Spatial‒temporal heterogeneities of liver cancer and the discovery of the invasive zone

Jiayan Yan , Zhifeng Jiang , Shiyu Zhang , Qichao Yu , Yijun Lu , Runze Miao , Zhaoyou Tang , Jia Fan , Liang Wu , Dan G. Duda , Jian Zhou , Xinrong Yang

Clinical and Translational Medicine ›› 2025, Vol. 15 ›› Issue (2) : e70224

PDF
Clinical and Translational Medicine ›› 2025, Vol. 15 ›› Issue (2) : e70224 DOI: 10.1002/ctm2.70224
REVIEW

Spatial‒temporal heterogeneities of liver cancer and the discovery of the invasive zone

Author information +
History +
PDF

Abstract

Solid tumours are intricate and highly heterogeneous ecosystems, which grow in and invade normal organs. Their progression is mediated by cancer cells’ interaction with different cell types, such as immune cells, stromal cells and endothelial cells, and with the extracellular matrix. Owing to its high incidence, aggressive growth and resistance to local and systemic treatments, liver cancer has particularly high mortality rates worldwide. In recent decades, spatial heterogeneity has garnered significant attention as an unfavourable biological characteristic of the tumour microenvironment, prompting extensive research into its role in liver tumour development. Advances in spatial omics have facilitated the detailed spatial analysis of cell types, states and cell‒cell interactions, allowing a thorough understanding of the spatial and temporal heterogeneities of tumour microenvironment and informing the development of novel therapeutic approaches. This review illustrates the latest discovery of the invasive zone, and systematically introduced specific macroscopic spatial heterogeneities, pathological spatial heterogeneities and tumour microenvironment heterogeneities of liver cancer.

Keywords

immunosuppression / invasive zone / liver cancer / spatial heterogeneity / tumour microenvironment

Cite this article

Download citation ▾
Jiayan Yan, Zhifeng Jiang, Shiyu Zhang, Qichao Yu, Yijun Lu, Runze Miao, Zhaoyou Tang, Jia Fan, Liang Wu, Dan G. Duda, Jian Zhou, Xinrong Yang. Spatial‒temporal heterogeneities of liver cancer and the discovery of the invasive zone. Clinical and Translational Medicine, 2025, 15(2): e70224 DOI:10.1002/ctm2.70224

登录浏览全文

4963

注册一个新账户 忘记密码

References

[1]

Zhou M, Wang H, Zeng X, et al. Mortality, morbidity, and risk factors in China and its provinces, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet. 2019; 394(10204): 1145-1158.

[2]

Chen W, Zheng R, Baade PD, et al. Cancer statistics in China, 2015. CA Cancer J Clin. 2016; 66(2): 115-132.

[3]

Sung H, Ferlay J, Siegel RL, et al. Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021; 71(3): 209-249.

[4]

Yang Y, Li M, Luo J, Yu H, Tian H, Wang X. Non-hemodynamic effects: repurposing of nonselective beta-blockers in cirrhosis? Portal Hypertens Cirrhosis. 2022; 1(2): 153-156.

[5]

Beal EW, Gorji L, Volney J, Sova L, McAlearney AS. Tsung A. Barriers to surveillance for hepatocellular cancer among patients with chronic liver disease-providers’ perspectives. Hepatoma Res. 2023; 9: 45.

[6]

Sun Y, Wu L, Zhong Y, et al. Single-cell landscape of the ecosystem in early-relapse hepatocellular carcinoma. Cell. 2021; 184(2): 404-421.e16.

[7]

Ma L, Hernandez MO, Zhao Y, et al. Tumor cell biodiversity drives microenvironmental reprogramming in liver cancer. Cancer Cell. 2019; 36(4): 418-430.e6.

[8]

Xue R, Chen L, Zhang C, et al. Genomic and transcriptomic profiling of combined hepatocellular and intrahepatic cholangiocarcinoma reveals distinct molecular subtypes. Cancer Cell. 2019; 35(6): 932-947.e8.

