, 2001–2016 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. 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 

  107. Duan, J. et al. Use of immunotherapy with programmed cell death 1 vs programmed cell death ligand 1 inhibitors in patients with cancer: a systematic review and meta-analysis. JAMA Oncol. 6, 375–384 (2020).

    Article  PubMed  Google Scholar 

  108. Latchman, Y. et al. PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nat. Immunol. 2, 261–268 (2001).

    Article  CAS  PubMed  Google Scholar 

  109. Bang, Y. J. et al. Ramucirumab and durvalumab for previously treated, advanced non-small-cell lung cancer, gastric/gastro-oesophageal junction adenocarcinoma, or hepatocellular carcinoma: an open-label, phase Ia/b study (JVDJ). Eur. J. Cancer 137, 272–284 (2020).

    Article  CAS  PubMed  Google Scholar 

  110. Tiwari, P. Ramucirumab: boon or bane. J. Egypt. Natl Canc. Inst. 28, 133–140 (2016).

    Article  PubMed  Google Scholar 

  111. Faivre, S., Rimassa, L. & Finn, R. S. Molecular therapies for HCC: looking outside the box. J. Hepatol. 72, 342–352 (2020).

    Article  CAS  PubMed  Google Scholar 

  112. Lin, Y. Y. et al. Immunomodulatory effects of current targeted therapies on hepatocellular carcinoma: implication for the future of immunotherapy. Semin. Liver Dis. 38, 379–388 (2018).

    Article  CAS  PubMed  Google Scholar 

  113. Cheng, A. L., Hsu, C., Chan, S. L., Choo, S. P. & Kudo, M. Challenges of combination therapy with immune checkpoint inhibitors for hepatocellular carcinoma. J. Hepatol. 72, 307–319 (2020).

    Article  CAS  PubMed  Google Scholar 

  114. Kimura, T. et al. Immunomodulatory activity of lenvatinib contributes to antitumor activity in the Hepa1-6 hepatocellular carcinoma model. Cancer Sci. 109, 3993–4002 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Zhu, S. et al. Combination strategies to maximize the benefits of cancer immunotherapy. J. Hematol. Oncol. 14, 156 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  116. 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 

  117. Yang, J.-H. et al. Pembrolizumab (Pembro) with or without lenvatinib (Lenva) in first-line metastatic NSCLC with PD-L1 TPS ≥1% (LEAP-007): a phase 3, randomized, double-blind study [abstract 120O]. Ann. Oncol. 32 (Suppl. 7), 1429–1430 (2021).

    Article  Google Scholar 

  118. Loriot, Y. et al. First-line pembrolizumab (pembro) with or without lenvatinib (lenva) in patients with advanced urothelial carcinoma (LEAP-011): a phase 3, randomized, double-blind study [abstract]. J. Clin. Oncol. 40 (Suppl. 6), 432 (2022).

    Article  Google Scholar 

  119. 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 

  120. Tannock, I. F., Pond, G. R. & Booth, C. M. Biased evaluation in cancer drug trials-how use of progression-free survival as the primary end point can mislead. JAMA Oncol. 8, 679–680 (2022).

    Article  PubMed  Google Scholar 

  121. Llovet, J. M., Montal, R. & Villanueva, A. Randomized trials and endpoints in advanced HCC: role of PFS as a surrogate of survival. J. Hepatol. 70, 1262–1277 (2019).

    Article  PubMed  Google Scholar 

  122. Cabibbo, G. et al. Progression-free survival early assessment is a robust surrogate endpoint of overall survival in immunotherapy trials of hepatocellular carcinoma. Cancers 13, 90 (2020).

    Article  PubMed Central  Google Scholar 

  123. Han, C. et al. Clinical activity and safety of penpulimab (anti-PD-1) with anlotinib as first-line therapy for unresectable hepatocellular carcinoma: an open-label, multicenter, phase Ib/II trial (AK105-203). Front. Oncol. 11, 684867 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  124. 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 

  125. Chen, J., Gingold, J. A. & Su, X. Immunomodulatory TGF-β signaling in hepatocellular carcinoma. Trends Mol. Med. 25, 1010–1023 (2019).

