Toll样受体7/8对肿瘤发生发展过程影响的研究进展

doi:10.13481/j.1671-587X.20260129

摘要/Abstract

摘要：

Toll样受体（TLRs）是特征最明显的模式识别受体（PRR）家族，在先天性免疫和适应性免疫过程中均发挥关键作用。除在免疫细胞中广泛表达外，许多肿瘤细胞群中也存在TLRs的表达，其激活可导致肿瘤进展或消退，这使得TLRs与肿瘤的临床相关性成为近年来的研究热点。其中，TLRs亚型TLR7/8在肿瘤发生发展中具有双重作用。一方面，其通过诱发有效抗肿瘤免疫反应，介导肿瘤细胞死亡而发挥抑瘤作用；另一方面，其还可通过调节肿瘤细胞行为和肿瘤微环境（TME）促进肿瘤进展。因此，TLR7/8已成为肿瘤防治的潜在靶点。现结合国内外最新研究成果，对TLR7/8的分子特征、信号通路及对肿瘤发生发展过程的影响等方面进行总结和分析，并系统综述了靶向TLR7/8小分子调节剂应用的研究进展，旨在为TLR7/8相关的肿瘤防治策略提供科学参考。

关键词: Toll样受体7/8, 肿瘤, 生物学功能, 小分子调节剂, 肿瘤微环境, 先天性免疫应答

Abstract:

Toll-like receptors （TLRs） are the most well-characterized family of pattern recognition receptors （PRRs）， playing key roles in both innate and adaptive immune processes. In addition to their widespread expression in immune cells， TLRs are also expressed in many tumor cell populations. Their activation can lead to tumor progression or regression， which has made the clinical relevance of TLRs to tumors a research hotspot in recent years. Among them， the TLR subtypes TLR7/8 have dual effects in tumorigenesis and development. On the one hand， they exert tumor-suppressive effects by inducing effective anti-tumor immune responses and mediating tumor cell death； on the other hand， they can also promote tumor progression by regulating tumor cell behavior and the tumor microenvironment （TME）. Therefore， TLR7/8 has become a potential target for tumor prevention and treatment. This article summarizes and analyzes the molecular characteristics and signaling pathways of TLR7/8 and their impact on the process of tumorigenesis and development based on the latest research findings at home and abroad， and systematically reviews the research progress in the application of small molecule modulators targeting TLR7/8， aiming to provide a reference for the discussion on the role of TLR7/8 in tumor prevention and treatment.

Key words: Toll-like receptor 7/8, Neoplasm, Biological function, Small molecule modulator, Tumor microenvironment, Innate immune response

中图分类号:

R730.51

王璐瑶,赵晨曦,杜锦程,刘林林. Toll样受体7/8对肿瘤发生发展过程影响的研究进展[J]. 吉林大学学报(医学版), 2026, 52(1): 264-271.

Luyao WANG,Chenxi ZHAO,Jincheng DU,Linlin LIU. Research progress in effect of Toll-like receptor 7/8 on occurrence and development of tumor[J]. Journal of Jilin University(Medicine Edition), 2026, 52(1): 264-271.