[9]

Chan A, Zhang WY, Chok K, et al. ALPPS versus portal vein embolization for hepatitis-related hepatocellular carcinoma: a changing paradigm in modulation of future liver remnant before major hepatectomy. Ann Surg. 2021; 273(5): 957-965.

[10]

Ji AL, Rubin AJ, Thrane K, et al. Multimodal analysis of composition and spatial architecture in human squamous cell carcinoma. Cell. 2020; 182(2): 497-514.e22.

[11]

Lewis SM, Asselin-Labat ML, Nguyen Q, et al. Spatial omics and multiplexed imaging to explore cancer biology. Nat Methods. 2021; 18(9): 997-1012.

[12]

Liang W, Jiayan Y, Yinqi B, et al. An invasive zone in human liver cancer identified by Stereo-seq promotes hepatocyte-tumor cell crosstalk, local immunosuppression and tumor progression. Cell Res. 2023; 33(8): 585-603.

[13]

Benjamin R, Matthias B, Sepideh B, et al. Tumor-associated macrophages trigger MAIT cell dysfunction at the HCC invasive margin. Cell. 2023; 186(17): 3686-3705.e32.

[14]

Yao L, Zhenzhen X, Kun M, et al. Identification of a tumour immune barrier in the HCC microenvironment that determines the efficacy of immunotherapy. J Hepatol. 2023; 78(4): 770-782.

[15]

Guang-Yu D, Jia-Qiang M, Jing-Ping Y, et al. Distribution and density of tertiary lymphoid structures predict clinical outcome in intrahepatic cholangiocarcinoma. J Hepatol. 2021; 76(3): 608-618.

[16]

Schurch CM, Bhate SS, Barlow GL, et al. Coordinated cellular neighborhoods orchestrate antitumoral immunity at the colorectal cancer invasive front. Cell. 2020; 182(5): 1341-1359.

[17]

Hendry S, Salgado R, Gevaert T, et al. Assessing tumor-infiltrating lymphocytes in solid tumors: a practical review for pathologists and proposal for a standardized method from the International Immunooncology Biomarkers Working Group: part 1: assessing the host immune response, TILs in invasive breast carcinoma and ductal carcinoma in situ, metastatic tumor deposits and areas for further research. Adv Anat Pathol. 2017; 24(5): 235-251.

[18]

Chew V. Unveiling the hidden battlefield: dissecting the invasive zone in liver cancer. Cell Res. 2023; 33(9): 651-652.

[19]

Wu L, Yan J, Bai Y, et al. An invasive zone in human liver cancer identified by Stereo-seq promotes hepatocyte-tumor cell crosstalk, local immunosuppression and tumor progression. Cell Res. 2023; 33(8): 585-603.

[20]

He M, Liu Y, Chen S, et al. Serum amyloid A promotes glycolysis of neutrophils during PD-1 blockade resistance in hepatocellular carcinoma. Nat Commun. 2024; 15(1): 1754.

[21]

Ming S, Rong-Ping G, Xiao-Jun L, et al. Partial hepatectomy with wide versus narrow resection margin for solitary hepatocellular carcinoma: a prospective randomized trial. Ann Surg. 2007; 245(1):36-43.

[22]

Ruf B, Bruhns M, Babaei S, et al. Tumor-associated macrophages trigger MAIT cell dysfunction at the HCC invasive margin. Cell. 2023; 186(17): 3686-3705.

[23]

Yuan Y. Spatial heterogeneity in the tumor microenvironment. Cold Spring Harb Perspect Med. 2016; 6(8): a026583.

[24]

Reig M, Forner A, Rimola J, Ferrer-Fabrega J, Burrel M, Garcia-Criado A, et al. BCLC strategy for prognosis prediction and treatment recommendation: the 2022 update. J Hepatol. 2022; 76(3): 681-693.

[25]

Huang P, Ni X, Zhou C, et al. Subcentimeter nodules with diagnostic hallmarks of hepatocellular carcinoma: comparison of pathological features and survival outcomes with nodules measuring 1–2 cm. J Hepatocell Carcinoma. 2023; 10: 169-180.

[26]

Villanueva A. Hepatocellular carcinoma. N Engl J Med. 2019; 380(15): 1450-1462.