    Article  CAS  PubMed  Google Scholar 

  126. Das, L. & Levine, A. D. TGF-β inhibits IL-2 production and promotes cell cycle arrest in TCR-activated effector/memory T cells in the presence of sustained TCR signal transduction. J. Immunol. 180, 1490–1498 (2008).

    Article  CAS  PubMed  Google Scholar 

  127. Thomas, D. A. & Massagué, J. TGF-β directly targets cytotoxic T cell functions during tumor evasion of immune surveillance. Cancer Cell 8, 369–380 (2005).

    Article  CAS  PubMed  Google Scholar 

  128. Derynck, R., Turley, S. J. & Akhurst, R. J. TGFβ biology in cancer progression and immunotherapy. Nat. Rev. Clin. Oncol. 18, 9–34 (2021).

    Article  PubMed  Google Scholar 

  129. Gorelik, L., Constant, S. & Flavell, R. A. Mechanism of transforming growth factor β-induced inhibition of T helper type 1 differentiation. J. Exp. Med. 195, 1499–1505 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Chen, W. et al. Conversion of peripheral CD4+CD25 naive T cells to CD4+CD25+ regulatory T cells by TGF-β induction of transcription factor Foxp3. J. Exp. Med. 198, 1875–1886 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Zhang, F. et al. TGF-β induces M2-like macrophage polarization via SNAIL-mediated suppression of a pro-inflammatory phenotype. Oncotarget 7, 52294–52306 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  132. Lee, C. R., Lee, W., Cho, S. K. & Park, S. G. Characterization of multiple cytokine combinations and TGF-β on differentiation and functions of myeloid-derived suppressor cells. Int. J. Mol. Sci. 19, 869 (2018).

    Article  PubMed Central  Google Scholar 

  133. Tauriello, D. V. F. et al. TGFβ drives immune evasion in genetically reconstituted colon cancer metastasis. Nature 554, 538–543 (2018).

    Article  CAS  PubMed  Google Scholar 

  134. Gupta, A. et al. Isoform specific anti-TGFβ therapy enhances antitumor efficacy in mouse models of cancer. Commun. Biol. 4, 1296 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Mariathasan, S. et al. TGFβ attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells. Nature 554, 544–548 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Chen, J. et al. Analysis of genomes and transcriptomes of hepatocellular carcinomas identifies mutations and gene expression changes in the transforming growth factor-β pathway. Gastroenterology 154, 195–210 (2018).

    Article  CAS  PubMed  Google Scholar 

  137. 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 

  138. Villanueva, L., Álvarez-Errico, D. & Esteller, M. The contribution of epigenetics to cancer immunotherapy. Trends Immunol. 41, 676–691 (2020).

    Article  CAS  PubMed  Google Scholar 

  139. Topper, M. J., Vaz, M., Marrone, K. A., Brahmer, J. R. & Baylin, S. B. The emerging role of epigenetic therapeutics in immuno-oncology. Nat. Rev. Clin. Oncol. 17, 75–90 (2020).

    Article  PubMed  Google Scholar 

  140. Kulis, M. & Esteller, M. DNA methylation and cancer. Adv. Genet. 70, 27–56 (2010).

    Article  PubMed  Google Scholar 

  141. Audia, J. E. & Campbell, R. M. Histone modifications and cancer. Cold Spring Harb. Perspect. Biol. 8, a019521 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  142. Jones, P. A., Ohtani, H., Chakravarthy, A. & De Carvalho, D. D. Epigenetic therapy in immune-oncology. Nat. Rev. Cancer 19, 151–161 (2019).

    Article  CAS  PubMed  Google Scholar 

  143. Scharer, C. D., Bally, A. P., Gandham, B. & Boss, J. M. Cutting edge: chromatin accessibility programs CD8 T cell memory. J. Immunol. 198, 2238–2243 (2017).

