Conclusion: Our findings indicate that CENPF, CYSLTR1, GLDN, PIGR and SCGB3A1 are independent prognostic biomarkers associated with acquired EGFR-TKI resistance and tumor immune cell infiltration in lung adenocarcinoma, and CENPF may be a potential target that can improve immunotherapy efficacy and overcome the acquired EGFR-TKI resistance. The gene discussed is CYSLTR1; the disease is lung adenocarcinoma.