[27]

Yang S, Zheng L, Li L, et al. Integrative multiomics analysis identifies molecular subtypes and potential targets of hepatocellular carcinoma. Clin Transl Med. 2024; 14(6): e1727.

[28]

Forlemu AN, Nana Sede Mbakop R, Bandaru P, et al. Liver segment disposition of hepatocellular carcinoma predicts microvascular invasion. Int J Hepatol. 2023; 2023: 5727701.

[29]

Renzulli M, Brandi N, Pecorelli A, et al. Segmental distribution of hepatocellular carcinoma in cirrhotic livers. Diagnostics. 2022; 12(4): 834.

[30]

Kanai T, Hirohashi S, Upton MP, et al. Pathology of small hepatocellular carcinoma. A proposal for a new gross classification. Cancer. 1987; 60(4): 810-819.

[31]

Joseph CA, Yi-Te L, Vatche GA, et al. Hepatocellular carcinoma surveillance: current practice and future directions. Hepatoma Res. 2022; 8(0): 10.

[32]

Fan Z, Jin M, Zhang L, et al. From clinical variables to multiomics analysis: a margin morphology-based gross classification system for hepatocellular carcinoma stratification. Gut. 2023; 72(11): 2149-2163.

[33]

Lu Y, Yang A, Quan C, et al. A single-cell atlas of the multicellular ecosystem of primary and metastatic hepatocellular carcinoma. Nat Commun. 2022; 13(1): 4594.

[34]

Llovet JM, Bru C, Bruix J. Prognosis of hepatocellular carcinoma: the BCLC staging classification. Seminars Liver Disease. 1999; 19(3): 329-338.

[35]

Heimbach JK, Kulik LM, Finn RS, et al. AASLD guidelines for the treatment of hepatocellular carcinoma. Hepatology. 2018; 67(1): 358-380.

[36]

European Association for the Study of the Liver. EASL Clinical Practice Guidelines: management of hepatocellular carcinoma. J Hepatol. 2018; 69(1): 182-236.

[37]

Sun YF, Wu L, Liu SP, et al. Dissecting spatial heterogeneity and the immune-evasion mechanism of CTCs by single-cell RNA-seq in hepatocellular carcinoma. Nat Commun. 2021; 12(1): 4091.

[38]

Moris D, Palta M, Kim C, Allen PJ, Morse MA, Lidsky ME. Advances in the treatment of intrahepatic cholangiocarcinoma: an overview of the current and future therapeutic landscape for clinicians. CA Cancer J Clin. 2023; 73(2): 198-222.

[39]

Mavros MN, Economopoulos KP, Alexiou VG, Pawlik TM. Treatment and prognosis for patients with intrahepatic cholangiocarcinoma: systematic review and meta-analysis. JAMA Surg. 2014; 149(6): 565-574.

[40]

Ji H, Hu C, Yang X, et al. Lymph node metastasis in cancer progression: molecular mechanisms, clinical significance and therapeutic interventions. Signal Transduct Targeted Ther. 2023; 8(1): 367.

[41]

Woo HY, Rhee H, Yoo JE, et al. Lung and lymph node metastases from hepatocellular carcinoma: comparison of pathological aspects. Liver Int. 2022; 42(1): 199-209.

[42]

Lee CK, Jeong SH, Jang C, et al. Tumor metastasis to lymph nodes requires YAP-dependent metabolic adaptation. Science. 2019; 363(6427): 644-649.

[43]

Sun Y, Wu P, Zhang Z, et al. Integrated multi-omics profiling to dissect the spatiotemporal evolution of metastatic hepatocellular carcinoma. Cancer Cell. 2024; 42(1): 135-156.e17.

[44]

Kanazawa H, Mitomi H, Nishiyama Y, et al. Tumour budding at invasive margins and outcome in colorectal cancer. Colorectal Disease. 2008; 10(1): 41-47.

[45]

Lugli A, Zlobec I, Berger MD, Kirsch R, Nagtegaal ID. Tumour budding in solid cancers. Nat Rev Clin Oncol. 2021; 18(2): 101-115.