    Article  CAS  PubMed  Google Scholar 

  144. Ghoneim, H. E. et al. De novo epigenetic programs inhibit PD-1 blockade-mediated T cell rejuvenation. Cell 170, 142–157.e19 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Wherry, E. J. & Kurachi, M. Molecular and cellular insights into T cell exhaustion. Nat. Rev. Immunol. 15, 486–499 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Pauken, K. E. et al. Epigenetic stability of exhausted T cells limits durability of reinvigoration by PD-1 blockade. Science 354, 1160–1165 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Hong, Y. K. et al. Epigenetic modulation enhances immunotherapy for hepatocellular carcinoma. Cell. Immunol. 336, 66–74 (2019).

    Article  CAS  PubMed  Google Scholar 

  148. Llopiz, D. et al. Enhanced anti-tumor efficacy of checkpoint inhibitors in combination with the histone deacetylase inhibitor belinostat in a murine hepatocellular carcinoma model. Cancer Immunol. Immunother. 68, 379–393 (2019).

    Article  CAS  PubMed  Google Scholar 

  149. Yang, W. et al. A selective HDAC8 inhibitor potentiates antitumor immunity and efficacy of immune checkpoint blockade in hepatocellular carcinoma. Sci. Transl. Med. 13, eaaz6804 (2021).

    Article  CAS  PubMed  Google Scholar 

  150. Yen, Y. T. et al. Protein phosphatase 2A inactivation induces microsatellite instability, neoantigen production and immune response. Nat. Commun. 12, 7297 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. O’Donnell, J. S., Massi, D., Teng, M. W. L. & Mandala, M. PI3K-AKT-mTOR inhibition in cancer immunotherapy, redux. Semin. Cancer Biol. 48, 91–103 (2018).

    Article  PubMed  Google Scholar 

  152. Dong, Y. et al. PTEN functions as a melanoma tumor suppressor by promoting host immune response. Oncogene 33, 4632–4642 (2014).

    Article  CAS  PubMed  Google Scholar 

  153. Peng, W. et al. Loss of PTEN promotes resistance to T cell-mediated immunotherapy. Cancer Discov. 6, 202–216 (2016).

    Article  CAS  PubMed  Google Scholar 

  154. Ying, H. et al. PTEN is a major tumor suppressor in pancreatic ductal adenocarcinoma and regulates an NF-κB-cytokine network. Cancer Discov. 1, 158–169 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Lastwika, K. J. et al. Control of PD-L1 expression by oncogenic activation of the AKT-mTOR pathway in non-small cell lung cancer. Cancer Res. 76, 227–238 (2016).

    Article  CAS  PubMed  Google Scholar 

  156. Zhu, S. et al. Synergistic antitumor activity of pan-PI3K inhibition and immune checkpoint blockade in bladder cancer. J. Immunother. Cancer 9, e002917 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  157. Yi, C. et al. Lenvatinib targets FGF receptor 4 to enhance antitumor immune response of anti-programmed cell death-1 in HCC. Hepatology 74, 2544–2560 (2021).

    Article  CAS  PubMed  Google Scholar 

  158. Saigi, M. et al. MET-oncogenic and JAK2-inactivating alterations are independent factors that affect regulation of PD-L1 expression in lung cancer. Clin. Cancer Res. 24, 4579–4587 (2018).

    Article  CAS  PubMed  Google Scholar 

  159. Albitar, M. et al. Correlation of MET gene amplification and TP53 mutation with PD-L1 expression in non-small cell lung cancer. Oncotarget 9, 13682–13693 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  160. Wang, D. et al. The hepatocyte growth factor antagonist NK4 inhibits indoleamine-2,3-dioxygenase expression via the c-Met-phosphatidylinositol 3-kinase-AKT signaling pathway. Int. J. Oncol. 48, 2303–2309 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Glodde, N. et al. Reactive neutrophil responses dependent on the receptor tyrosine kinase c-MET limit cancer immunotherapy. Immunity 47, 789–802.e9 (2017).