参考文献 65

[1]	ZHANG E J， MA Z Y， LU M J. Contribution of T- and B-cell intrinsic toll-like receptors to the adaptive immune response in viral infectious diseases［J］. Cell Mol Life Sci， 2022， 79（11）： 547.
[2]	KAWASAKI T， KAWAI T. Toll-like receptor signaling pathways［J］. Front Immunol， 2014， 5： 461.
[3]	RAKOFF-NAHOUM S， MEDZHITOV R. Toll-like receptors and cancer［J］. Nat Rev Cancer， 2009， 9（1）： 57-63.
[4]	BEHZADI P， GARCÍA-PERDOMO H A， KARPIŃSKI T M. Toll-like receptors： general molecular and structural biology［J］. J Immunol Res， 2021， 2021： 9914854.
[5]	BAYRAKTAR R， BERTILACCIO M T S， CALIN G A. The interaction between two worlds： microRNAs and toll-like receptors［J］. Front Immunol， 2019， 10： 1053.
[6]	ASAMI J， SHIMIZU T. Structural and functional understanding of the toll-like receptors［J］. Protein Sci， 2021， 30（4）： 761-772.
[7]	CHEN L F， ZHENG L L， CHEN P Q， et al. Myeloid differentiation primary response protein 88 （MyD88）： the central hub of TLR/IL-1R signaling［J］. J Med Chem， 2020， 63（22）： 13316-13329.
[8]	DUAN T H， DU Y， XING C S， et al. Toll-like receptor signaling and its role in cell-mediated immunity［J］. Front Immunol， 2022， 13： 812774.
[9]	URBAN-WOJCIUK Z， KHAN M M， OYLER B L， et al. The role of TLRs in anti-cancer immunity and tumor rejection［J］. Front Immunol， 2019， 10： 2388.
[10]	PRADERE J P， DAPITO D H， SCHWABE R F. The Yin and Yang of toll-like receptors in cancer［J］. Oncogene， 2014， 33（27）： 3485-3495.
[11]	WOLSKA A， LECH-MARAŃDA E， ROBAK T. Toll-like receptors and their role in carcinogenesis and anti-tumor treatment［J］. Cell Mol Biol Lett， 2009， 14（2）： 248-272.
[12]	ROLFO C， GIOVANNETTI E， MARTINEZ P， et al. Applications and clinical trial landscape using Toll-like receptor agonists to reduce the toll of cancer［J］. NPJ Precis Oncol， 2023， 7（1）： 26.
[13]	CHEN J Q， SZODORAY P， ZEHER M. Toll-like receptor pathways in autoimmune diseases［J］. Clin Rev Allergy Immunol， 2016， 50（1）： 1-17.
[14]	FITZGERALD K A， KAGAN J C. Toll-like receptors and the control of immunity［J］. Cell， 2020， 180（6）： 1044-1066.
[15]	TANJI H， OHTO U， SHIBATA T， et al. Structural reorganization of the Toll-like receptor 8 dimer induced by agonistic ligands［J］. Science， 2013， 339（6126）： 1426-1429.
[16]	ZHANG Z K， OHTO U， SHIBATA T， et al. Structural analysis reveals that toll-like receptor 7 is a dual receptor for guanosine and single-stranded RNA［J］. Immunity， 2016， 45（4）： 737-748.
[17]	TANJI H， OHTO U， SHIBATA T， et al. Toll-like receptor 8 senses degradation products of single-stranded RNA［J］. Nat Struct Mol Biol， 2015， 22（2）： 109-115.
[18]	ZHANG Z K， OHTO U， SHIBATA T， et al. Structural analyses of toll-like receptor 7 reveal detailed RNA sequence specificity and recognition mechanism of agonistic ligands［J］. Cell Rep， 2018， 25（12）： 3371-3381.
[19]	JURK M， HEIL F， VOLLMER J， et al. Human TLR7 or TLR8 independently confer responsiveness to the antiviral compound R-848［J］. Nat Immunol， 2002， 3（6）： 499.
[20]	VASILAKOS J P， TOMAI M A. The use of Toll-like receptor 7/8 agonists as vaccine adjuvants［J］. Expert Rev Vaccines， 2013， 12（7）： 809-819.
[21]	KAWAI T， AKIRA S. Toll-like receptors and their crosstalk with other innate receptors in infection and immunity［J］. Immunity， 2011， 34（5）： 637-650.
[22]	O’NEILL L A J， BOWIE A G. The family of five： TIR-domain-containing adaptors in Toll-like receptor signalling［J］. Nat Rev Immunol， 2007， 7（5）： 353-364.
[23]	TAN Y H， KAGAN J C. Innate immune signaling organelles display natural and programmable signaling flexibility［J］. Cell， 2019， 177（2）： 384-398.e11.
[24]	KAWAI T， AKIRA S. TLR signaling［J］. Semin Immunol， 2007， 19（1）： 24-32.
