STAT3 signaling inhibitors for cancer treatment.

Pharmacological targeting of Signal Transducer and Activator of Transcription 3 (STAT3) in cancer has demonstrable antitumor efficacy. However, suitably potent, efficacious, and safe STAT3 inhibitors are scarce, and only a handful have entered clinical trials, limiting our knowledge of the extent of clinical benefit. Outcomes of recently completed trials in advanced cancers range from improved overall survival and complete responses in a cohort of patients with phosphotyrosine STAT3 positivity to partial responses and progressive disease in unselected patients. Advancements in oligonucleotide technologies and the integration of E3 ligase-specific proteolysis-targeting chimeras and molecular glue protein degrader strategies are accelerating the transition of STAT3 inhibitors into clinical testing. This review examines recent STAT3-targeted modalities and their preclinical and clinical activities. It concludes by underscoring the value of biomarker-informed approaches to optimize patient outcomes, combination therapies to improve clinical benefits, and artificial intelligence/machine learning tools to accelerate development.