Current Strategies for the Treatment of Hepatocellular Carcinoma by Modulating the Tumor Microenvironment via Nano-Delivery Systems: A Review

References

• IARC. International Agency for Research on Cancer.GLOBOCAN 2018. Available from: https://gco.iarc.fr/today/online-analysis-map?v=2020&mode=population&mode_population=continents&population=900&populations=900&key=asr&sex=0&cancer=11&type=0&statistic=5&prevalence=0&population_group=0&ages_group%5B%5D=0&ages_group%5B%5D=17.
   Google Scholar
• Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394–424. doi:10.3322/caac.21492
   PubMed Web of Science ®Google Scholar
• Llovet JM, Kelley RK, Villanueva A, et al. Hepatocellular carcinoma. Nature Reviews Disease Primers. 2021;7:6. doi:10.1038/s41572-020-00240-3
   PubMed Web of Science ®Google Scholar
• Nishida N, Kudo M. Oncogenic Signal and Tumor Microenvironment in Hepatocellular Carcinoma. Oncology. 2017;93(Suppl 1):160–164. doi:10.1159/000481246
   PubMed Web of Science ®Google Scholar
• Wang K, Sun D. Cancer stem cells of hepatocellular carcinoma. Oncotarget. 2018;9(33):23306–23314. doi:10.18632/oncotarget.24623
   PubMedGoogle Scholar
• Sevic I, Spinelli FM, Cantero MJ, et al. The role of the tumor microenvironment in the development and progression of hepatocellular carcinoma. J Med. 2019;4:29–45.
   Google Scholar
• Cho K, Wang X, Nie S, Chen Z, Shin DM. Therapeutic nanoparticles for drug delivery in cancer. Clin Cancer Res. 2008;14(5):1310–1316. doi:10.1158/1078-0432.Ccr-07-1441
   PubMed Web of Science ®Google Scholar
• Zamboni WC, Torchilin V, Patri AK, et al. Best Practices in Cancer Nanotechnology: perspective from NCI Nanotechnology Alliance. Clin Cancer Res. 2012;18(12):3229–3241. doi:10.1158/1078-0432.Ccr-11-2938
   PubMed Web of Science ®Google Scholar
• Prabhakar U, Maeda H, Jain RK, et al. Challenges and Key Considerations of the Enhanced Permeability and Retention Effect for Nanomedicine Drug Delivery in Oncology. Cancer Res. 2013;73(8):2412–2417. doi:10.1158/0008-5472.Can-12-4561
   PubMed Web of Science ®Google Scholar
• Bae YH, Park K. Targeted drug delivery to tumors: myths, reality and possibility. J Control Release. 2011;153(3):198–205. doi:10.1016/j.jconrel.2011.06.001
   PubMed Web of Science ®Google Scholar
• Dixit V, Van den Bossche J, Sherman DM, Thompson DH, Andres RP. Synthesis and grafting of thioctic acid-PEG-folate conjugates onto Au nanoparticles for selective targeting of folate receptor-positive tumor cells. Bioconjug Chem. 2006;17(3):603–609. doi:10.1021/bc050335b
   PubMed Web of Science ®Google Scholar
• Birgani MT, Carloni V. Tumor Microenvironment, a Paradigm in Hepatocellular Carcinoma Progression and Therapy. Int J Mol Sci. 2017;18:(2)405. doi:10.3390/ijms18020405
   Web of Science ®Google Scholar
• Leonardi GC, Candido S, Cervello M, et al. The tumor microenvironment in hepatocellular carcinoma. Int J Oncol. 2012;40(6):1733–1747. doi:10.3892/ijo.2012.1408
   PubMed Web of Science ®Google Scholar
• Yang JD, Nakamura I, Roberts LR. The tumor microenvironment in hepatocellular carcinoma: current status and therapeutic targets. Semin Cancer Biol. 2011;21(1):35–43. doi:10.1016/j.semcancer.2010.10.007
   PubMed Web of Science ®Google Scholar
• Kalluri R, Zeisberg M. Fibroblasts in cancer. Nat Rev Cancer. 2006;6(5):392–401. doi:10.1038/nrc1877
   PubMed Web of Science ®Google Scholar
• Shimoda M, Mellody KT, Orimo A. Carcinoma-associated fibroblasts are a rate-limiting determinant for tumour progression. Semin Cell Dev Biol. 2010;21(1):19–25. doi:10.1016/j.semcdb.2009.10.002
   PubMed Web of Science ®Google Scholar
• Yin ZY, Dong CY, Jiang KQ, et al. Heterogeneity of cancer-associated fibroblasts and roles in the progression, prognosis, and therapy of hepatocellular carcinoma. J Hematol Oncol. 2019;12:(1)101. doi:10.1186/s13045-019-0782-x
   Web of Science ®Google Scholar
• Reid LM, Fiorino AS, Sigal SH, Brill S, Holst PA. Extracellular matrix gradients in the space of Disse: relevance to liver biology. Hepatology. 1992;15(6):1198–1203. doi:10.1002/hep.1840150635
   PubMed Web of Science ®Google Scholar
• Pickup MW, Mouw JK, Weaver VM. The extracellular matrix modulates the hallmarks of cancer. EMBO Rep. 2014;15(12):1243–1253. doi:10.15252/embr.201439246
   PubMed Web of Science ®Google Scholar
• Lu P, Weaver VM, Werb Z. The extracellular matrix: a dynamic niche in cancer progression. J Cell Biol. 2012;196(4):395–406. doi:10.1083/jcb.201102147
