Kullberg Max, Francian Alexandra, Arabi Ameneh, Olsson Troy, Mann Kristine, Martinson Holly A
WWAMI School of Medical Education, University of Alaska Anchorage, 3211 Providence Drive, Anchorage, AK 99508, USA.
Department of Biological Sciences, University of Alaska Anchorage, Anchorage, AK 99508, USA.
Pharm Front. 2019;1. doi: 10.20900/pf20190007. Epub 2019 Nov 28.
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.
在肿瘤微环境中，细胞因子、生长因子和癌基因介导癌细胞和浸润免疫细胞中信号转导子和转录激活子3（STAT3）信号通路的组成性激活。癌细胞中的STAT3激活驱动致瘤性变化，从而提高细胞存活率、增殖能力并增强对凋亡的抗性。免疫细胞的调节则更为复杂且存在矛盾。STAT3信号传导促使髓样细胞表型向免疫抑制状态转变，进而介导T细胞抑制。另一方面，T细胞中的STAT3信号传导会导致抗肿瘤反应所需的T细胞增殖和活性。因此，将STAT3抑制剂靶向递送至癌细胞和髓样细胞可能会改善治疗效果。许多用于癌症治疗的抑制STAT3途径的化合物包括肽类药物、小分子抑制剂和天然化合物。然而，抑制STAT3的天然化合物通常具有疏水性，这会降低它们的生物利用度并导致不良的药代动力学特性。本综述特别关注脂质体包裹的天然STAT3抑制剂及其靶向癌细胞和髓样细胞以减少肿瘤生长并降低STAT3介导的免疫抑制的能力。许多此类脂质体制剂已使肿瘤显著缩小，并且联合制剂的实例已显示可通过免疫调节消除肿瘤。
