The PTTG1/AURKA Axis Drives Acquired Anlotinib Resistance in Non-Small Cell Lung Cancer by Remodeling the Tumor...

PTTG1 has been implicated in tumor progression and drug resistance, but its role in acquired anlotinib resistance in non-small cell lung cancer (NSCLC) remains unclear. This study investigated whether PTTG1 contributes to resistance and immune remodeling in NSCLC. We analyzed peripheral blood from NSCLC patients collected before treatment, during response, and after acquired resistance to define clinical changes associated with anlotinib failure. Anlotinib-resistant A549/AL and NCI-H1975/AL cell models were established and subjected to lentiviral shRNA-mediated PTTG1 silencing to assess tumor-intrinsic functions and drug sensitivity. Tumor cell proliferation, migration, invasion, and molecular changes were evaluated using CCK-8, EdU, Transwell, reverse transcription quantitative polymerase chain reaction, Western blotting, immunofluorescence, immunohistochemistry, co-immunoprecipitation, STRING analysis, and humanized mouse models. Immune remodeling was assessed by flow cytometry in PBMC co-culture and tumor samples to examine T-cell subsets and cytotoxic effector activity. PTTG1 was upregulated in resistant clinical samples and resistant NSCLC cell models. Silencing PTTG1 suppressed proliferation, migration, invasion, epithelial-mesenchymal transition, tumor growth and metastasis in vivo, with enhanced anlotinib efficacy observed in subcutaneous xenografts. PTTG1 knockdown reprogrammed the tumor immune microenvironment (experimental models) toward an activated cytotoxic state, characterized by increased CD8+ T-cell infiltration and enhanced cytotoxic effector activity, with reduction of immune checkpoint-associated suppression. Mechanistically, STRING analysis and co-immunoprecipitation identified AURKA as a direct PTTG1-interacting protein, and AURKA overexpression reversed the immune-activating effects of PTTG1 depletion. In conclusion, PTTG1 promotes acquired anlotinib resistance in NSCLC by coupling malignant progression with immune suppression via the PTTG1-AURKA axis. Targeting PTTG1 may be a strategy to overcome resistance and restore anti-tumor immunity.