   PubMed Web of Science ®Google Scholar
• Dudley AC. Tumor Endothelial Cells. Cold Spring Harbor Perspectives in Medicine. Medicine. 2012;2(3):a006536. doi:10.1101/cshperspect.a006536
   Web of Science ®Google Scholar
• Davis GE, Senger DR. Endothelial extracellular matrix - Biosynthesis, remodeling, and functions during vascular morphogenesis and neovessel stabilization. Circ Res. 2005;97(11):1093–1107. doi:10.1161/01.RES.0000191547.64391.e3
   PubMed Web of Science ®Google Scholar
• Hashizume H, Baluk P, Morikawa S, et al. Openings between defective endothelial cells explain tumor vessel leakiness. Am J Pathol. 2000;156(4):1363–1380. doi:10.1016/s0002-9440(10
   PubMed Web of Science ®Google Scholar
• Baluk P, Hashizume H, McDonald DM. Cellular abnormalities of blood vessels as targets in cancer. Curr Opin Genet Dev. 2005;15(1):102–111. doi:10.1016/j.gde.2004.12.005
   PubMed Web of Science ®Google Scholar
• Finn RS, Zhu AX. Targeting angiogenesis in hepatocellular carcinoma: focus on VEGF and bevacizumab. Expert Rev Anticancer Ther. 2009;9(4):503–509. doi:10.1586/era.09.6
   PubMed Web of Science ®Google Scholar
• Santhakumar C, Gane EJ, Liu K, McCaughan GW. Current perspectives on the tumor microenvironment in hepatocellular carcinoma. Hepatol Int. 2020;14(6):947–957. doi:10.1007/s12072-020-10104-3
   PubMed Web of Science ®Google Scholar
• Mills CD. M1 and M2 Macrophages: oracles of Health and Disease. Crit Rev Immunol. 2012;32(6):463–488. doi:10.1615/CritRevImmunol.v32.i6.10
   PubMed Web of Science ®Google Scholar
• Amann T, Bataille F, Spruss T, et al. Activated hepatic stellate cells promote tumorigenicity of hepatocellular carcinoma. Cancer Sci. 2009;100(4):646–653. doi:10.1111/j.1349-7006.2009.01087.x
   PubMed Web of Science ®Google Scholar
• Mantovani A, Allavena P, Sica A, Balkwill F. Cancer-related inflammation. Nature. 2008;454(7203):436–444. doi:10.1038/nature07205
   PubMed Web of Science ®Google Scholar
• Steinman RM, Hawiger D, Nussenzweig MC. Tolerogenic dendritic cells. Annu Rev Immunol. 2003;21:685–711. doi:10.1146/annurev.immunol.21.120601.141040
   PubMed Web of Science ®Google Scholar
• Tanaka K, Miyata H, Sugimura K, et al. miR-27 is associated with chemoresistance in esophageal cancer through transformation of normal fibroblasts to cancer-associated fibroblasts. Carcinogenesis. 2015;36(8):894–903. doi:10.1093/carcin/bgv067
   PubMed Web of Science ®Google Scholar
• Min A, Zhu C, Peng S, et al. Downregulation of Microrna-148a in Cancer-Associated Fibroblasts from Oral Cancer Promotes Cancer Cell Migration and Invasion by Targeting Wnt10b. J Biochem Mol Toxic. 2016;30(4):186–191. doi:10.1002/jbt.21777
   PubMed Web of Science ®Google Scholar
• Kojima Y, Acar A, Eaton EN, et al. Autocrine TGF-β and stromal cell-derived factor-1 (SDF-1) signaling drives the evolution of tumor-promoting mammary stromal myofibroblasts. Proceedings of the National Academy of Sciences of the United States of America. 2010;107(46):20009–20014. doi:10.1073/pnas.1013805107
   PubMed Web of Science ®Google Scholar
• Billottet C, Tuefferd M, Gentien D, et al. Modulation of several waves of gene expression during FGF‐1 induced epithelial‐mesenchymal transition of carcinoma cells. Journal of Cellular Biochemistry. 2008;104(3):826–839. doi:10.1002/jcb.21667
   PubMed Web of Science ®Google Scholar
• Potenta S, Zeisberg E, Kalluri R. The role of endothelial-to-mesenchymal transition in cancer progression. British Journal of Cancer. 2008;99(9):1375–1379. doi:10.1038/sj.bjc.6604662
   PubMed Web of Science ®Google Scholar
• Xu J, Lamouille S, Derynck R. TGF-β-induced epithelial to mesenchymal transition. Cell Biosci. 2009;19(2):156–172. doi:10.1038/cr.2009.5
   Web of Science ®Google Scholar
• Zhang J, Gu CY, Song QQ, et al. Identifying cancer-associated fibroblasts as emerging targets for hepatocellular carcinoma. Cell Biosci. 2020;10:(1)127. doi:10.1186/s13578-020-00488-y
   Web of Science ®Google Scholar
• Miao L, Liu Q, Lin CM, et al. Targeting tumor-associated fibroblasts for therapeutic delivery in desmoplastic tumors. Cancer Research. 2017;77(3):719–731. doi:10.1158/0008-5472.CAN-16-0866
   PubMed Web of Science ®Google Scholar
• Murakami M, Ernsting MJ, Undzys E, Holwell N, Foltz WD. Docetaxel conjugate nanoparticles that target α-smooth muscle actin–expressing stromal cells suppress breast cancer metastasis. J med. 2013;73(15):4862–4871.
