Effect of JAK/STAT signaling on anti-PD-L1 immunotherapy efficacy in lung cancer

Lung cancer remains the leading cause of cancer-related mortality worldwide, with advanced-stage non-small cell lung cancer (NSCLC) patients often showing limited responses to immunotherapies, notably those targeting the PD-1/PD-L1 axis. This study aimed to elucidate the role of the JAK/STAT signaling pathway in modulating PD-L1 expression and its impact on the efficacy of anti-PD-L1 immunotherapy in lung cancer. By comprehensively reviewing molecular mechanisms and recent experimental evidence, we investigated how aberrant JAK/STAT activation, through genetic alterations, cytokine-mediated signals, and environmental influences, drives PD-L1 upregulation and contributes to an immunosuppressive tumor microenvironment. Our findings reveal that enhanced JAK/STAT signaling facilitates immune evasion by promoting transcriptional activation of PD-L1 and supporting oncogenic processes such as cell proliferation, survival, and metastasis. Conversely, impaired JAK/STAT function can diminish PD-L1 expression, thereby altering the sensitivity of tumor cells to checkpoint blockade. Importantly, preclinical studies highlighted the potential of combination therapeutic strategies that target both the JAK/STAT pathway and PD-L1 to restore effective T cell responses and overcome resistance to immunotherapy. These insights underscore the need for tailored treatment approaches that integrate JAK/STAT inhibitors with PD-L1 blockade, potentially paving the way for improved clinical outcomes in lung cancer patients.