[46]

Kairaluoma V, Kemi N, Pohjanen VM, Saarnio J, Helminen O. Tumour budding and tumour-stroma ratio in hepatocellular carcinoma. Br J Cancer. 2020; 123(1): 38-45.

[47]

Unal B, Celik MY, Gedik EO, Bassorgun CI, Elpek GO. Tumor budding as a potential prognostic marker in determining the behavior of primary liver cancers. World J Hepatol. 2023; 15(6): 775-785.

[48]

Wei L, Delin Z, Kefei Y, Hong W, Jiwei H, Yange Z. A classification based on tumor budding and immune score for patients with hepatocellular carcinoma. Oncoimmunology. 2020; 9(1): 1672495.

[49]

Alessandro L, Inti Z, Martin DB, Richard K, Iris DN. Tumour budding in solid cancers. Nat Rev Clin Oncol. 2020; 18(2): 101-115.

[50]

Zheng Z, Guan R, Jianxi W, et al. Microvascular invasion in hepatocellular carcinoma: a review of its definition, clinical significance, and comprehensive management. J Oncol. 2022; 2022: 9567041.

[51]

Wang W, Guo Y, Zhong J, et al. The clinical significance of microvascular invasion in the surgical planning and postoperative sequential treatment in hepatocellular carcinoma. Sci Rep. 2021; 11(1): 2415.

[52]

Li K, Zhang R, Wen F, et al. Single-cell dissection of the multicellular ecosystem and molecular features underlying microvascular invasion in HCC. Hepatology. 2024;79:1293-1309.

[53]

Ke L, Rui Z, Fukai W, et al. Single-cell dissection of the multicellular ecosystem and molecular features underlying microvascular invasion in HCC. Hepatology. 2023; 79(6): 1293-1309.

[54]

Xudong Z, Yudan W, Haoming X, et al. Roles and molecular mechanisms of biomarkers in hepatocellular carcinoma with microvascular invasion: a review. J Clin Transl Hepatol. 2023; 11(5): 1170-1183.

[55]

Sun W, Zhang Y, Liu B, Duan Y, Li W, Chen J. Gene polymorphism of MUC15, MMP14, BRAF, and COL1A1 is associated with capsule formation in hepatocellular carcinoma. Can J Gastroenterol Hepatol. 2021; 2021: 9990305.

[56]

Wu R, Guo W, Qiu X, Wang S, Sui C, Lian Q, et al. Comprehensive analysis of spatial architecture in primary liver cancer. Sci Adv. 2021; 7(51): eabg3750.

[57]

Rahmanzade R. Redefinition of tumor capsule: rho-dependent clustering of cancer-associated fibroblasts in favor of tensional homeostasis. Med Hypotheses. 2020; 135: 109425.

[58]

Shi JY, Gao Q, Wang ZC, et al. Margin-infiltrating CD20(+) B cells display an atypical memory phenotype and correlate with favorable prognosis in hepatocellular carcinoma. Clin Cancer Res. 2013; 19(21): 5994-6005.

[59]

Li X, Ramadori P, Pfister D, Seehawer M, Zender L, Heikenwalder M. The immunological and metabolic landscape in primary and metastatic liver cancer. Nat Rev Cancer. 2021; 21(9): 541-557.

[60]

Zheng C, Zheng L, Yoo JK, et al. Landscape of infiltrating T cells in liver cancer revealed by single-cell sequencing. Cell. 2017; 169(7): 1342-1356.e16.

[61]

Jiang Y, Li Y, Zhu B. T-cell exhaustion in the tumor microenvironment. Cell Death Dis. 2015; 6: e1792.

[62]

Xue R, Zhang Q, Cao Q, et al. Liver tumour immune microenvironment subtypes and neutrophil heterogeneity. Nature. 2022; 612(7938): 141-147.

[63]

Wu Y, Ma J, Yang X, et al. Neutrophil profiling illuminates anti-tumor antigen-presenting potency. Cell. 2024; 187(6): 1422-1439.e24.