   Google Scholar
• Zou B, Liu X, Zhang B, et al. The Expression of FAP in Hepatocellular Carcinoma Cells is Induced by Hypoxia and Correlates with Poor Clinical Outcomes. J Cancer. 2018;9(18):3278–3286. doi:10.7150/jca.25775
   PubMed Web of Science ®Google Scholar
• Beljaars L, Weert B, Geerts A, Meijer DK, Poelstra K. The preferential homing of a platelet derived growth factor receptor-recognizing macromolecule to fibroblast-like cells in fibrotic tissue. Biochemical Pharmacology. 2003;66(7):1307–1317. doi:10.1016/s0006-2952(03)00445-3
   PubMed Web of Science ®Google Scholar
• Lakins MA, Ghorani E, Munir H, Martins CP, Shields J. Cancer-associated fibroblasts induce antigen-specific deletion of CD8+ T Cells to protect tumour cells. Cell Biosci. 2018;9(1):1–9.
   Google Scholar
• Fitzgerald AA, Weiner LMJC, Reviews M. The role of fibroblast activation protein in health and malignancy. Cancer Metastasis Reviews. 2020;39(3):783–803. doi:10.1007/s10555-020-09909-3
   PubMed Web of Science ®Google Scholar
• Keane FM, Yao T-W, Seelk S, et al. Quantitation of fibroblast activation protein (FAP)-specific protease activity in mouse, baboon and human fluids and organs. J Med. 2014;4:43–54.
   Google Scholar
• Li L, Zhou SY, Lv NN, et al. Photosensitizer-Encapsulated Ferritins Mediate Photodynamic Therapy against Cancer-Associated Fibroblasts and Improve Tumor Accumulation of Nanoparticles. Mol Pharmaceut. 2018;15(8):3595–3599. doi:10.1021/acs.molpharmaceut.8b00419
   PubMed Web of Science ®Google Scholar
• Yu QW, Qiu Y, Li JP, et al. Targeting cancer-associated fibroblasts by dual-responsive lipid-albumin nanoparticles to enhance drug perfusion for pancreatic tumor therapy. Article J Control Release. 2020;321:564–575. doi:10.1016/j.jconrel.2020.02.040
   PubMed Web of Science ®Google Scholar
• Yang ZT, Zhang L, Zhu H, et al. Nanoparticle formulation of mycophenolate mofetil achieves enhanced efficacy against hepatocellular carcinoma by targeting tumour-associated fibroblast. J Cell Mol Med. 2021;25(7):3511–3523. doi:10.1111/jcmm.16434
   PubMed Web of Science ®Google Scholar
• Yang J, Lu Y, Lin -Y-Y, et al. Vascular mimicry formation is promoted by paracrine TGF-β and SDF1 of cancer-associated fibroblasts and inhibited by miR-101 in hepatocellular carcinoma. Cancer Letters. 2016;383(1):18–27. doi:10.1016/j.canlet.2016.09.012
   PubMed Web of Science ®Google Scholar
• Giannelli G, Villa E, Lahn M. Transforming growth factor-β as a therapeutic target in hepatocellular carcinoma. Cancer Research. 2014;74(7):1890–1894. doi:10.1158/0008-5472.CAN-14-0243
   PubMed Web of Science ®Google Scholar
• Farazi PA, DePinho R. Hepatocellular carcinoma pathogenesis: from genes to environment. Nature Reviews. Cancer. 2006;6(9):674–687. doi:10.1038/nrc1934
   PubMed Web of Science ®Google Scholar
• Morén A, Bellomo C, Tsubakihara Y, et al. LXRα limits TGFβ-dependent hepatocellular carcinoma associated fibroblast differentiation. Oncogenesis. 2019;8(6):36. doi:10.1038/s41389-019-0140-4
   PubMed Web of Science ®Google Scholar
• Mazzocca A, Fransvea E, Dituri F, Lupo L, Antonaci S, Giannelli GJH. Down‐regulation of connective tissue growth factor by inhibition of transforming growth factor β blocks the tumor–stroma cross‐talk and tumor progression in hepatocellular carcinoma. Hepatology (Baltimore, Md.). 2010;51(2):523–534. doi:10.1002/hep.23285
   PubMed Web of Science ®Google Scholar
• Zhang Y, Elechalawar CK, Hossen MN, et al. Gold nanoparticles inhibit activation of cancer-associated fibroblasts by disrupting communication from tumor and microenvironmental cells. Bioactive Materials. 2021;6(2):326–332. doi:10.1016/j.bioactmat.2020.08.009
   PubMed Web of Science ®Google Scholar
• Frantz C, Stewart KM, Weaver VM. The extracellular matrix at a glance. J Cell Sci. 2010;123(24):4195–4200. doi:10.1242/jcs.023820
