The Functional Mechanisms of Toll-Like Receptor 3 and Its Implications in Digestive System Tumors

¹ Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, 030032 Taiyuan, Shanxi, China

² Department of Hepatobiliary Surgery, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, 030032 Taiyuan, Shanxi, China

³ Hepatic Surgery Center, Institute of Hepato-Pancreato-Biliary Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030 Wuhan, Hubei, China

⁴ Department of Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430022 Wuhan, Hubei, China

^*Correspondence: zhangl7803@126.com (Lei Zhang); tli2007@hust.edu.cn (Tao Li); hejiefeng2005@163.com (Jiefeng He); haoliangzhao@hotmail.com (Haoliang Zhao)
^†These authors contributed equally.

Front. Biosci. (Landmark Ed) 2023, 28(11), 297; https://doi.org/10.31083/j.fbl2811297

Submitted: 30 April 2023 | Revised: 19 July 2023 | Accepted: 1 August 2023 | Published: 24 November 2023

This is an open access article under the CC BY 4.0 license.

Abstract

Toll-like receptor 3 (TLR3) is a prominent member of the Toll-like receptor (TLR) family and has the ability to recognize and bind intracellular double-stranded RNA (dsRNA). Once triggered by a viral infection or other pathological condition, TLR3 activates immune cells and induces the production of interferons and other immune response molecules. Additionally, TLR3 is considered an important immune modulator, as it can regulate cell apoptosis and promote anticancer immunity. The investigation and application of TLR3 agonists in digestive system tumors have attracted widespread attention and are regarded as a promising cancer treatment strategy with potential clinical applications. TLR3 expression levels are generally elevated in most digestive system tumors, and higher TLR3 expression is associated with a better prognosis. Therefore, TLR3 has emerged as a novel therapeutic target for digestive system tumors. It has been used in combination with chemotherapy, radiotherapy, and targeted therapy and demonstrated excellent efficacy and tolerability. This has provided new ideas and hopes for the treatment of digestive system tumors. This review discusses the mechanisms of TLR3 and its frontier research in digestive system tumors.

Keywords

Toll-like receptor 3

digestive system tumors

dsRNA

TLR3 agonist

Funding

82073090/National Natural Science Foundation of China

20210001/Human Resources and Social Security Department System of Shanxi Province

2021-116/Research Project Supported by Shanxi Scholarship Council of China

2019XY002/Shanxi ‘136’ Leading Clinical Key Specialty

Key Laboratory of Hepatobiliary and Pancreatic Diseases of Shanxi Province (Preparatory)

Figures

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Fig. 1.

Structure and regulatory mechanisms of Toll-like receptor 3 (TLR3). (A) The three-dimensional structure of Toll-like receptor 3 (source: https://alphafold.ebi.ac.uk/entry/O15455, Copyright [2023], permission granted). (B) After double-stranded RNA (dsRNA) binds to two TLR3 molecules, the TIR domain of TLR3 binds to the TIR domain of TICAM-1/TRIF, and TRAF3 links TBK1 to TICAM-1/TRIF. TBK1, NAP1, and IKK $\epsilon{}$ then form an activated complex, which mediates the activation of IRF3. Activated IRF3 translocates into the nucleus. The RHIM domain of RIP1 binds to the RHIM domain of TICAM-1/TRIF, leading to RIP1 activation. Activated RIP1 and TNF receptor-associated factor 6 (TRAF6) activate TGF- $\beta{}$ -activated kinase 1 (TAK1), which then associates with TAK1-binding protein 1 (TAB1) and TAK1-binding protein 2 (TAB2) to form an activated complex. This complex activates IKK $\alpha{}$ and IKK $\beta{}$ , leading to the phosphorylation of I $\kappa{}$ B. The p50 and p65 subunits of nuclear factor kappa B (NF- $\kappa{}$ B) then form a heterodimer that translocates into the nucleus. When TAK1 associates with TAB1 and TAB2 to form an activated complex, it also activates mitogen-activated protein kinase kinase 4 (MKK4) and MKK7. Activated MKK4 and MKK7 then activate c-Jun N-terminal kinase (JNK), ultimately leading to the translocation of activated activator protein-1 (AP-1) into the nucleus.

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