A novel mouse cell line model reveals the tumor intrinsic and immune characteristics of EGFR-mutant lung cancer

<b>Background:</b> Epidermal growth factor receptor (EGFR) mutations occur frequently in lung adenocarcinoma (LUAD). However, the lack of practical preclinical models has limited our understanding of how EGFR mutations reshape the tumor immune microenvironment. <b>Methods:</b> EGFR^{E19del/E19del}; Trp53^-/- (EP) cell lines were established from a human EGFR exon 19 deletion mutated genetically engineered mouse model (GEMM). These cell lines were applied to generate orthotopic tumors in both immunodeficient and immunocompetent mice. Drug sensitivity assays were performed to evaluate responses to Osimertinib. Multi-omics analyses, including transcriptomic and metabolic profiling, were conducted to compare EP tumors with KRAS-mutant models and human EGFR-mutant LUAD. <b>Results:</b> EP cell lines formed tumors in both immunodeficient and immunocompetent mice and showed sensitivity to Osimertinib comparable to human EGFR-mutant cell lines. EP tumors further developed acquired resistance to EGFR-TKI therapy, accompanied by transcriptional reprogramming marked by enhanced epithelial-mesenchymal transition (EMT) and Wnt/β-catenin signaling. Multi-omics analysis revealed that EP tumors closely recapitulate the molecular features of human EGFR-mutant LUAD, while exhibiting distinct transcriptomic and metabolic profiles compared to KRAS-mutant models. Immune profiling demonstrated a suppressed adaptive immune response in EP tumors, including reduced infiltration of tissue-resident memory T cell and increased M2-like polarization of macrophage. <b>Conclusions:</b> This study presents a novel preclinical model that practically represents EGFR-mutant LUAD. Unlike traditional models relying on exogenous EGFR mutations, EP cells are endogenously driven by EGFR signaling and accurately reflect the immunosuppressive microenvironment observed in patients. This model provides an efficient platform for investigating mechanisms of immune evasion and for developing innovative therapeutic strategies.