   PubMed Web of Science ®Google Scholar
• Hynes RO. The Extracellular Matrix: not Just Pretty Fibrils. Science. 2009;326(5957):1216–1219. doi:10.1126/science.1176009
   PubMed Web of Science ®Google Scholar
• Hernandez-Gea V, Toffanin S, Friedman SL, Llovet JM. Role of the Microenvironment in the Pathogenesis and Treatment of Hepatocellular Carcinoma. Gastroenterology. 2013;144(3):512–527. doi:10.1053/j.gastro.2013.01.002
   PubMed Web of Science ®Google Scholar
• Barry-Hamilton V, Spangler R, Marshall D, et al. Allosteric inhibition of lysyl oxidase-like-2 impedes the development of a pathologic microenvironment. Nat Med. 2010;16(9):1009–1017. doi:10.1038/nm.2208
   PubMed Web of Science ®Google Scholar
• Schrader J, Gordon-Walker TT, Aucott RL, et al. Matrix Stiffness Modulates Proliferation, Chemotherapeutic Response, and Dormancy in Hepatocellular Carcinoma Cells. Hepatology. 2011;53(4):1192–1205. doi:10.1002/hep.24108
   PubMed Web of Science ®Google Scholar
• Ali MRK, Wu Y, Tang Y, et al. Targeting cancer cell integrins using gold nanorods in photothermal therapy inhibits migration through affecting cytoskeletal proteins. P Natl Acad Sci USA. 2017;114(28):E5655–E5663. doi:10.1073/pnas.1703151114
   PubMed Web of Science ®Google Scholar
• Duong HTT, Dong Z, Su L, et al. The use of nanoparticles to deliver nitric oxide to hepatic stellate cells for treating liver fibrosis and portal hypertension. Small. 2015;11(19):2291–2304. doi:10.1002/smll.201402870
   PubMed Web of Science ®Google Scholar
• Scodeller P, Catalano PN, Salguero N, Duran H, Wolosiuk A, Soler-Illia GJAA. Hyaluronan degrading silica nanoparticles for skin cancer therapy. Nanoscale. 2013;5(20):9690–9698. doi:10.1039/c3nr02787b
   PubMed Web of Science ®Google Scholar
• Solis GP, Bilousov O, Koval A, Lüchtenborg AM, Lin C, Katanaev VL. Golgi-Resident Gαo Promotes Protrusive Membrane Dynamics. Cell. Cell. 2017;170(5):939–955.e24. doi:10.1016/j.cell.2017.07.015
   PubMed Web of Science ®Google Scholar
• Luo JW, Gong T, Ma LX. Chondroitin-modified lipid nanoparticles target the Golgi to degrade extracellular matrix for liver cancer management. Article Carbohyd Polym. 2020;249:116887. doi:10.1016/j.carbpol.2020.116887
   PubMed Web of Science ®Google Scholar
• Suzuki H, Bae YH. Evaluation of drug penetration with cationic micelles and their penetration mechanism using an in vitro tumor model. Biomaterials. 2016;98:120–130. doi:10.1016/j.biomaterials.2016.04.037
   PubMed Web of Science ®Google Scholar
• Ling D, Park W, Park S-J, et al. Multifunctional tumor pH-sensitive self-assembled nanoparticles for bimodal imaging and treatment of resistant heterogeneous tumors. J Am Chem Soc. 2014;136(15):5647–5655. doi:10.1021/ja4108287
   PubMed Web of Science ®Google Scholar
• Liu YY, Li L, Li LJ, et al. Programmed drug delivery system based on optimized ”size decrease and hydrophilicity/hydrophobicity transformation” for enhanced hepatocellular carcinoma therapy of doxorubicin. Nanomed-Nanotechnol. 2018;14(4):1111–1122. doi:10.1016/j.nano.2018.02.006
   PubMed Web of Science ®Google Scholar
• Lv F, He X, Wu L, Liu T. Lactose substituted zinc phthalocyanine: a near infrared fluorescence imaging probe for liver cancer targeting. Bioorg Med Chem Lett. 2013;23(6):1878–1882. doi:10.1016/j.bmcl.2012.12.103
   PubMed Web of Science ®Google Scholar
• Mukherjee A, Madamsetty VS, Paul MK, Mukherjee S. Recent Advancements of Nanomedicine towards Antiangiogenic Therapy in Cancer. Int J Mol Sci. 2020;21:(2)455. doi:10.3390/ijms21020455
   Web of Science ®Google Scholar
• Ho JWY, Pang RWC, Lau C, et al. Significance of circulating endothelial progenitor cells in hepatocellular carcinoma. Hepatology. 2006;44(4):836–843. doi:10.1002/hep.21353
   PubMed Web of Science ®Google Scholar