    Article  CAS  PubMed  Google Scholar 

  162. He, M. et al. Peritumoral stromal neutrophils are essential for c-Met-elicited metastasis in human hepatocellular carcinoma. Oncoimmunology 5, e1219828 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  163. Titmarsh, H. F., O’Connor, R., Dhaliwal, K. & Akram, A. R. The emerging role of the c-MET-HGF axis in non-small cell lung cancer tumor immunology and immunotherapy. Front. Oncol. 10, 54 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  164. Llovet, J. M., Montal, R., Sia, D. & Finn, R. S. Molecular therapies and precision medicine for hepatocellular carcinoma. Nat. Rev. Clin. Oncol. 15, 599–616 (2018).

    Article  PubMed  Google Scholar 

  165. 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 

  166. Feng, J. et al. ACSL4 is a predictive biomarker of sorafenib sensitivity in hepatocellular carcinoma. Acta Pharmacol. Sin. 42, 160–170 (2021).

    Article  CAS  PubMed  Google Scholar 

  167. Horwitz, E. et al. Human and mouse VEGFA-amplified hepatocellular carcinomas are highly sensitive to sorafenib treatment. Cancer Discov. 4, 730–743 (2014).

    Article  CAS  PubMed  Google Scholar 

  168. Myojin, Y. et al. ST6GAL1 is a novel serum biomarker for lenvatinib-susceptible FGF19-driven hepatocellular carcinoma. Clin. Cancer Res. 27, 1150–1161 (2021).

    Article  CAS  PubMed  Google Scholar 

  169. Finn, R. S. et al. Pharmacodynamic biomarkers predictive of survival benefit with lenvatinib in unresectable hepatocellular carcinoma: from the phase III REFLECT study. Clin. Cancer Res. 27, 4848–4858 (2021).

    Article  CAS  PubMed  Google Scholar 

  170. Yamauchi, M. et al. Tumor fibroblast growth factor receptor 4 level predicts the efficacy of lenvatinib in patients with advanced hepatocellular carcinoma. Clin. Transl. Gastroenterol. 11, e00179 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  171. Teufel, M. et al. Biomarkers associated with response to regorafenib in patients with hepatocellular carcinoma. Gastroenterology 156, 1731–1741 (2019).

    Article  CAS  PubMed  Google Scholar 

  172. Kelley, R. K. et al. Serum alpha-fetoprotein levels and clinical outcomes in the phase III CELESTIAL study of cabozantinib versus placebo in patients with advanced hepatocellular carcinoma. Clin. Cancer Res. 26, 4795–4804 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. 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 

  174. 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 

  175. 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 

  176. Pinato, D. J. et al. Clinical implications of heterogeneity in PD-L1 immunohistochemical detection in hepatocellular carcinoma: the Blueprint-HCC study. Br. J. Cancer 120, 1033–1036 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  177. Marabelle, A. et al. Association of tumour mutational burden with outcomes in patients with advanced solid tumours treated with pembrolizumab: prospective biomarker analysis of the multicohort, open-label, phase 2 KEYNOTE-158 study. Lancet Oncol. 21, 1353–1365 (2020).

    Article  CAS  PubMed  Google Scholar 

  178. Chan, T. A. et al. Development of tumor mutation burden as an immunotherapy biomarker: utility for the oncology clinic. Ann. Oncol. 30, 44–56 (2019).

    Article  CAS  PubMed  Google Scholar 

  179. McGrail, D. J. et al. High tumor mutation burden fails to predict immune checkpoint blockade response across all cancer types. Ann. Oncol. 32, 661–672 (2021).

    Article  CAS  PubMed  Google Scholar 

  180. 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 

  181. Zhu, A. X. et al. Abstract CT044: Genomic correlates of clinical benefits from atezolizumab combined with bevacizumab vs. atezolizumab alone in patients with advanced hepatocellular carcinoma (HCC) [abstract]. Cancer Res. 80 (16 Suppl.), CT044 (2020).

    Article  Google Scholar 

  182. 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 

  183. Sia, D. et al. Identification of an immune-specific class of hepatocellular carcinoma, based on molecular features. Gastroenterology 153, 812–826 (2017).

    Article  CAS  PubMed  Google Scholar 

  184. Pinyol, R., Sia, D. & Llovet, J. M. Immune exclusion-Wnt/CTNNB1 class predicts resistance to immunotherapies in HCC. Clin. Cancer Res. 25, 2021–2023 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Montironi, C. et al. Inflamed and non-inflamed classes of HCC: a revised immunogenomic classification. Gut https://doi.org/10.1136/gutjnl-2021-325918 (2022).

