Reprogramming Tumor-associated Macrophages (TAMs) by Targeting Signaling Pathway
Reprogramming M2-like tumor-associated macrophages (TAMs) toward tumoricidal M1 phenotype is especially intriguing in terms of the restoration of antitumor immunity for anticancer immunotherapy. Experienced in macrophage development and with a dedicated commitment to the scientific community, Creative Biolabs has perfected our technical pipelines in reprogramming TAMs to M1 phenotype by targeting signaling pathways. We offer high-quality customized services to meet every specific requirement.
Molecular Mechanisms in Macrophage Polarization
Reprogramming tumor-promoting M2-like TAMs toward tumoricidal M1 phenotype provides an intriguing opportunity to restore the antitumor immunity to elicit therapeutic efficacy. The polarization of macrophages is influenced by several mechanisms, such as interferon-regulatory factor/signal transducer and activator of transcription (IRF/STAT) signaling pathway, nuclear factor kappa B (NF-κB) signaling pathway, phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway or Janus kinase (JAK)/STAT signaling pathway, which are driven by transcription factors and miRNAs.
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IRF/STAT signaling pathway
IRF/STAT signaling is a central pathway in controlling macrophage M1–M2 polarization. Toll-like receptor signaling, particularly Toll-like receptor 4 (TLR4) stimulated by lipopolysaccharide (LPS) and other microbial ligands, drives macrophages to a preferentially M1 phenotype. Two adaptors, MyD88 and TRIF, mediate the signaling downstream of TLR4. The signaling pathway through the MyD88 adaptor results in the activation of a cascade of kinases, which finally leads to the activation of NF-κB.
NF-κb regulates thousands of response genes including cytokines, chemokines, transcription factors, antimicrobial peptides, and interferon-stimulated genes. NF-κB signaling pathway is important in cancer-related inflammation and malignant progression. NF-κB plays a central role in M1 macrophages. Indeed, the active heterodimer nfκb (p50–p65) promotes the transcription of inflammatory genes while the inhibitory heterodimer nfκb (p50–p50) prevents the transcription of these genes in M2 macrophages.
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PI3K/AKT signaling pathway
PI3K/Akt pathway regulates macrophage survival, migration, and proliferation but also responds to different metabolic and inflammatory signals in macrophages. The PI3K/AKT pathway is activated by TLR4 and other receptors, cytokine, and chemokine. As a result, the PI3K/AKT pathway converges inflammatory and metabolic signals to regulate macrophage responses modulating their activation phenotype.
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JAK/STAT signaling pathway
There are four mammalian members of the Jak family of receptor-associated tyrosine kinases and seven STATs have been identified. The JAK/STAT signaling pathway has been implicated in mediating biologic responses induced by many cytokines. Moreover, accumulated evidence has shown that macrophage phenotype and activation are regulated by cytokines that use the JAK/STAT signaling pathway.
Reprogramming TAMs by Targeting Signaling Pathway at Creative Biolabs
Targeting the signaling pathways of TAMs toward M1-like macrophages would be an efficient way to promote tumor regression. Creative Biolabs has organized a staff of outstanding scientists who have engaged in the research of signaling pathways in macrophage polarization for many years. With our state-of-the-art technology and industry-leading expertise, Creative Biolabs has developed an unparalleled Macrophage Therapeutics Development Platform. Based on this cutting-edging platform, our scientists have successfully reprogrammed TAMs by targeting signaling pathways, including IRF/STAT signaling pathway, NF-κb signaling pathway, PI3K/Akt signaling pathway and JAK/STAT signaling pathway. TLR, colony-stimulating factor 1 (CSF1), CD40, Interleukin 12 (IL-12), Triggering receptor expressed on myeloid cells 1 (TREM-1), Bruton's tyrosine kinase (BTK) and cyclooxygenase 2 (COX2) are commonly used as targets. Creative Biolabs offers accurate and effective solutions for researchers who are interested in TAM reprogramming.
Fig.1 The JAK/STAT-signalling pathway in macrophage reprogramming.1,2
Integrating state-of-the-art technologies with industry-leading expertise in TAM reprogramming, Creative Biolabs is fully competent and dedicated to helping our clients' research and project development. For more detailed information, please feel free to contact us or directly send us an inquiry.
References
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Malyshev, Igor, and Yuri Malyshev. "Current concept and update of the macrophage plasticity concept: intracellular mechanisms of reprogramming and M3 macrophage “switch” phenotype." BioMed Research International 2015 (2015).
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Under Open Access license CC BY 4.0, without modification.
