Definition

A Toll-like receptor 9 (TLR9) agonist/STAT3 siRNA conjugate composed of a CpG oligodeoxynucleotide (ODN) and a short interfering RNA (siRNAs) directed against signal transducer and activator of transcription 3 (STAT3), with potential immunostimulating and antineoplastic activities. Upon administration of CpG-STAT3 siRNA CAS3/SS3, the CpG ODN moiety binds to and activates TLR9, and the conjugate is internalized by various antigen-presenting cells (APCs), including dendritic cells (DCs), macrophages and B cells. This activates numerous signaling transduction pathways which results in the release of multiple cytokines, such as immunoglobulins (Igs), interferons (IFNs), interleukins (ILs) and tumor necrosis factor (TNF) and induces innate and adaptive immune responses. In addition, the internalization results in the delivery of anti-STAT siRNA moiety into myeloid and B-cells. The siRNA binds to STAT mRNA and inhibits both the translation and expression of the STAT protein. This prevents STAT3 binding to responsive gene promoters and blocks STAT3-mediated regulation of gene expression. STAT3 regulates the transcription of genes involved in several cellular functions. It is constitutively activated in a variety of human cancers and plays a key role in neoplastic transformation, uncontrolled tumor cell proliferation, resistance to apoptosis, metastasis, immune evasion, tumor angiogenesis, epithelial-mesenchymal transition (EMT) and the Warburg effect. Altogether, this may result in tumor cell death and inhibit tumor cell proliferation, angiogenesis and metastasis.