• Couri T, Pillai A. Goals and targets for personalized therapy for HCC. Hepatol Int. 2019;13(2):125–137. doi:10.1007/s12072-018-9919-1
   PubMed Web of Science ®Google Scholar
• Fire A, Xu SQ, Montgomery MK, Kostas SA, Driver SE, Mello CC. Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature. 1998;391(6669):806–811. doi:10.1038/35888
   PubMed Web of Science ®Google Scholar
• Wu HP, Feng GS, Liang HM, Zheng CS, Li X. Vascular endothelial growth factor antisense oligodeoxynucleotides with lipiodol in arterial embolization of liver cancer in rats. World J Gastroentero. 2004;10(6):813–818. doi:10.3748/wjg.v10.i6.813
   PubMed Web of Science ®Google Scholar
• Wang G, Gao X, Gu G, et al. Polyethylene glycol-poly(epsilon-benzyloxycarbonyl-llysine)-conjugated VEGF siRNA for antiangiogenic gene therapy in hepatocellular carcinoma. Int J Nanomed. 2017;12:3591–3603. doi:10.2147/ijn.S131078
   PubMed Web of Science ®Google Scholar
• Xu B, Zhang Y, Yang H, et al. siVEGF-loaded nanoparticle uptake by tumor-associated vascular endothelial cells for hepatocellular carcinoma. Nanomedicine-Uk. 2020;15(13):1297–1314. doi:10.2217/nnm-2020-0082
   Web of Science ®Google Scholar
• Yang ZG, Ma YF, Zhao H, Yuan Y, Kim BYS. Nanotechnology platforms for cancer immunotherapy. Wiley Interdisciplinary Rev. 2020;12:(2)e1590. doi:10.1002/wnan.1590
   PubMedGoogle Scholar
• Gupta B, Kim JO. Recent progress in cancer immunotherapy approaches based on nanoparticle delivery devices. J Pharmaceutical Investigation. 2021;51(4):399–412. doi:10.1007/s40005-021-00527-x
   Web of Science ®Google Scholar
• Sica A, Allavena P, Mantovani A. Cancer related inflammation: the macrophage connection. Cancer Lett. 2008;267(2):204–215. doi:10.1016/j.canlet.2008.03.028
   PubMed Web of Science ®Google Scholar
• Dong PP, Ma LJ, Liu LZ, et al. CD86(+)/CD206(+), Diametrically Polarized Tumor-Associated Macrophages, Predict Hepatocellular Carcinoma Patient Prognosis. Int J Mol Sci. 2016;17:(3)320. doi:10.3390/ijms17030320
   Web of Science ®Google Scholar
• Kong LX, Zhou YJ, Bu H, Lv T, Shi YJ, Yang JY. Deletion of interleukin-6 in monocytes/macrophages suppresses the initiation of hepatocellular carcinoma in mice. J Exp Clin Cancer Res. 2016;35131. doi:10.1186/s13046-016-0412-1
   Web of Science ®Google Scholar
• Ataseven H, Bahcecioglu IH, Kuzu N, et al. The levels of ghrelin, leptin, TNF-alpha, and IL-6 in liver cirrhosis and hepatocellular carcinoma due to HBV and HDV infection. Mediators Inflamm. 2006:200678380. doi:10.1155/mi/2006/78380
   Web of Science ®Google Scholar
• Peng SH, Deng H, Yang JF, et al. Significance and relationship between infiltrating inflammatory cell and tumor angiogenesis in hepatocellular carcinoma tissues. World J Gastroentero. 2005;11(41):6521–6524. doi:10.3748/wjg.v11.i41.6521
   PubMed Web of Science ®Google Scholar
• Mano Y, Aishima S, Fujita N, et al. Tumor-Associated Macrophage Promotes Tumor Progression via STAT3 Signaling in Hepatocellular Carcinoma. Pathobiology. 2013;80(3):146–154. doi:10.1159/000346196
   PubMed Web of Science ®Google Scholar
• Chen Y, Ramjiawan RR, Reiberger T, et al. CXCR4 inhibition in tumor microenvironment facilitates anti-programmed death receptor-1 immunotherapy in sorafenib-treated hepatocellular carcinoma in mice. Hepatology. 2015;61(5):1591–1602. doi:10.1002/hep.27665
   PubMed Web of Science ®Google Scholar
• Chen Y, Huang Y, Reiberger T, et al. Differential effects of sorafenib on liver versus tumor fibrosis mediated by stromal-derived factor 1 alpha/C-X-C receptor type 4 axis and myeloid differentiation antigen-positive myeloid cell infiltration in mice. Hepatology. 2014;59(4):1435–1447. doi:10.1002/hep.26790
   PubMed Web of Science ®Google Scholar
