Zhai, W. et al. The spatial organization of intra-tumour heterogeneity and evolutionary trajectories of metastases in hepatocellular carcinoma. Nat. Commun. 8, 4565 (2017).
Rumgay, H. et al. Global burden of primary liver cancer in 2020 and predictions to 2040. J. Hepatol. 77, 1598–1606 (2022).
Wu, J. et al. A noninvasive approach to evaluate tumor immune microenvironment and predict outcomes in hepatocellular carcinoma. Phenomics 3, 549–564 (2023).
Brown, Z. J. et al. Management of hepatocellular carcinoma: a review. JAMA Surgery 158, 410–420 (2023).
Singal, A. G., Kudo, M. & Bruix, J. Breakthroughs in hepatocellular carcinoma therapies. Clin. Gastroenterol. Hepatol. 21, 2135–2149 (2023).
Elderkin, J. et al. Hepatocellular carcinoma: surveillance, diagnosis, evaluation and management. Cancers 15, 5118 (2023).
Schürch, C. M. et al. Coordinated cellular neighborhoods orchestrate antitumoral immunity at the colorectal cancer invasive front. Cell 182, 1341–1359.e19 (2020).
Casasent, A. K. et al. Multiclonal invasion in breast tumors identified by topographic single cell sequencing. Cell 172, 205–217.e12 (2018).
Sun, C., Sun, H.-y, Xiao, W.-h, Zhang, C. & Tian, Z.-g Natural killer cell dysfunction in hepatocellular carcinoma and NK cell-based immunotherapy. Acta Pharmacol. Sin. 36, 1191–1199 (2015).
Nersesian, S. et al. NK cell infiltration is associated with improved overall survival in solid cancers: a systematic review and meta-analysis. Transl. Oncol. 14, 100930 (2021).
Lee, H. A. et al. Natural killer cell activity is a risk factor for the recurrence risk after curative treatment of hepatocellular carcinoma. BMC Gastroenterol. 21, 258 (2021).
Juengpanich, S. et al. The role of natural killer cells in hepatocellular carcinoma development and treatment: a narrative review. Transl. Oncol. 12, 1092–1107 (2019).
Xue, J. S. et al. The prognostic value of natural killer cells and their receptors/ligands in hepatocellular carcinoma: a systematic review and meta-analysis. Front. Immunol. 13, 872353 (2022).
Zhao, J.-J. et al. Interleukin-37 mediates the antitumor activity in hepatocellular carcinoma: role for CD57+ NK cells. Sci. Rep. 4, 5177 (2014).
Chew, V. et al. Toll-like receptor 3 expressing tumor parenchyma and infiltrating natural killer cells in hepatocellular carcinoma patients. J. Natl Cancer Inst. 104, 1796–1807 (2012).
Wu, Y. et al. Monocyte/macrophage-elicited natural killer cell dysfunction in hepatocellular carcinoma is mediated by CD48/2B4 interactions. Hepatology 57, 1107–1116 (2013).
Sun, H. et al. Accumulation of tumor-infiltrating CD49a+ NK cells correlates with poor prognosis for human hepatocellular carcinoma. Cancer Immunol. Res. 7, 1535–1546 (2019).
Sun, H. et al. Human CD96 correlates to natural killer cell exhaustion and predicts the prognosis of human hepatocellular carcinoma. Hepatology 70, 168–183 (2019).
Wu, M., Mei, F., Liu, W. & Jiang, J. Comprehensive characterization of tumor infiltrating natural killer cells and clinical significance in hepatocellular carcinoma based on gene expression profiles. Biomed. Pharmacother. 121, 109637 (2020).
Pinyol, R. et al. Molecular predictors of prevention of recurrence in HCC with sorafenib as adjuvant treatment and prognostic factors in the phase 3 STORM trial. Gut 68, 1065–1075 (2019).
Li, J. H. & O’Sullivan, T. E. Back to the future: spatiotemporal determinants of NK cell antitumor function. Front. Immunol. 12, 816658 (2022).
Fu, T. et al. Spatial architecture of the immune microenvironment orchestrates tumor immunity and therapeutic response. J. Hematol. Oncol. 14, 98 (2021).
