Abstract
In the tumor microenvironment, cytokines, growth factors, and oncogenes mediate constitutive activation of the signal transducer and activator of transcription 3 (STAT3) signaling pathway in both cancer cells and infiltrating immune cells. STAT3 activation in cancer cells drives tumorigenic changes that allow for increased survival, proliferation, and resistance to apoptosis. The modulation of immune cells is more complicated and conflicting. STAT3 signaling drives the myeloid cell phenotype towards an immune suppressive state, which mediates T cell inhibition. On the other hand, STAT3 signaling in T cells leads to proliferation and T cell activity required for an anti-tumor response. Targeted delivery of STAT3 inhibitors to cancer cells and myeloid cells could therefore improve therapeutic outcomes. Many compounds that inhibit the STAT3 pathways for cancer treatment include peptide drugs, small molecule inhibitors, and natural compounds. However, natural compounds that inhibit STAT3 are often hydrophobic, which reduces their bioavailability and leads to unfavorable pharmacokinetics. This review focuses specifically on liposome-encapsulated natural STAT3 inhibitors and their ability to target cancer cells and myeloid cells to reduce tumor growth and decrease STAT3-mediated immune suppression. Many of these liposome formulations have led to profound tumor reduction and examples of combination formulations have been shown to eliminate tumors through immune modulation.
Highlights
The signal transducer and activator of transcription 3 (STAT3) signaling pathway is often constitutively activated in tumor cells of breast, colorectal, prostate, glioblastoma and other types of cancers [1]
Because of the necessity of STAT3 signaling for an anti-tumor T cell immune response, the most effective delivery of STAT3 inhibitors would be through a mechanism that targets tumor cells and myeloid cells, without delivering to T cells
There are limited studies on betulinic acid in liposomal formulations for the treatment of cancer, these results show the possibility of enhancing cancer treatment with liposomal encapsulation and direct administration to the tumor
Summary
The signal transducer and activator of transcription 3 (STAT3) signaling pathway is often constitutively activated in tumor cells of breast, colorectal, prostate, glioblastoma and other types of cancers [1]. STAT3 constitutive activity in tumors drives inflammation, apoptosis, cell survival, proliferation, cellular transformation, angiogenesis, metastasis and epithelial to mesenchymal transition (EMT) in cancer progression [5,6]. STAT3 activation can result in conflicting immune modulation between myeloid cells and T cells [2,9]. STAT3 impairs myeloid cell differentiation, antigen presentation, and promotes immunosuppressive and proangiogenic potential through the secretion of cytokines (IL-10, TGF-B, VEGF) and modulation of metabolic processes (Reactive Oxygen Species, Arginase 1, IDO-1) all which can interfere with T cell activity [11,12]. With respect to T cells, STAT3 activation corresponds with proliferation and is a necessary component of a healthy T cell immune response [13,14]. Nanoparticle delivery is one possibility for increasing specificity of STAT3 inhibition to myeloid and tumor cells
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