[64]

Laumont CM, Banville AC, Gilardi M, Hollern DP, Nelson BH. Tumour-infiltrating B cells: immunological mechanisms, clinical impact and therapeutic opportunities. Nat Rev Cancer. 2022; 22(7): 414-430.

[65]

Bertens KA, Hawel J, Lung K, Buac S, Pineda-Solis K, Hernandez-Alejandro R. ALPPS: challenging the concept of unresectability—a systematic review. Int J Surg. 2015; 13: 280-287.

[66]

Ma J, Wu Y, Ma L, et al. A blueprint for tumor-infiltrating B cells across human cancers. Science. 2024; 384(6695): eadj4857.

[67]

Galon J, Costes A, Sanchez-Cabo F, et al. Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science. 2006; 313(5795): 1960-1964.

[68]

Zheng BH, Ma JQ, Tian LY, et al. The distribution of immune cells within combined hepatocellular carcinoma and cholangiocarcinoma predicts clinical outcome. Clin Transl Med. 2020; 10(1): 45-56.

[69]

Galon J, Bruni D. Approaches to treat immune hot, altered and cold tumours with combination immunotherapies. Nat Rev Drug Discov. 2019; 18(3): 197-218.

[70]

Zheng B, Wang D, Qiu X, et al. Trajectory and functional analysis of PD-1(high) CD4(+)CD8(+) T cells in hepatocellular carcinoma by single-cell cytometry and transcriptome sequencing. Adv Sci. 2020; 7(13): 2000224.

[71]

Liu LZ, Zhang Z, Zheng BH, et al. CCL15 recruits suppressive monocytes to facilitate immune escape and disease progression in hepatocellular carcinoma. Hepatology. 2019; 69(1): 143-159.

[72]

Ding GY, Ma JQ, Yun JP, et al. Distribution and density of tertiary lymphoid structures predict clinical outcome in intrahepatic cholangiocarcinoma. J Hepatol. 2022; 76(3): 608-618.

[73]

Salina Y, Robert JN, Ben ZS. Cellular plasticity in cancer. Cancer Discov. 2019; 9(7): 837-851.

[74]

Samra T, Andrea S, Trevor G, Charles S. Resolving genetic heterogeneity in cancer. Nat Rev Genet. 2019; 20(7): 65.

[75]

Stefan CD, Ignaty L, Kerstin H, et al. Characterizing genetic intra-tumor heterogeneity across 2, 658 human cancer genomes. Cell. 2021; 184(8): 2239-2254.e39.

[76]

Andrew LJ, Adam JR, Kim T, et al. Multimodal analysis of composition and spatial architecture in human squamous cell carcinoma. Cell. 2020; 182(2): 497-514.e22.

[77]

Christian MS, Salil SB, Graham LB, et al. Coordinated cellular neighborhoods orchestrate antitumoral immunity at the colorectal cancer invasive front. Cell. 2020; 183(3): 1341-1359.e19.

[78]

Chen Y, Haigang G, Xupeng Y, et al. Targeting the immune privilege of tumor-initiating cells to enhance cancer immunotherapy. Cancer Cell. 2024; 42(12): 2064-2081.e19.

[79]

Daniel SC, Ira M. Oncology meets immunology: the cancer-immunity cycle. Immunity. 2013; 39(1): 1-10.

[80]

Chen C, Zehua W, Yi D, Yanru Q. Tumor microenvironment-mediated immune evasion in hepatocellular carcinoma. Front Immunol. 2023; 14(0): 1133308.

[81]

Katherine EL, Marina RDG, Amaia L. Tumor-intrinsic mechanisms regulating immune exclusion in liver cancers. Front Immunol. 2021; 12(0): 642958.

[82]

Josep ML, Sergio R, Vincenzo M, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008; 359(4): 378-390.

[83]

Weiwei T, Ziyi C, Wenling Z, et al. The mechanisms of sorafenib resistance in hepatocellular carcinoma: theoretical basis and therapeutic aspects. Signal Transduct Target Ther. 2020; 5(1): 87.

[84]

Ito Y, Takeda T, Sakon M, et al. Expression and clinical significance of erb-B receptor family in hepatocellular carcinoma. Br J Cancer. 2001; 84(10): 1377-1138.