Wu, L. et al. Spatially-resolved transcriptomics analyses of invasive fronts in solid tumors. Preprint at bioRxiv https://doi.org/10.1101/2021.10.21.465135 (2021).
Sorin, M. et al. Single-cell spatial landscapes of the lung tumour immune microenvironment. Nature 614, 548–554 (2023).
Elhanani, O., Ben-Uri, R. & Keren, L. Spatial profiling technologies illuminate the tumor microenvironment. Cancer Cell 41, 404–420 (2023).
Zhao, N. et al. Spatial maps of hepatocellular carcinoma transcriptomes highlight an unexplored landscape of heterogeneity and a novel gene signature for survival. Cancer Cell Int. 22, 57 (2022).
Wu, R. et al. Comprehensive analysis of spatial architecture in primary liver cancer. Sci. Adv. 7, eabg3750 (2021).
Sun, Y. et al. Single-cell landscape of the ecosystem in early-relapse hepatocellular carcinoma. Cell 184, 404–421.e16 (2021).
Chang, J. et al. Genomic alterations driving precancerous to cancerous lesions in esophageal cancer development. Cancer Cell 41, 2038–2050.e5 (2023).
Li, L. et al. Comprehensive proteogenomic characterization of early duodenal cancer reveals the carcinogenesis tracks of different subtypes. Nat. Commun. 14, 1751 (2023).
Mund, A. et al. Deep Visual Proteomics defines single-cell identity and heterogeneity. Nat. Biotechnol. 40, 1231–1240 (2022).
Xiang, H. et al. Region-resolved multi-omics of the mouse eye. Cell Rep. 42, 112121 (2023).
Qu, Y. et al. A proteogenomic analysis of clear cell renal cell carcinoma in a Chinese population. Nat. Commun. 13, 2052 (2022).
Cheung, C. C. L. et al. Residual SARS-CoV-2 viral antigens detected in GI and hepatic tissues from five recovered patients with COVID-19. Gut 71, 226–229 (2022).
Kaya, N. A. et al. Multimodal molecular landscape of response to Y90-resin microsphere radioembolization followed by nivolumab for advanced hepatocellular carcinoma. J. Immunother. Cancer 11, e007106 (2023).
Xu, X. F. et al. Risk factors, patterns, and outcomes of late recurrence after liver resection for hepatocellular carcinoma: a multicenter study from China. JAMA Surg. 154, 209–217 (2019).
Lee, S. K. et al. Immunological markers, prognostic factors and challenges following curative treatments for hepatocellular carcinoma. Int. J. Mol. Sci. 22, 10271 (2021).
Jin, S. et al. Inference and analysis of cell–cell communication using CellChat. Nat. Commun. 12, 1088 (2021).
Medaglia, C. et al. Spatial reconstruction of immune niches by combining photoactivatable reporters and scRNA-seq. Science 358, 1622–1626 (2017).
Predina, J. D. et al. Characterization of surgical models of postoperative tumor recurrence for preclinical adjuvant therapy assessment. Am. J. Transl. Res. 4, 206–218 (2012).
Feng, Y. X. et al. Sorafenib suppresses postsurgical recurrence and metastasis of hepatocellular carcinoma in an orthotopic mouse model. Hepatology 53, 483–492 (2011).
Lim, K. C. et al. Microvascular invasion is a better predictor of tumor recurrence and overall survival following surgical resection for hepatocellular carcinoma compared to the Milan criteria. Ann. Surg. 254, 108–113 (2011).
Roayaie, S. et al. A system of classifying microvascular invasion to predict outcome after resection in patients with hepatocellular carcinoma. Gastroenterology 137, 850–855 (2009).
Hack, S. P. et al. IMbrave 050: a phase III trial of atezolizumab plus bevacizumab in high-risk hepatocellular carcinoma after curative resection or ablation. Future Oncol. 16, 975–989 (2020).
Bajorin, D. F. et al. Adjuvant nivolumab versus placebo in muscle-invasive urothelial carcinoma. N. Engl. J. Med. 384, 2102–2114 (2021).
Zhou, Y. et al. Metascape provides a biologist-oriented resource for the analysis of systems-level datasets. Nat. Commun. 10, 1523 (2019).