    Article  PubMed  Google Scholar 

  186. 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  PubMed Central  Google Scholar 

  187. 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 

  188. Hsu, C.-H. et al. Longitudinal and personalized detection of circulating tumor DNA (ctDNA) for monitoring efficacy of atezolizumab plus bevacizumab in patients with unresectable hepatocellular carcinoma (HCC) [abstract]. J. Clin. Oncol. 38 (Suppl. 15), 3531 (2020).

    Article  Google Scholar 

  189. Zucman-Rossi, J., Villanueva, A., Nault, J. C. & Llovet, J. M. Genetic landscape and biomarkers of hepatocellular carcinoma. Gastroenterology 149, 1226–1239.e4 (2015).

    Article  CAS  PubMed  Google Scholar 

  190. Nault, J. C. et al. Telomerase reverse transcriptase promoter mutation is an early somatic genetic alteration in the transformation of premalignant nodules in hepatocellular carcinoma on cirrhosis. Hepatology 60, 1983–1992 (2014).

    Article  CAS  PubMed  Google Scholar 

  191. Kotiyal, S. & Evason, K. J. Exploring the interplay of telomerase reverse transcriptase and β-catenin in hepatocellular carcinoma. Cancers 13, 4202 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  192. Ningarhari, M. et al. Telomere length is key to hepatocellular carcinoma diversity and telomerase addiction is an actionable therapeutic target. J. Hepatol. 74, 1155–1166 (2021).

    Article  CAS  PubMed  Google Scholar 

  193. Vilchez, V., Turcios, L., Marti, F. & Gedaly, R. Targeting Wnt/β-catenin pathway in hepatocellular carcinoma treatment. World J. Gastroenterol. 22, 823–832 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  194. Zhang, Y. & Wang, X. Targeting the Wnt/β-catenin signaling pathway in cancer. J. Hematol. Oncol. 13, 165 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  195. Jung, Y. S. & Park, J. I. Wnt signaling in cancer: therapeutic targeting of Wnt signaling beyond β-catenin and the destruction complex. Exp. Mol. Med. 52, 183–191 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  196. Aubrey, B. J., Strasser, A. & Kelly, G. L. Tumor-suppressor functions of the TP53 pathway. Cold Spring Harb. Perspect. Med. 6, a026062 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  197. Morris, L. G. & Chan, T. A. Therapeutic targeting of tumor suppressor genes. Cancer 121, 1357–1368 (2015).

    Article  CAS  PubMed  Google Scholar 

  198. Chen, S. et al. Arsenic trioxide rescues structural p53 mutations through a cryptic allosteric site. Cancer Cell 39, 225–239.e8 (2021).

    Article  PubMed  Google Scholar 

  199. Schuler, M. et al. A phase I study of adenovirus-mediated wild-type p53 gene transfer in patients with advanced non-small cell lung cancer. Hum. Gene Ther. 9, 2075–2082 (1998).

    Article  CAS  PubMed  Google Scholar 

  200. Shangary, S. et al. Temporal activation of p53 by a specific MDM2 inhibitor is selectively toxic to tumors and leads to complete tumor growth inhibition. Proc. Natl Acad. Sci. USA 105, 3933–3938 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  201. Weissmueller, S. et al. Mutant p53 drives pancreatic cancer metastasis through cell-autonomous PDGF receptor β signaling. Cell 157, 382–394 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  202. Dauch, D. et al. A MYC-aurora kinase A protein complex represents an actionable drug target in p53-altered liver cancer. Nat. Med. 22, 744–753 (2016).

    Article  CAS  PubMed  Google Scholar 

  203. Yang, C. et al. Mapping the landscape of synthetic lethal interactions in liver cancer. Theranostics 11, 9038–9053 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  204. Wang, C. et al. Inducing and exploiting vulnerabilities for the treatment of liver cancer. Nature 574, 268–272 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  205. Settleman, J., Neto, J. M. F. & Bernards, R. Thinking differently about cancer treatment regimens. Cancer Discov. 11, 1016–1023 (2021).