[85]

Marie-José B-VE, Hamza C, Laetitia F, et al. Epidermal growth factor receptor and HER-3 restrict cell response to sorafenib in hepatocellular carcinoma cells. J Hepatol. 2012; 57(1): 108-15.

[86]

Zakaria E, Christophe L, Eric T, et al. EGFR activation is a potential determinant of primary resistance of hepatocellular carcinoma cells to sorafenib. Int J Cancer. 2012; 131(12): 2961-9.

[87]

Kuen-Feng C, Wei-Tien T, Cheng-Yi H, et al. Blockade of STAT3 activation by sorafenib derivatives through enhancing SHP-1 phosphatase activity. Eur J Med Chem. 2012; 55: 220-7.

[88]

Li-Ping L, Rocky LKH, George GC, Paul BSL. Sorafenib inhibits hypoxia-inducible factor-1α synthesis: implications for antiangiogenic activity in hepatocellular carcinoma. Clin Cancer Res. 2012; 18(20): 5662-5671.

[89]

Weidong L, Xuesong D, Changjun H, et al. LncRNA SNHG1 contributes to sorafenib resistance by activating the Akt pathway and is positively regulated by miR-21 in hepatocellular carcinoma cells. J Exp Clin Cancer Res. 2019; 38(1): 183.

[90]

Hongdan L, Cheng Y, Yijie S, Liang Z. Exosomes derived from siRNA against GRP78 modified bone-marrow-derived mesenchymal stem cells suppress Sorafenib resistance in hepatocellular carcinoma. J Nanobiotechnol. 2018; 16(1): 103.

[91]

Zili Z, Mei G, Yujia L, et al. RNA-binding protein ZFP36/TTP protects against ferroptosis by regulating autophagy signaling pathway in hepatic stellate cells. Autophagy. 2019; 16(8): 1482-1505.

[92]

Yunching C, Rakesh RR, Thomas R, et al. CXCR4 inhibition in tumor microenvironment facilitates anti-programmed death receptor-1 immunotherapy in sorafenib-treated hepatocellular carcinoma in mice. Hepatology. 2014; 61(5): 1591-602.

[93]

Richard SF, Shukui Q, Masafumi I, et al. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N Engl J Med. 2020; 382(20): 1894-1905.

[94]

Abou-Alfa G, Lau G, Kudo M, et al. Tremelimumab plus durvalumab in unresectable hepatocellular carcinoma. NEJM Evidence. 2022; 1(8): EVIDoa2100070.

[95]

Werner W, Kuzminskaya M, Lurje I, Tacke F, Hammerich L. Overcoming resistance to immune checkpoint blockade in liver cancer with combination therapy: stronger together? Semin Liver Disease. 2024; 44(2): 159-179.

[96]

Deldar Abad Paskeh M, Mirzaei S, Ashrafizadeh M, Zarrabi A, Sethi G. Wnt/β-catenin signaling as a driver of hepatocellular carcinoma progression: an emphasis on molecular pathways. J Hepatocellular Carcinoma. 2021; 8: 1415-1444.

[97]

Ruiz de Galarreta M, Bresnahan E, Molina-Sánchez P, et al. β-Catenin activation promotes immune escape and resistance to anti-PD-1 therapy in hepatocellular carcinoma. Cancer Discov. 2019; 9(8): 1124-1141.

[98]

Xiao Q, Werner J, Venkatachalam N, Boonekamp K, Ebert M, Zhan T. Cross-talk between p53 and Wnt signaling in cancer. Biomolecules. 2022; 12(3): 453.

[99]

Peng W, Chen J, Liu C, et al. Loss of PTEN promotes resistance to T cell-mediated immunotherapy. Cancer Discov. 2016; 6(2): 202-216.

[100]

Mortezaee K. WNT/β-catenin regulatory roles on PD-(L)1 and immunotherapy responses. Clin Exp Med. 2024; 24(1): 15.

[101]

Saha S, Parachoniak C, Bardeesy N. IDH mutations in liver cell plasticity and biliary cancer. Cell Cycle. 2014; 13(20): 3176-3182.

