核因子-κB及干扰素调节因子3在抗肿瘤免疫中的作用.docx

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Abstract
NF-κB and IRF3 are important transcription factors in the regulation of tumor immunity. The activation of these factors is critical for the initiation and maintenance of immune responses against cancer. NF-κB is a key regulator of pro-inflammatory cytokines and chemokines, while IRF3 controls the expression of type I interferons and other immune-related genes. In this review, we summarize the roles of NF-κB and IRF3 in antitumor immunity and the mechanisms that control their activity. We also discuss the potential of targeting these factors as a therapeutic approach to enhance the effectiveness of current cancer therapies.
Introduction
Cancer is a leading cause of death worldwide, and its incidence is expected to continue to rise in the coming years. Immunotherapy has emerged as a promising strategy for the treatment of cancer, harnessing the power of the immune system to recognize and destroy tumor cells. The success of immunotherapy relies on the activation of immune cells, such as T cells and natural killer (NK) cells, and the production of cytokines and chemokines that orchestrate the immune response. Transcription factors play a critical role in the regulation of these immune processes, and the dysregulation of these factors can contribute to tumor immune evasion and progression.
NF-κB in tumor immunity
NF-κB is a transcription factor that plays a central role in the regulation of immune responses. In its inactive state, NF-κB is sequestered in the cytoplasm by inhibitory proteins called IκBs. Upon stimulation by pro-inflammatory cytokines, Toll-like receptor (TLR) ligands, or other signals, IκBs are phosphorylated and degraded, allowing NF-κB to translocate to the nucleus and activate gene expression. NF-κB can control the transcription of a wide range of genes involved in pro-inflammatory cytokine production, cell survival, and cell proliferation.
In the context of tumor immunity, NF-κB plays a dual role. On the one hand, NF-κB activation can promote the recruitment of immune cells and the production of pro-inflammatory cytokines and chemokines, which can help to eliminate tumor cells. On the other hand, NF-κB activation can also contribute to tumor growth and survival by inducing the expression of genes that promote angiogenesis, cell proliferation, and cell survival. In addition, some tumors have been shown to hijack the NF-κB pathway to evade immune surveillance and promote immune suppression.
Several studies have demonstrated the importance of NF-κB in antitumor immunity. For example, NF-κB activation has been shown to enhance the recruitment of NK cells and promote their cytotoxic activity. NF-κB-induced cytokines, such as IL-12 and IFN-γ, have also been shown to play a critical role in the activation of T cells and the induction of antitumor immunity. In addition, the upregulation of NF-κB activity has been associated with improved survival in several cancer types, including lung cancer and melanoma.
IRF3 in tumor immunity
IRF3 is another important transcription factor in the regulation of tumor immunity. IRF3 is activated in response to TLR ligands and other pathogen-associated molecular patterns (PAMPs), as well as some danger-associated molecular patterns (DAMPs). Upon activation, IRF3 translocates to the nucleus and induces the expression of type I interferons (IFN-α and IFN-β), which can activate immune cells and enhance antitumor immunity. In addition, IRF3 can also induce the expression of other immune-related genes, such as chemokines, that can promote the recruitment of immune cells to the tumor site.
Like NF-κB, IRF3 can play a dual role in tumor immunity. While IRF3 activation can enhance antitumor immunity, it can also contribute to tumor progression by inducing the expression of genes that promote angiogenesis and cell survival. However, recent studies have shown that the activation of IRF3 may be a key factor in the success of some cancer therapies, such as radiation therapy and some chemotherapeutic agents. These therapies induce the release of DAMPs, which can activate IRF3 and promote the production of pro-inflammatory cytokines and chemokines that enhance antitumor immunity.
Regulation of NF-κB and IRF3 activity
The activity of NF-κB and IRF3 is tightly regulated by a variety of mechanisms, including post-translational modifications, protein-protein interactions, and cellular localization. For example, the phosphorylation and ubiquitination of IκBs is a key step in the activation of NF-κB, while the phosphorylation and dimerization of IRF3 is critical for its nuclear translocation and activation. Several negative regulators of these factors have also been identified, including the suppressor of cytokine signaling (SOCS) family, which can inhibit the activity of both NF-κB and IRF3.
Therapeutic potential of targeting NF-κB and IRF3
Given the critical roles of NF-κB and IRF3 in tumor immunity, targeting these factors has emerged as a potential therapeutic strategy for enhancing the efficacy of cancer immunotherapy. Several inhibitors of NF-κB and IRF3 are currently in preclinical or clinical development, and have shown promising results in some cancer models. For example, the inhibition of NF-κB has been shown to enhance the antitumor activity of NK cells and improve the efficacy of checkpoint inhibitors in some cancer types. Similarly, the activation of IRF3 has been shown to enhance the response to radiation therapy and chemotherapy in some cancers.
Conclusion
NF-κB and IRF3 are important transcription factors in the regulation of tumor immunity, playing critical roles in the activation of immune cells and the production of cytokines and chemokines. While these factors can promote antitumor immunity in some contexts, they can also contribute to tumor progression in others. Understanding the mechanisms that control the activity of these factors, and developing therapeutic strategies to target them, may help to improve the efficacy of current cancer therapies and enhance immune-mediated tumor control.