[25]	KAWAI T， AKIRA S. Signaling to NF-kappaB by Toll-like receptors［J］. Trends Mol Med， 2007， 13（11）： 460-469.
[26]	WEST A P， KOBLANSKY A A， GHOSH S. Recognition and signaling by Toll-like receptors［J］. Annu Rev Cell Dev Biol， 2006， 22： 409-437.
[27]	LI S， STRELOW A， FONTANA E J， et al. IRAK-4： a novel member of the IRAK family with the properties of an IRAK-kinase［J］. Proc Natl Acad Sci USA， 2002， 99（8）： 5567-5572.
[28]	FERRAO R， ZHOU H， SHAN Y B， et al. IRAK4 dimerization and trans-autophosphorylation are induced by Myddosome assembly［J］. Mol Cell， 2014， 55（6）： 891-903.
[29]	LIN S C， LO Y C， WU H. Helical assembly in the MyD88-IRAK4-IRAK2 complex in TLR/IL-1R signalling［J］. Nature， 2010， 465（7300）： 885-890.
[30]	SUN J， LI N， OH K S， et al. Comprehensive RNAi-based screening of human and mouse TLR pathways identifies species-specific preferences in signaling protein use［J］. Sci Signal， 2016， 9（409）： ra3.
[31]	PEREIRA M， GAZZINELLI R T. Regulation of innate immune signaling by IRAK proteins［J］. Front Immunol， 2023， 14： 1133354.
[32]	CHEN Z J. Ubiquitination in signaling to and activation of IKK［J］. Immunol Rev， 2012， 246（1）： 95-106.
[33]	LIU T， ZHANG L Y， JOO D， et al. NF-κB signaling in inflammation［J］. Signal Transduct Target Ther， 2017， 2： 17023.
[34]	LITVAK V， RAMSEY S A， RUST A G， et al. Function of C/EBPdelta in a regulatory circuit that discriminates between transient and persistent TLR4-induced signals［J］. Nat Immunol， 2009， 10（4）： 437-443.
[35]	IWASAKI A， MEDZHITOV R. Toll-like receptor control of the adaptive immune responses［J］. Nat Immunol， 2004， 5（10）： 987-995.
[36]	YANG Y， FENG R， WANG Y Z， et al. Toll-like receptors： Triggers of regulated cell death and promising targets for cancer therapy［J］. Immunol Lett， 2020， 223： 1-9.
[37]	RIDNOUR L A， CHENG R Y， SWITZER C H， et al. Molecular pathways： toll-like receptors in the tumor microenvironment-poor prognosis or new therapeutic opportunity［J］. Clin Cancer Res， 2013， 19（6）： 1340-1346.
[38]	PALUCKA K， BANCHEREAU J. Cancer immunotherapy via dendritic cells［J］. Nat Rev Cancer， 2012， 12（4）： 265-277.
[39]	WU J， LI S， YANG Y， et al. TLR-activated plasmacytoid dendritic cells inhibit breast cancer cell growth in vitro and in vivo ［J］. Oncotarget， 2017， 8（7）： 11708-11718.
[40]	LU H L， DIETSCH G N， MATTHEWS M H， et al. VTX-2337 is a novel TLR8 agonist that activates NK cells and augments ADCC［J］. Clin Cancer Res， 2012， 18（2）： 499-509.
[41]	VENEZIANI I， ALICATA C， MORETTA L， et al. Human toll-like receptor 8 （TLR8） in NK cells： Implication for cancer immunotherapy［J］. Immunol Lett， 2023， 261： 13-16.
[42]	ZHOU Z X， YU X， ZHANG J， et al. TLR7/8 agonists promote NK-DC cross-talk to enhance NK cell anti-tumor effects in hepatocellular carcinoma［J］. Cancer Lett， 2015， 369（2）： 298-306.
[43]	LEE M， PARK C S， LEE Y R， et al. Resiquimod， a TLR7/8 agonist， promotes differentiation of myeloid-derived suppressor cells into macrophages and dendritic cells［J］. Arch Pharm Res， 2014， 37（9）： 1234-1240.
[44]	SAFARZADEH E， MOHAMMADI A， MANSOORI B， et al. STAT3 silencing and TLR7/8 pathway activation repolarize and suppress myeloid-derived suppressor cells from breast cancer patients［J］. Front Immunol， 2020， 11： 613215.
[45]	ROUANET M， HANOUN N， LULKA H， et al. The antitumoral activity of TLR7 ligands is corrupted by the microenvironment of pancreatic tumors［J］. Mol Ther， 2022， 30（4）： 1553-1563.
[46]	YEH D W， HUANG L R， CHEN Y W， et al. Interplay between inflammation and stemness in cancer cells： the role of toll-like receptor signaling［J］. J Immunol Res， 2016， 2016： 4368101.