Zhang, X. et al. CellMarker: a manually curated resource of cell markers in human and mouse. Nucleic Acids Res. 47, D721–D728 (2019).
Hu, C. et al. CellMarker 2.0: an updated database of manually curated cell markers in human/mouse and web tools based on scRNA-seq data. Nucleic Acids Res. 51, D870–D876 (2023).
Mootha, V. K. et al. PGC-1α-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nat. Genet. 34, 267–273 (2003).
Subramanian, A. et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc. Natl Acad. Sci. USA 102, 15545–15550 (2005).
Lim, J. C. T. et al. An automated staining protocol for seven-colour immunofluorescence of human tissue sections for diagnostic and prognostic use. Pathology 50, 333–341 (2018).
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).
Yeong, J. et al. Prognostic value of CD8+PD-1+ immune infiltrates and PDCD1 gene expression in triple negative breast cancer. J. Immunother. Cancer 7, 34 (2019).
Yeong, J. et al. High densities of tumor-associated plasma cells predict improved prognosis in triple negative breast cancer. Front. Immunol. 9, 1209 (2018).
Bankhead, P. et al. QuPath: open source software for digital pathology image analysis. Sci. Rep. 7, 16878 (2017).
Van Acker, H. H., Capsomidis, A., Smits, E. L. & Van Tendeloo, V. F. CD56 in the immune system: more than a marker for cytotoxicity? Front. Immunol. 8, 892 (2017).
Sung, J. J. et al. Immunohistochemical expression and clinical significance of suggested stem cell markers in hepatocellular carcinoma. J. Pathol. Transl. Med. 50, 52–57 (2016).
Tsuchiya, A. et al. Hepatocellular carcinoma with progenitor cell features distinguishable by the hepatic stem/progenitor cell marker NCAM. Cancer Lett. 309, 95–103 (2011).
Phillips, D. et al. Highly multiplexed phenotyping of immunoregulatory proteins in the tumor microenvironment by CODEX tissue imaging. Front. Immunol. 12, 687673 (2021).
Black, S. et al. CODEX multiplexed tissue imaging with DNA-conjugated antibodies. Nat. Protoc. 16, 3802–3835 (2021).
Wu, H. et al. Postmortem high-dimensional immune profiling of severe COVID-19 patients reveals distinct patterns of immunosuppression and immunoactivation. Nat. Commun. 13, 269 (2022).
Li, R. et al. A body map of somatic mutagenesis in morphologically normal human tissues. Nature 597, 398–403 (2021).
Emmert-Buck, M. R. et al. Laser capture microdissection. Science 274, 998–1001 (1996).
Deng, M. et al. Proteogenomic characterization of cholangiocarcinoma. Hepatology 77, 411–429 (2023).
Schwanhäusser, B. et al. Global quantification of mammalian gene expression control. Nature 473, 337–342 (2011).
Li, T. et al. TIMER2.0 for analysis of tumor-infiltrating immune cells. Nucleic Acids Res. 48, W509–W514 (2020).
Andersen, P. K. & Gill, R. D. Cox’s regression model for counting processes: a large sample study. Ann. Stat. 10, 1100–1120 (1982).
Therneau, T. M. & Grambsch, P. M. Modeling survival data: extending the Cox model. Stat. Biol. Health https://doi.org/10.1007/978-1-4757-3294-8 (2000).
Li, J. et al. Biodegradable electrospun nanofibrous platform integrating antiplatelet therapy–chemotherapy for preventing postoperative tumor recurrence and metastasis. Theranostics 12, 3503–3517 (2022).
Tang, M. et al. Three-dimensional bioprinted glioblastoma microenvironments model cellular dependencies and immune interactions. Cell Res. 30, 833–853 (2020).
Wu, Y. et al. Blockade of T-cell receptor with Ig and ITIM domains elicits potent antitumor immunity in naturally occurring HBV-related HCC in mice. Hepatology 77, 965–981 (2023).
Xu, X. et al. Group-2 innate lymphoid cells promote HCC progression through CXCL2-neutrophil-induced immunosuppression. Hepatology 74, 2526–2543 (2021).