    Article  CAS  PubMed  Google Scholar 

  206. Wang, L. et al. High-throughput functional genetic and compound screens identify targets for senescence induction in cancer. Cell Rep. 21, 773–783 (2017).

    Article  CAS  PubMed  Google Scholar 

  207. Prahallad, A. et al. Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR. Nature 483, 100–103 (2012).

    Article  CAS  PubMed  Google Scholar 

  208. Sun, C. et al. Reversible and adaptive resistance to BRAF(V600E) inhibition in melanoma. Nature 508, 118–122 (2014).

    Article  CAS  PubMed  Google Scholar 

  209. Manchado, E. et al. A combinatorial strategy for treating KRAS-mutant lung cancer. Nature 534, 647–651 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  210. Sun, C. et al. Intrinsic resistance to MEK inhibition in KRAS mutant lung and colon cancer through transcriptional induction of ERBB3. Cell Rep. 7, 86–93 (2014).

    Article  CAS  PubMed  Google Scholar 

  211. Kopetz, S. et al. Encorafenib, binimetinib, and cetuximab in BRAF V600E-mutated colorectal cancer. N. Engl. J. Med. 381, 1632–1643 (2019).

    Article  CAS  PubMed  Google Scholar 

  212. Fernandes Neto, J. M. et al. Multiple low dose therapy as an effective strategy to treat EGFR inhibitor-resistant NSCLC tumours. Nat. Commun. 11, 3157 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  213. O’Neil, N. J., Bailey, M. L. & Hieter, P. Synthetic lethality and cancer. Nat. Rev. Genet. 18, 613–623 (2017).

    Article  PubMed  Google Scholar 

  214. Fong, P. C. et al. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N. Engl. J. Med. 361, 123–134 (2009).

    Article  CAS  PubMed  Google Scholar 

  215. Tang, L., Chen, R. & Xu, X. Synthetic lethality: a promising therapeutic strategy for hepatocellular carcinoma. Cancer Lett. 476, 120–128 (2020).

    Article  CAS  PubMed  Google Scholar 

  216. Wang, L. & Bernards, R. Taking advantage of drug resistance, a new approach in the war on cancer. Front. Med. 12, 490–495 (2018).

    Article  PubMed  Google Scholar 

  217. Pogrebniak, K. L. & Curtis, C. Harnessing tumor evolution to circumvent resistance. Trends Genet. 34, 639–651 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  218. Wang, L. et al. An acquired vulnerability of drug-resistant melanoma with therapeutic potential. Cell 173, 1413–1425.e4 (2018).

    Article  CAS  PubMed  Google Scholar 

  219. Vander Velde, R. et al. Resistance to targeted therapies as a multifactorial, gradual adaptation to inhibitor specific selective pressures. Nat. Commun. 11, 2393 (2020).

    Article  Google Scholar 

  220. Acar, A. et al. Exploiting evolutionary steering to induce collateral drug sensitivity in cancer. Nat. Commun. 11, 1923 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  221. Laskowski, T. & Rezvani, K. Adoptive cell therapy: living drugs against cancer. J. Exp. Med. 217, e20200377 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  222. Akhoundi, M., Mohammadi, M., Sahraei, S. S., Sheykhhasan, M. & Fayazi, N. CAR T cell therapy as a promising approach in cancer immunotherapy: challenges and opportunities. Cell. Oncol. 44, 495–523 (2021).

    Article  CAS  Google Scholar 

  223. Takayama, T. et al. Adoptive immunotherapy to lower postsurgical recurrence rates of hepatocellular carcinoma: a randomised trial. Lancet 356, 802–807 (2000).

    Article  CAS  PubMed  Google Scholar 

  224. Shi, M. et al. Autologous cytokine-induced killer cell therapy in clinical trial phase I is safe in patients with primary hepatocellular carcinoma. World J. Gastroenterol. 10, 1146–1151 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  225. Jiang, S. S. et al. A phase I clinical trial utilizing autologous tumor-infiltrating lymphocytes in patients with primary hepatocellular carcinoma. Oncotarget 6, 41339–41349 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  226. Rochigneux, P. et al. Adoptive cell therapy in hepatocellular carcinoma: biological rationale and first results in early phase clinical trials. Cancers 13, 271 (2021).

