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Background <p>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.</p> Methods <p>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.</p> Results <p>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.</p> Conclusion <p>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.</p> Graphical abstract <p> Osteopontin (OPN) overexpression in lung cancer cells activates NF-κB signaling by promoting p65 nuclear translocation, leading to transcriptional upregulation of PD-L1 on the tumor cell surface. Elevated PD-L1 suppresses CD8⁺ T-cell infiltration and effector function, characterized by impaired proliferation, cytotoxicity, IFN-γ production, and TCR signaling. Genetic inhibition of p65 restores antitumor immunity and re-sensitizes OPN-overexpressing tumors to PD-L1 blockade in vivo.</p>

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Osteopontin Promotes Lung Cancer Growth through NF-κB-Dependent Upregulation of PD-L1 and Suppression of Anti-Tumor Immunity

  • 期刊论文

  • 发表日期：

    2026年8月4日

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  • Min Hou,
  • Long Cheng,
  • Honglei Zhu,
  • Yan Gui,
  • Jing Lei

摘要

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.

Graphical abstract

Osteopontin (OPN) overexpression in lung cancer cells activates NF-κB signaling by promoting p65 nuclear translocation, leading to transcriptional upregulation of PD-L1 on the tumor cell surface. Elevated PD-L1 suppresses CD8⁺ T-cell infiltration and effector function, characterized by impaired proliferation, cytotoxicity, IFN-γ production, and TCR signaling. Genetic inhibition of p65 restores antitumor immunity and re-sensitizes OPN-overexpressing tumors to PD-L1 blockade in vivo.