• Cai JJ, Zhang Q, Qian XM, et al. Extracellular ubiquitin promotes hepatoma metastasis by mediating M2 macrophage polarization via the activation of the CXCR4/ERK signaling pathway. Ann Transl Med. 2020;8(15):929. doi:10.21037/atm-20-1054
   PubMed Web of Science ®Google Scholar
• Gao DY, Lin TT, Sung YC, et al. CXCR4-targeted lipid-coated PLGA nanoparticles deliver sorafenib and overcome acquired drug resistance in liver cancer. Article Biomaterials. 2015;67:194–203. doi:10.1016/j.biomaterials.2015.07.035
   PubMed Web of Science ®Google Scholar
• Liu JY, Chiang T, Liu CH, et al. Delivery of siRNA Using CXCR4-targeted Nanoparticles Modulates Tumor Microenvironment and Achieves a Potent Antitumor Response in Liver Cancer. Mol Ther. 2015;23(11):1772–1782. doi:10.1038/mt.2015.147
   PubMed Web of Science ®Google Scholar
• Wang Y, Tiruthani K, Li SR, et al. mRNA Delivery of a Bispecific Single-Domain Antibody to Polarize Tumor-Associated Macrophages and Synergize Immunotherapy against Liver Malignancies. Adv Mater. 2021;33(23):2007603. doi:10.1002/adma.202007603
   Web of Science ®Google Scholar
• Cheng Q, Wei T, Farbiak L, Johnson LT, Dilliard SA, Siegwart DJ. Selective organ targeting (SORT) nanoparticles for tissue-specific mRNA delivery and CRISPR-Cas gene editing. Nat Nanotechnol. 2020;15(4):313–320. doi:10.1038/s41565-020-0669-6
   PubMed Web of Science ®Google Scholar
• Henze A-T, Mazzone M. The impact of hypoxia on tumor-associated macrophages. J Clin Invest. 2016;126(10):3672–3679. doi:10.1172/JCI84427
   PubMed Web of Science ®Google Scholar
• Duran SR, Jaquiss RDB. Hepatocellular Carcinoma. N Eng J Med. 2019;381(1):548.
   Google Scholar
• Dai XM, Ruan J, Guo YX, et al. Enhanced radiotherapy efficacy and induced anti-tumor immunity in HCC by improving hypoxia microenvironment using oxygen microcapsules. Chem Eng J. 2021:422130109. doi:10.1016/j.cej.2021.130109
   Web of Science ®Google Scholar
• Huang Y, Gao X, Chen J. Leukocyte-derived biomimetic nanoparticulate drug delivery systems for cancer therapy. Acta Pharmaceutica Sinica B. 2018;8(1):4–13. doi:10.1016/j.apsb.2017.12.001
   PubMed Web of Science ®Google Scholar
• Xie Q, Ding J, Chen Y. Role of CD8(+) T lymphocyte cells: interplay with stromal cells in tumor microenvironment. Acta Pharmaceutica Sinica B. 2021;11(6):1365–1378. doi:10.1016/j.apsb.2021.03.027
   PubMed Web of Science ®Google Scholar
• Breart B, Lemaitre F, Celli S, Bousso P. Two-photon imaging of intratumoral CD8(+) T cell cytotoxic activity during adoptive T cell therapy in mice. J Clin Invest. 2008;118(4):1390–1397. doi:10.1172/jci34388
   PubMed Web of Science ®Google Scholar
• Slaney CY, Kershaw MH, Darcy PK. Trafficking of T Cells into Tumors. Cancer Res. 2014;74(24):7168–7174. doi:10.1158/0008-5472.Can-14-2458
   PubMed Web of Science ®Google Scholar
• Jonuleit H, Bopp T, Becker C. Treg cells as potential cellular targets for functionalized nanoparticles in cancer therapy. Nanomedicine-Uk. 2016;11(20):2699–2709. doi:10.1158/0008-5472.CAN-14-2458
   PubMed Web of Science ®Google Scholar
• Ohue Y, Nishikawa H. Regulatory T (Treg) cells in cancer: can Treg cells be a new therapeutic target? Cancer Sci. 2019;110(7):2080–2089. doi:10.1111/cas.14069
   PubMed Web of Science ®Google Scholar
• Wing K, Onishi Y, Prieto-Martin P, et al. CTLA-4 control over Foxp3(+) regulatory T cell function. Science. 2008;322(5899):271–275. doi:10.1126/science.1160062
   PubMed Web of Science ®Google Scholar
• Fridman WH, Pages F, Sautes-Fridman C, Galon J. The immune contexture in human tumours: impact on clinical outcome. Nat Rev Cancer. 2012;12(4):298–306. doi:10.1038/nrc3245
   PubMed Web of Science ®Google Scholar
• Schorer M, Kuchroo VK, Joller N. Role of Co-stimulatory Molecules in T Helper Cell Differentiation. In: azuma M, Yagita H, eds. Co-Signal Molecules in T Cell Activation: immune Regulation in Health and Disease. Adv Exp Med Biol. 2019;1:153–177.
