High expression and phosphorylation of signal transducer and transcription activator 3 (STAT3) are correlated with progression and poor prognosis in various types of cancer. The constitutive activation of STAT3 in cancer affects processes such as cell proliferation, apoptosis, metastasis, angiogenesis, and drug resistance. The importance of STAT3 in cancer makes it a potential therapeutic target. Various methods of directly and indirectly blocking STAT3 activity at different steps of the STAT3 pathway have been investigated. However, the outcome has been limited, mainly by the number of upstream proteins that can reactivate STAT3 or the relatively low specificity of the inhibitors. A new branch of molecules with significant therapeutic potential has emerged thanks to recent developments in the regulatory function of non-coding nucleic acids. Oligonucleotide-based therapeutics can silence target transcripts or edit genes, leading to the modification of gene expression profiles, causing cell death or restoring cell function. Moreover, they can reach untreatable targets, such as transcription factors. This review briefly describes oligonucleotide-based therapeutics that found application to target STAT3 activity in cancer. Additionally, this review comprehensively summarizes how the inhibition of STAT3 activity by nucleic acid-based therapeutics such as siRNA, shRNA, ASO, and ODN-decoy affected the therapy of different types of cancer in preclinical and clinical studies. Moreover, due to some limitations of oligonucleotide-based therapeutics, the importance of carriers that can deliver nucleic acid molecules to affect the STAT3 in cancer cells and cells of the tumor microenvironment (TME) was pointed out. Combining a high specificity of oligonucleotide-based therapeutics toward their targets and functionalized nanoparticles toward cell type can generate very efficient formulations.
信号转导与转录激活因子3（STAT3）的高表达及磷酸化与多种癌症的进展及不良预后密切相关。STAT3在癌症中的持续激活影响细胞增殖、凋亡、转移、血管生成及耐药性等多个过程。STAT3在癌症中的重要性使其成为潜在的治疗靶点。目前已有研究探索在STAT3通路的不同环节直接或间接阻断其活性的多种方法，但效果有限，主要受限于可能重新激活STAT3的上游蛋白数量或抑制剂相对较低的特异性。得益于非编码核酸调控功能研究的最新进展，一类具有显著治疗潜力的新型分子分支应运而生。基于寡核苷酸的疗法能够沉默靶向转录本或编辑基因，从而改变基因表达谱，诱导细胞死亡或恢复细胞功能。此外，这类疗法还能作用于传统难以靶向的目标，如转录因子。本综述简要介绍了应用于靶向STAT3活性的寡核苷酸治疗策略，并系统总结了在临床前及临床研究中，siRNA、shRNA、ASO及ODN-decoy等核酸疗法通过抑制STAT3活性对不同类型癌症治疗产生的影响。同时，针对寡核苷酸疗法的局限性，本文强调了能将核酸分子递送至癌细胞及肿瘤微环境（TME）细胞以调控STAT3的载体系统的重要性。通过结合寡核苷酸疗法对靶点的高特异性与功能化纳米颗粒对细胞类型的定向递送能力，可构建出高效的治疗体系。
Oligonucleotide-Based Therapeutics for STAT3 Targeting in Cancer—Drug Carriers Matter
肿瘤(癌症)患者之家