[102]

Sharma P, Hu-Lieskovan S, Wargo J, Ribas A. Primary, adaptive, and acquired resistance to cancer immunotherapy. Cell. 2017; 168(4): 707-723.

[103]

Wu Y, Yi M, Niu M, Mei Q, Wu K. Myeloid-derived suppressor cells: an emerging target for anticancer immunotherapy. Mol Cancer. 2022; 21(1): 184.

[104]

Kuang D, Zhao Q, Peng C, et al. Activated monocytes in peritumoral stroma of hepatocellular carcinoma foster immune privilege and disease progression through PD-L1. J Exp Med. 2009; 206(6): 1327-1337.

[105]

Zhou S, Zhao Z, Zhong H, et al. The role of myeloid-derived suppressor cells in liver cancer. Discov Oncol. 2023; 14(1): 77.

[106]

Katagata M, Okayama H, Nakajima S, et al. TIM-3 expression and M2 polarization of macrophages in the TGFβ-activated tumor microenvironment in colorectal cancer. Cancers. 2023; 15(20): 4943.

[107]

Woo S, Turnis M, Goldberg M, et al. Immune inhibitory molecules LAG-3 and PD-1 synergistically regulate T-cell function to promote tumoral immune escape. Cancer Res. 2012; 72(4): 917-927.

[108]

Guo M, Yuan F, Qi F, et al. Expression and clinical significance of LAG-3, FGL1, PD-L1 and CD8T cells in hepatocellular carcinoma using multiplex quantitative analysis. J Transl Med. 2020; 18(1): 306.

[109]

Yan W, Liu X, Ma H, et al. Tim-3 fosters HCC development by enhancing TGF-β-mediated alternative activation of macrophages. Gut. 2015; 64(10): 1593-1604.

[110]

Ramachandran P, Dobie R, Wilson-Kanamori J, et al. Resolving the fibrotic niche of human liver cirrhosis at single-cell level. Nature. 2019; 575(7783): 512-518.

[111]

Bai Q, Li R, He X, et al. Single-cell landscape of immune cells during the progression from HBV infection to HBV cirrhosis and HBV-associated hepatocellular carcinoma. Front Immunol. 2023; 14: 1320414.

[112]

Xiong X, Kuang H, Ansari S, et al. Landscape of intercellular crosstalk in healthy and NASH liver revealed by single-cell secretome gene analysis. Mol Cell. 2019; 75(3): 644-660.e5.

[113]

Andrews T, Nakib D, Perciani C, et al. Single-cell, single-nucleus, and spatial transcriptomics characterization of the immunological landscape in the healthy and PSC human liver. J Hepatol. 2024; 80(5): 730-743.

[114]

Cho C, Xi J, Si Y, et al. Microscopic examination of spatial transcriptome using Seq-Scope. Cell. 2021; 184(13): 3559-3572.e22.

[115]

Chung B, Øgaard J, Reims H, Karlsen T, Melum E. Spatial transcriptomics identifies enriched gene expression and cell types in human liver fibrosis. Hepatol Commun. 2022; 6(9): 2538-2550.

[116]

Su X, Zhao L, Shi Y, et al. Clonal evolution in liver cancer at single-cell and single-variant resolution. J Hematol Oncol. 2021; 14(1): 22.

[117]

Wu R, Guo W, Qiu X, et al. Comprehensive analysis of spatial architecture in primary liver cancer. Sci Adv. 2021; 7(51): eabg3750.

[118]

Shibata T, Arai Y, Totoki Y. Molecular genomic landscapes of hepatobiliary cancer. Cancer Sci. 2018; 109(5): 1282-1291.

[119]

Le D, Durham J, Smith K, et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science. 2017; 357(6349): 409-413.

[120]

Campani C, Imbeaud S, Couchy G, et al. Circulating tumour DNA in patients with hepatocellular carcinoma across tumour stages and treatments. Gut. 2024; 73(11): 1870-1882.

[121]

Xue R, Chen L, Zhang C, et al. Genomic and transcriptomic profiling of combined hepatocellular and intrahepatic cholangiocarcinoma reveals distinct molecular subtypes. Cancer Cell. 2019; 35(6): 932-947.e8.