   Web of Science ®Google Scholar
• Del Vecchio M, Bajetta E, Canova S, et al. Interleukin-12: biological properties and clinical application. Clin Cancer Res. 2007;13(16):4677–4685. doi:10.1158/1078-0432.Ccr-07-0776
   PubMed Web of Science ®Google Scholar
• Smyth MJ, Taniguchi M, Street SEA. The anti-tumor activity of IL-12: mechanisms of innate immunity that are model and dose dependent. J Immunol. 2000;165(5):2665–2670. doi:10.4049/jimmunol.165.5.2665
   PubMed Web of Science ®Google Scholar
• Szabo SJ, Dighe AS, Gubler U, Murphy KM. Regulation of the interleukin (IL)-12R beta 2 subunit expression in developing T helper 1 (Th1) and Th2 cells. J Exp Med. 1997;185(5):817–824. doi:10.1084/jem.185.5.817
   PubMed Web of Science ®Google Scholar
• Cheever MAM. Twelve immunotherapy drugs that could cure cancers. Immunol Rev. 2008;222:357–368. doi:10.1111/j.1600-065X.2008.00604.x
   PubMed Web of Science ®Google Scholar
• Li JY, Lin WS, Chen HJ, Xu ZP, Ye YB, Chen MS. Dual-target IL-12-containing nanoparticles enhance T cell functions for cancer immunotherapy. Cell Immunol. 2020;349104042. doi:10.1016/j.cellimm.2020.104042
   Web of Science ®Google Scholar
• Aktas E, Kucuksezer UC, Bilgic S, Erten G, Deniz G. Relationship between CD107a expression and cytotoxic activity. Cell Immunol. 2009;254(2):149–154. doi:10.1016/j.cellimm.2008.08.007
   PubMed Web of Science ®Google Scholar
• Lai I, Swaminathan S, Baylot V, et al. Lipid nanoparticles that deliver IL-12 messenger RNA suppress tumorigenesis in MYC oncogene-driven hepatocellular carcinoma. J Immunotherapy Cancer. 2018;4:6125. doi:10.1186/s40425-018-0431-x
   Web of Science ®Google Scholar
• Guan H, Nagarkatti PS, Nagarkatti M. Role of CD44 in the Differentiation of Th1 and Th2 Cells: CD44-Deficiency Enhances the Development of Th2 Effectors in Response to Sheep RBC and Chicken Ovalbumin. J Immunol. 2009;183(1):172–180. doi:10.4049/jimmunol.0802325
   PubMed Web of Science ®Google Scholar
• Schumann J, Stanko K, Schliesser U, Appelt C, Sawitzki B. Differences in CD44 Surface Expression Levels and Function Discriminates IL-17 and IFN-gamma Producing Helper T Cells. PLoS One. 2015;10(7):e0132479. doi:10.1371/journal.pone.0132479
   PubMed Web of Science ®Google Scholar
• Zhang N, Yang Y, Cheng L, et al. Combination of Caspy2 and IP-10 Gene Therapy Significantly Improves Therapeutic Efficacy Against Murine Malignant Neoplasm Growth and Metastasis. Hum Gene Ther. 2012;23(8):837–846. doi:10.1089/hum.2011.136
   PubMed Web of Science ®Google Scholar
• Yates-Binder CC, Rodgers M, Jaynes J, Wells A, Bodnar RJ, Turner T. An IP-10 (CXCL10)-Derived Peptide Inhibits Angiogenesis. PLoS One. 2012;7(7):e40812. doi:10.1371/journal.pone.0040812
   PubMed Web of Science ®Google Scholar
• Lai CH, Yu X, Zhuo HQ, et al. Anti-Tumor Immune Response of Folate-Conjugated Chitosan Nanoparticles Containing the IP-10 Gene in Mice with Hepatocellular Carcinoma. J Biomed Nanotechnol. 2014;10(12):3576–3589. doi:10.1166/jbn.2014.2051
   PubMed Web of Science ®Google Scholar
• Palucka K, Ueno H, Fay J, Banchereau J. Dendritic cells and immunity against cancer. J Intern Med. 2011;269(1):64–73. doi:10.1111/j.1365-2796.2010.02317.x
   PubMed Web of Science ®Google Scholar