    Article  CAS  PubMed Central  Google Scholar 

  227. Zhao, Q. et al. Engineered TCR-T cell immunotherapy in anticancer precision medicine: pros and cons. Front. Immunol. 12, 658753 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  228. Roddy, H., Meyer, T. & Roddie, C. Novel cellular therapies for hepatocellular carcinoma. Cancers 14, 504 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  229. Shi, D. et al. Chimeric antigen receptor-glypican-3 T-cell therapy for advanced hepatocellular carcinoma: results of phase I trials. Clin. Cancer Res. 26, 3979–3989 (2020).

    Article  CAS  PubMed  Google Scholar 

  230. Liu, Z. et al. Immunotherapy for hepatocellular carcinoma: current status and future prospects. Front. Immunol. 12, 765101 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  231. Nakagawa, H. et al. Association between high-avidity T-cell receptors, induced by α-fetoprotein-derived peptides, and anti-tumor effects in patients with hepatocellular carcinoma. Gastroenterology 152, 1395–1406.e10 (2017).

    Article  CAS  PubMed  Google Scholar 

  232. Sawada, Y. et al. Phase II study of the GPC3-derived peptide vaccine as an adjuvant therapy for hepatocellular carcinoma patients. Oncoimmunology 5, e1129483 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  233. Mizukoshi, E. et al. Phase I trial of multidrug resistance-associated protein 3-derived peptide in patients with hepatocellular carcinoma. Cancer Lett. 369, 242–249 (2015).

    Article  CAS  PubMed  Google Scholar 

  234. Santos, P. M. & Butterfield, L. H. Dendritic cell-based cancer vaccines. J. Immunol. 200, 443–449 (2018).

    Article  CAS  PubMed  Google Scholar 

  235. Melcher, A., Harrington, K. & Vile, R. Oncolytic virotherapy as immunotherapy. Science 374, 1325–1326 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  236. Palmer, D. H. et al. A phase II study of adoptive immunotherapy using dendritic cells pulsed with tumor lysate in patients with hepatocellular carcinoma. Hepatology 49, 124–132 (2009).

    Article  PubMed  Google Scholar 

  237. Heo, J. et al. Randomized dose-finding clinical trial of oncolytic immunotherapeutic vaccinia JX-594 in liver cancer. Nat. Med. 19, 329–336 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  238. Tian, Y., Xie, D. & Yang, L. Engineering strategies to enhance oncolytic viruses in cancer immunotherapy. Signal. Transduct. Target. Ther. 7, 117 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  239. Dahlén, E., Veitonmäki, N. & Norlén, P. Bispecific antibodies in cancer immunotherapy. Ther. Adv. Vaccines Immunother. 6, 3–17 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  240. Dovedi, S. J. et al. Design and efficacy of a monovalent bispecific PD-1/CTLA4 antibody that enhances CTLA4 blockade on PD-1(+) activated T cells. Cancer Discov. 11, 1100–1117 (2021).

    Article  CAS  PubMed  Google Scholar 

  241. Yu, L. et al. A novel targeted GPC3/CD3 bispecific antibody for the treatment hepatocellular carcinoma. Cancer Biol. Ther. 21, 597–603 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  242. Bai, L. et al. Phase 2 study of AK104 (PD-1/CTLA-4 bispecific antibody) plus lenvatinib as first-line treatment of unresectable hepatocellular carcinoma [abstract]. J. Clin. Oncol. 39 (Suppl. 15), 4101 (2021).

    Article  Google Scholar 

  243. Temraz, S. et al. Hepatocellular carcinoma immunotherapy and the potential influence of gut microbiome. Int. J. Mol. Sci. 22, 7800 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  244. Zheng, Y. et al. Gut microbiome affects the response to anti-PD-1 immunotherapy in patients with hepatocellular carcinoma. J. Immunother. Cancer 7, 193 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  245. Mao, J. et al. Gut microbiome is associated with the clinical response to anti-PD-1 based immunotherapy in hepatobiliary cancers. J. Immunother. Cancer 9, e003334 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  246. 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 

  247. Gao, Q. et al. Integrated proteogenomic characterization of HBV-related hepatocellular carcinoma. Cell 179, 561–577.e22 (2019).