[122]

Calderaro J, Ghaffari Laleh N, Zeng Q, et al. Deep learning-based phenotyping reclassifies combined hepatocellular-cholangiocarcinoma. Nat Commun. 2023; 14(1): 8290.

[123]

Guo D, Zhang X, Zhang S, et al. Single-cell tumor heterogeneity landscape of hepatocellular carcinoma: unraveling the pro-metastatic subtype and its interaction loop with fibroblasts. Mol Cancer. 2024; 23(1): 157.

[124]

Liu Y, Xun Z, Ma K, et al. Identification of a tumour immune barrier in the HCC microenvironment that determines the efficacy of immunotherapy. J Hepatol. 2023; 78(4): 770-782.

[125]

Ruf B, Bruhns M, Babaei S, et al. Tumor-associated macrophages trigger MAIT cell dysfunction at the HCC invasive margin. Cell. 2023; 186(17): 3686-3705.e32.

[126]

Su K, Guo L, He K, et al. PD-L1 expression on circulating tumor cells can be a predictive biomarker to PD-1 inhibitors combined with radiotherapy and antiangiogenic therapy in advanced hepatocellular carcinoma. Front Oncol. 2022; 12: 873830.

[127]

Ma B, Zhang Y, Ma J, Chen X, Sun C, Qin C. Spatially resolved visualization of reprogrammed metabolism in hepatocellular carcinoma by mass spectrometry imaging. Cancer Cell Int. 2023; 23(1): 177.

[128]

He M, Pu W, Wang X, et al. Spatial metabolomics on liver cirrhosis to hepatocellular carcinoma progression. Cancer Cell Int. 2022; 22(1): 366.

[129]

Hijazi A, Bifulco C, Baldin P, Galon J. Digital pathology for better clinical practice. Cancers. 2024; 16(9): 1686.

[130]

Shi J, Wang X, Ding G, et al. Exploring prognostic indicators in the pathological images of hepatocellular carcinoma based on deep learning. Gut. 2021; 70(5): 951-961.

[131]

Liu Y, Yang M, Deng Y, et al. High-spatial-resolution multi-omics sequencing via deterministic barcoding in tissue. Cell. 2020; 183(6): 1665-1681.

[132]

Liu Y, DiStasio M, Su G, et al. High-plex protein and whole transcriptome co-mapping at cellular resolution with spatial CITE-seq. Nat Biotechnol. 2023; 41(10): 1405-1409.

[133]

Zhang D, Deng Y, Kukanja P, et al. Spatial epigenome-transcriptome co-profiling of mammalian tissues. Nature. 2023; 616(7955): 113-122.

[134]

Ben-Chetrit N, Niu X, Swett A, et al. Integration of whole transcriptome spatial profiling with protein markers. Nat Biotechnol. 2023; 41(6): 788-793.

[135]

Long Y, Ang K, Sethi R, et al. Deciphering spatial domains from spatial multi-omics with SpatialGlue. Nat Methods. 2024; 21(9): 1658-1667.

[136]

Hudson W, Sudmeier L. Localization of T cell clonotypes using the Visium spatial transcriptomics platform. STAR Protocols. 2022; 3(2): 101391.

[137]

Zhiliang B, Dingyao Z, Yan G, et al. Spatially exploring RNA biology in archival formalin-fixed paraffin-embedded tissues. Cell. 2024; 187(23): 6760-6779.e24.

[138]

Yahui L, Kok Siong A, Raman S, et al. Deciphering spatial domains from spatial multi-omics with SpatialGlue. Nat Methods. 2024; 21(9): 1658–1667.

[139]

Xiaojie Q, Daniel YZ, Yifan L, et al. Spatiotemporal modeling of molecular holograms. Cell. 2024; 187(26): 7351-7373.e61.

RIGHTS & PERMISSIONS

2025 The Author(s). Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.

AI Summary AI Mindmap
PDF

107

Accesses

0

Citation

Detail

Sections
Recommended

AI思维导图

/