• Banchereau J, Steinman RM. Dendritic cells and the control of immunity. Nature. 1998;392(6673):245–252. doi:10.1038/32588
   PubMed Web of Science ®Google Scholar
• Geissmann F, Dieu-Nosjean MC, Dezutter C, et al. Accumulation of immature Langerhans cells in human lymph nodes draining chronically inflamed skin. J Exp Med. 2002;196(4):417–430. doi:10.1084/jem.20020018
   PubMed Web of Science ®Google Scholar
• Turley SJ, Inaba K, Garrett WS, et al. Transport of peptide-MHC class II complexes in developing dendritic cells. Science. 2000;288(5465):522–527. doi:10.1126/science.288.5465.522
   PubMed Web of Science ®Google Scholar
• Walker WA. Immunology. Curr Opin Gastroenterol. 2007;23(6):644–646. doi:10.1097/MOG.0b013e3282f0769b
   PubMed Web of Science ®Google Scholar
• Kaliński P, Hilkens CM, Wierenga EA, Kapsenberg ML. T-cell priming by type-1 and type-2 polarized dendritic cells: the concept of a third signal. Immunol Today. 1999;20(12):561–567. doi:10.1016/s0167-5699(99
   PubMedGoogle Scholar
• Matsui M, Machida S, Itani-Yohda T, Akatsuka T. Downregulation of the proteasome subunits, transporter, and antigen presentation in hepatocellular carcinoma, and their restoration by interferon-gamma. J Gastroenterol Hepatol. 2002;17(8):897–907. doi:10.1046/j.1440-1746.2002.02837.x
   PubMed Web of Science ®Google Scholar
• Ninomiya T, Akbar F, Masumoto T, Horiike N, Onji M. Dendritic cells with immature phenotype and defective function in the peripheral blood from patients with hepatocellular carcinoma. J Hepatol. 1999;31(2):323–331. doi:10.1016/s0168-8278(99
   PubMed Web of Science ®Google Scholar
• Nakamoto Y, Guidotti LG, Kuhlen CV, Fowler P, Chisari FV. Immune pathogenesis of hepatocellular carcinoma. J Exp Med. 1998;188(2):341–350. doi:10.1084/jem.188.2.341
   PubMed Web of Science ®Google Scholar
• Kakumu S, Ito S, Ishikawa T, et al. Decreased function of peripheral blood dendritic cells in patients with hepatocellular carcinoma with hepatitis B and C virus infection. J Gastroenterol Hepatol. 2000;15(4):431–436. doi:10.1046/j.1440-1746.2000.02161.x
   PubMed Web of Science ®Google Scholar
• Reddy ST, van der Vlies AJ, Simeoni E, et al. Exploiting lymphatic transport and complement activation in nanoparticle vaccines. Nat Biotechnol. 2007;25(10):1159–1164. doi:10.1038/nbt1332
   PubMed Web of Science ®Google Scholar
• Yang XM, Lai CH, Liu AQ, et al. Anti-Tumor Activity of Mannose-CpG-Oligodeoxynucleotides-Conjugated and Hepatoma Lysate-Loaded Nanoliposomes for Targeting Dendritic Cells In Vivo. J Biomed Nanotechnol. 2019;15(5):1018–1032. doi:10.1166/jbn.2019.2755
   PubMed Web of Science ®Google Scholar
• Xi L, Lin ZB, Qiu F, et al. Enhanced uptake and anti-maturation effect of celastrol-loaded mannosylated liposomes on dendritic cells for psoriasis treatment. Article Acta Pharmaceutica Sinica B. 2022;12(1):339–352. doi:10.1016/j.apsb.2021.07.0192211-3835
   PubMed Web of Science ®Google Scholar
• Ulmer JB, Mason PW, Geall A, Mandl CW. RNA-based vaccines. Vaccine. 2012;30(30):4414–4418. doi:10.1016/j.vaccine.2012.04.060
   PubMed Web of Science ®Google Scholar
• Zhang Y, Xie F, Yin Y, et al. Immunotherapy of Tumor RNA-Loaded Lipid Nanoparticles Against Hepatocellular Carcinoma. Int J Nanomed. 2021;16:1553–1564. doi:10.2147/ijn.S291421
   PubMed Web of Science ®Google Scholar