    Article  CAS  PubMed  Google Scholar 

  248. Bruix, J. et al. Prognostic factors and predictors of sorafenib benefit in patients with hepatocellular carcinoma: analysis of two phase III studies. J. Hepatol. 67, 999–1008 (2017).

    Article  CAS  PubMed  Google Scholar 

  249. Jackson, R., Psarelli, E. E., Berhane, S., Khan, H. & Johnson, P. Impact of viral status on survival in patients receiving sorafenib for advanced hepatocellular cancer: a meta-analysis of randomized phase III trials. J. Clin. Oncol. 35, 622–628 (2017).

    Article  PubMed  Google Scholar 

  250. Park, J., Cho, J., Lim, J. H., Lee, M. H. & Kim, J. Relative efficacy of systemic treatments for patients with advanced hepatocellular carcinoma according to viral status: a systematic review and network meta-analysis. Target. Oncol. 14, 395–403 (2019).

    Article  PubMed  Google Scholar 

  251. Yang, Y. et al. A high baseline HBV load and antiviral therapy affect the survival of patients with advanced HBV-related HCC treated with sorafenib. Liver Int. 35, 2147–2154 (2015).

    Article  CAS  PubMed  Google Scholar 

  252. Tomonari, T. et al. Therapeutic efficacy of lenvatinib in nonviral unresectable hepatocellular carcinoma. JGH Open 5, 1275–1283 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  253. 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 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  255. Anstee, Q. M., Reeves, H. L., Kotsiliti, E., Govaere, O. & Heikenwalder, M. From NASH to HCC: current concepts and future challenges. Nat. Rev. Gastroenterol. Hepatol. 16, 411–428 (2019).

    Article  PubMed  Google Scholar 

  256. Howell, J. et al. Impact of NAFLD on clinical outcomes in hepatocellular carcinoma treated with sorafenib: an international cohort study [abstract]. J. Clin. Oncol. 39 (Suppl. 3), 289 (2021).

    Article  Google Scholar 

  257. Hiraoka, A. et al. Efficacy of lenvatinib for unresectable hepatocellular carcinoma based on background liver disease etiology: multi-center retrospective study. Sci. Rep. 11, 16663 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  258. Lopez, J. S. & Banerji, U. Combine and conquer: challenges for targeted therapy combinations in early phase trials. Nat. Rev. Clin. Oncol. 14, 57–66 (2017).

    Article  CAS  PubMed  Google Scholar 

  259. Park, R., Lopes, L., Cristancho, C. R., Riano, I. M. & Saeed, A. Treatment-related adverse events of combination immune checkpoint inhibitors: systematic review and meta-analysis. Front. Oncol. 10, 258 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  260. Gu, L. et al. The safety and tolerability of combined immune checkpoint inhibitors (anti-PD-1/PD-L1 plus anti-CTLA-4): a systematic review and meta-analysis. BMC Cancer 19, 559 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  261. Zhou, X. et al. Treatment-related adverse events of PD-1 and PD-L1 inhibitor-based combination therapies in clinical trials: a systematic review and meta-analysis. Lancet Oncol. 22, 1265–1274 (2021).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The research of the authors was funded by grants from the European Research Council (ERC 787925 to R.B.), the National Natural Science Foundation of China (81920108025 (W.Q.), 81874229 (C.W.), 82072633 (C.W.) and 82122047 (C.W.)) and the Innovative Research Team of High-level Local Universities in Shanghai (SHSMU-ZLCX20211602 (C.W.)). The authors apologize to those researchers whose work was not included in this Review due to space constraints.

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Yang, C., Zhang, H., Zhang, L. et al. Evolving therapeutic landscape of advanced hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol (2022). https://doi.org/10.1038/s41575-022-00704-9

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