Exploring Novel Frontiers: Leveraging STAT3 Signaling for Advanced Cancer Therapeutics

Simple Summary Signal Transducer and Activator of Transcription 3 (STAT3) is involved in many normal cellular processes that are tightly regulated. However, aberrant activation of STAT3 has been implicated in cancer development, recurrence, and metastasis in addition to development of resistance to therapy. Significant progress has been made in targeting STAT3 directly and indirectly through the development of novel therapeutic agents, although some drugs remain in the early phases of development, demonstrating promising potential for future clinical applications. There are several STAT3 inhibitors in clinical trials as monotherapy, and in combination with chemotherapeutic agents and biomarker analysis from these trials, will be critical to inform which patients will benefit from prolonged STAT3 inhibition.Abstract Signal Transducer and Activator of Transcription 3 (STAT3) plays a significant role in diverse physiologic processes, including cell proliferation, differentiation, angiogenesis, and survival. STAT3 activation via phosphorylation of tyrosine and serine residues is a complex and tightly regulated process initiated by upstream signaling pathways with ligand binding to receptor and non-receptor-linked kinases. Through downstream deregulation of target genes, aberrations in STAT3 activation are implicated in tumorigenesis, metastasis, and recurrence in multiple cancers. While there have been extensive efforts to develop direct and indirect STAT3 inhibitors using novel drugs as a therapeutic strategy, direct clinical application remains in evolution. In this review, we outline the mechanisms of STAT3 activation, the resulting downstream effects in physiologic and malignant settings, and therapeutic strategies for targeting STAT3. We also summarize the pre-clinical and clinical evidence of novel drug therapies targeting STAT3 and discuss the challenges of establishing their therapeutic efficacy in the current clinical landscape.