[47]	LI W， ZHANG L Y， GUO B B， et al. Exosomal FMR1-AS1 facilitates maintaining cancer stem-like cell dynamic equilibrium via TLR7/NFκB/c-Myc signaling in female esophageal carcinoma［J］. Mol Cancer， 2019， 18（1）： 22.
[48]	CHERFILS-VICINI J， PLATONOVA S， GILLARD M， et al. Triggering of TLR7 and TLR8 expressed by human lung cancer cells induces cell survival and chemoresistance［J］. J Clin Invest， 2010， 120（4）： 1285-1297.
[49]	GRIMMIG T， MATTHES N， HOELAND K， et al. TLR7 and TLR8 expression increases tumor cell proliferation and promotes chemoresistance in human pancreatic cancer［J］. Int J Oncol， 2015， 47（3）： 857-866.
[50]	YE J， MA C L， HSUEH E C， et al. TLR8 signaling enhances tumor immunity by preventing tumor-induced T-cell senescence［J］. EMBO Mol Med， 2014， 6（10）： 1294-1311.
[51]	DAJON M， IRIBARREN K， PETITPREZ F， et al. Toll like receptor 7 expressed by malignant cells promotes tumor progression and metastasis through the recruitment of myeloid derived suppressor cells［J］. Oncoimmunology， 2019， 8（1）： e1505174.
[52]	SIDBURY R， NEUSCHLER N， NEUSCHLER E， et al. Topically applied imiquimod inhibits vascular tumor growth in vivo ［J］. J Invest Dermatol， 2003， 121（5）： 1205-1209.
[53]	MORADI-MARJANEH R， HASSANIAN S M， HASANZADEH M， et al. Therapeutic potential of toll-like receptors in treatment of gynecological cancers［J］. IUBMB Life， 2019， 71（5）： 549-564.
[54]	ZHANG L， JING D， WANG L， et al. Unique photochemo-immuno-nanoplatform against orthotopic xenograft oral cancer and metastatic syngeneic breast cancer［J］. Nano Lett， 2018， 18（11）： 7092-7103.
[55]	PATINOTE C， KARROUM N B， MOARBESS G， et al. Agonist and antagonist ligands of toll-like receptors 7 and 8： Ingenious tools for therapeutic purposes［J］. Eur J Med Chem， 2020， 193： 112238.
[56]	RYNN C， UMEHARA K， JIANG T Y， et al. A translational strategy employing physiologically based modelling to predict the pharmacological active dose of RO7119929， an oral prodrug of a targeted cancer immunotherapy TLR7 agonist［J］. Xenobiotica， 2022， 52（8）： 855-867.
[57]	ZUO X Y， CHENG Q P， WANG Z M， et al. A novel oral TLR7 agonist orchestrates immune response and synergizes with PD-L1 blockade via type I IFN pathway in lung cancer［J］. Int Immunopharmacol， 2024， 137： 112478.
[58]	MONK B J， FACCIABENE A， BRADY W E， et al. Integrative development of a TLR8 agonist for ovarian cancer chemoimmunotherapy［J］. Clin Cancer Res， 2017， 23（8）： 1955-1966.
[59]	FERRIS R L， SABA N F， GITLITZ B J， et al. Effect of adding motolimod to standard combination chemotherapy and cetuximab treatment of patients with squamous cell carcinoma of the head and neck： the Active8 randomized clinical trial［J］. JAMA Oncol， 2018， 4（11）： 1583-1588.
[60]	DIETSCH G N， RANDALL T D， GOTTARDO R， et al. Late-stage cancer patients remain highly responsive to immune activation by the selective TLR8 agonist motolimod （VTX-2337）［J］. Clin Cancer Res， 2015， 21（24）： 5445-5452.
[61]	CHENG Y W， BORCHERDING N， OGUNSAKIN A， et al. The anti-tumor effects of cetuximab in combination with VTX-2337 are T cell dependent［J］. Sci Rep， 2021， 11（1）： 1535.
[62]	WANG Y X， YANG H P， LI H P， et al. Development of a novel TLR8 agonist for cancer immunotherapy［J］. Mol Biomed， 2020， 1（1）： 6.
[63]	ROOK A H， GELFAND J M， WYSOCKA M， et al. Topical resiquimod can induce disease regression and enhance T-cell effector functions in cutaneous T-cell lymphoma［J］. Blood， 2015， 126（12）： 1452-1461.
[64]	ZHANG S， HU Z， TANJI H， et al. Structural basis for small-molecule inhibition of toll-like receptor 8［J］. Nat Chem Biol， 2018， 14： 58-64.
[65]	MATBOLI M， HOSSAM N， FARAG D， et al. miRNAs： possible regulators of toll like receptors and inflammatory tumor microenvironment in colorectal cancer［J］. BMC Cancer， 2024， 24（1）： 824.