Abstract

Background Immune evasion is a critical determinant of cancer progression, yet mechanisms underlying early-stage acquisition of these capabilities remain poorly understood. This study builds an early lung adenocarcinoma mouse model to explore the key regulator of tumor immune evasion process in the very early stage of human lung adenocarcinoma. Methods We introduced Kras G12D/+ and Trp53 −/− oncogenic mutations into murine lung organoids to model newly transformed lung adenocarcinoma cells. Sequential orthotopic injections subjected these cells to iterative immune selection pressure, facilitating the progressive acquisition of immune evasion capabilities. Transcriptomic analyses revealed progressive upregulation of HOXA10, a homeobox transcription factor, throughout the in vivo immune selection process. The tumor microenvironment was evaluated through single-cell RNA sequencing, flow cytometry, and immunohistochemical analysis. Chromatin immunoprecipitation (ChIP) assays, dual-luciferase reporter assays, enzyme-linked immunosorbent assays (ELISA), migration assays, and Western blot analysis were performed to identify downstream targets and elucidate the mechanism by which HOXA10 mediates immune evasion. Immune checkpoint blockade (ICB) treatment was administered to investigate the role of HOXA10 in cancer immunotherapy. Results Our study demonstrated that HOXA10 is upregulated in our lung adenocarcinoma mouse model and in early-stage clinical lung adenocarcinoma specimens. Patients with higher HOXA10 expression exhibited significantly poorer survival. Hoxa10 knockdown substantially inhibited tumor growth, increased cytotoxic CD8 + T cell infiltration, reduced tumor-infiltrating barrier (TIB) density at tumor margins, and decreased immunosuppressive macrophage populations while enhancing macrophage-CD8 + T cell interactions. Mechanistically, Hoxa10 directly binds t