Molecular biology reports · 2026
Osteopontin Promotes Lung Cancer Growth through NF-κB-Dependent Upregulation of PD-L1 and Suppression of Anti-Tumor Immunity.
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Hou Min, Cheng Long, Zhu Honglei, Gui Yan, Lei Jing
Аннотация
BACKGROUND: Resistance to immune checkpoint blockade (ICB) remains a major clinical challenge in lung cancer. Osteopontin (OPN) is frequently overexpressed in lung tumors and correlates with poor prognosis, yet its mechanistic role in shaping the immunosuppressive tumor microenvironment remains incompletely defined.
METHODS: Using OPN-overexpressing and p65-manipulated lung cancer models, combined with in vivo anti-PD-L1 therapy, we evaluated tumor growth, NF-κB activation, PD-L1 expression, and intratumoral immune composition. Biochemical and molecular assays, including nuclear-cytoplasmic fractionation, ChIP-qPCR, RT-qPCR, and flow cytometry, were performed to delineate the OPN-p65-PD-L1 signaling axis.
RESULTS: OPN robustly activated NF-κB signaling, driving p65 nuclear translocation and direct promoter binding to induce PD-L1 transcription. Elevated PD-L1 expression in OPN-overexpressing tumors resulted in markedly reduced CD8⁺ T-cell infiltration, impaired cytokine production, diminished cytotoxicity, and enhanced exhaustion phenotypes. OPN also suppressed Th1 differentiation without expanding Treg or IL-10⁺ CD4⁺ subsets. Importantly, genetic silencing of p65 abrogated OPN-induced PD-L1 upregulation, restored CD8⁺ T-cell recruitment and effector activity, and re-sensitized OPN-overexpressing tumors to anti-PD-L1 therapy in vivo.
CONCLUSION: OPN promotes immune evasion and resistance to PD-L1 blockade by activating the NF-κB/p65 pathway and transcriptionally inducing PD-L1. Targeting the OPN-p65-PD-L1 axis represents a promising therapeutic strategy to enhance ICB responsiveness in lung cancer.
METHODS: Using OPN-overexpressing and p65-manipulated lung cancer models, combined with in vivo anti-PD-L1 therapy, we evaluated tumor growth, NF-κB activation, PD-L1 expression, and intratumoral immune composition. Biochemical and molecular assays, including nuclear-cytoplasmic fractionation, ChIP-qPCR, RT-qPCR, and flow cytometry, were performed to delineate the OPN-p65-PD-L1 signaling axis.
RESULTS: OPN robustly activated NF-κB signaling, driving p65 nuclear translocation and direct promoter binding to induce PD-L1 transcription. Elevated PD-L1 expression in OPN-overexpressing tumors resulted in markedly reduced CD8⁺ T-cell infiltration, impaired cytokine production, diminished cytotoxicity, and enhanced exhaustion phenotypes. OPN also suppressed Th1 differentiation without expanding Treg or IL-10⁺ CD4⁺ subsets. Importantly, genetic silencing of p65 abrogated OPN-induced PD-L1 upregulation, restored CD8⁺ T-cell recruitment and effector activity, and re-sensitized OPN-overexpressing tumors to anti-PD-L1 therapy in vivo.
CONCLUSION: OPN promotes immune evasion and resistance to PD-L1 blockade by activating the NF-κB/p65 pathway and transcriptionally inducing PD-L1. Targeting the OPN-p65-PD-L1 axis represents a promising therapeutic strategy to enhance ICB responsiveness in lung cancer.