The JAK/STAT Signaling Pathway in Lung Cancer: Mechanisms, Clinical Implications, and Therapeutic Opportunities

Abstract

Lung cancer remains the leading cause of cancer-related mortality worldwide, with persistently poor survival outcomes despite advances in targeted therapies and immunotherapy. The Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway have emerged as a central regulator of lung cancer pathogenesis, integrating extracellular cytokine and growth factor signals into transcriptional programs that drive tumor progression. This review provides a comprehensive overview of the molecular mechanisms underlying JAK/STAT activation and dysregulation in lung cancer, with particular emphasis on the dominant oncogenic role of STAT3. Aberrant pathway activation arises through multiple converging mechanisms, including cytokine-driven stimulation from the tumor microenvironment, oncogenic receptor signaling, and epigenetic silencing of negative regulators. Functionally, JAK/STAT signaling promotes tumor cell proliferation, survival, epithelial–mesenchymal transition (EMT), metastasis, and immune evasion, notably through upregulation of programmed death-ligand 1 (PD-L1) and modulation of the tumor immune microenvironment. Therapeutically, targeting the JAK/STAT axis has shown promise in preclinical models, particularly in overcoming resistance to tyrosine kinase inhibitors and enhancing immunotherapy responses. Early-phase clinical studies highlight the potential of combination strategies, including JAK inhibitors with immune checkpoint blockade, demonstrating encouraging response rates and durable clinical benefit in selected patient populations. However, clinical translation remains challenged by pathway complexity, limited efficacy of monotherapies, and safety concerns. Future directions should focus on the development of isoform-selective inhibitors, identification of predictive biomarkers, and rational combination regimens to optimize therapeutic outcomes. Overall, the JAK/STAT pathway represents a critical and actionable target in lung cancer, with significant potential to advance precision oncology.