Nanomedicine strategies targeting STAT3 in cancer: From tumor suppression to microenvironment modulation

Signal transducer and activator of transcription 3 (STAT3) is a central oncogenic signaling hub that regulates tumor proliferation, survival, metastasis, angiogenesis, immune evasion, and therapeutic resistance across multiple cancer types. Persistent STAT3 activation, driven by aberrant cytokine signaling, growth factor receptors, and oncogenic kinases, promotes transcriptional programs that support malignant progression and suppress antitumor immunity. Despite its recognized role as an attractive therapeutic target, direct pharmacological inhibition of STAT3 has been challenging because of poor bioavailability, off-target toxicity, and limited tumor specificity of conventional inhibitors. In recent years, nanocarrier-based drug delivery systems have emerged as promising platforms to overcome these limitations by enabling targeted, protected, and sustained STAT3 inhibition. Diverse nanocarrier modalities, including polymeric nanoparticles, lipid-based systems, inorganic nanomaterials, and hybrid or covalent-organic frameworks, have been developed to deliver STAT3 inhibitors, small interfering RNA, short hairpin RNA, and plasmid DNA with improved therapeutic indices. These platforms not only enhance intracellular delivery and tumor accumulation but also enable combination strategies that simultaneously modulate STAT3 and complementary oncogenic pathways. This review provides a comprehensive mechanistic overview of STAT3 signaling in cancer and critically evaluates recent advances in nanocarrier-mediated STAT3 inhibition. Furthermore, it discusses key challenges, including immune context dependency, adaptive resistance, safety concerns, and translational barriers, while highlighting future directions for precision nanomedicine. Collectively, this work underscores the potential of nanotechnology-enabled STAT3 targeting as a next-generation anticancer strategy. SIGNIFICANCE STATEMENT: Persistent activation of signal transducer and activator of transcription 3 represents a critical driver of tumor progression and therapeutic resistance across diverse malignancies, yet its direct pharmacological targeting has remained limited by suboptimal drug properties and systemic toxicity. This review highlights how nanocarrier-based delivery platforms redefine signal transducer and activator of transcription 3 inhibition by improving tumor specificity, intracellular bioavailability, and combinatorial therapeutic potential.