Coordinating oncogenesis and immune evasion: KPNA2, GOLM1, and TK1 as novel CAR T-cell targets in lung adenocarcinoma

作者：Wangrui Liu, Hui Zou, Lei Guo, Zhonghua Zhou, Yahui Xie, Huaqi Guo, Gang Wei, Kai Zhang, Hui Yin, Shiyin Wei, Jiachang Chi · 发表于：European journal of medical research · 年份：2025 · DOI：10.1186/s40001-025-02955-z · 被引用次数：4 · 研究领域：CAR-T cell therapy research、Single-cell and spatial transcriptomics、Cancer Immunotherapy and Biomarkers

Although immune checkpoint inhibitors (ICIs) hold promise for those diagnosed with advanced human lung adenocarcinoma (LUAD), notable heterogeneity in patient responses and the complex tumor microenvironment (TME) limits their clinical utility while providing clinical benefit. To identify new therapeutic targets to pursue in chimeric antigen receptor (CAR) T-cell therapy, we leveraged an integrative multi-omic approach. This study identified three oncogenic drivers, karyopherin α2 (KPNA2), golgi membrane protein 1 (GOLM1) and thymidine kinase 1 (TK1), that are overexpressed in LUAD, spatially enriched in malignant niches and associated with significantly reduced overall survival (log-rank P < 0.01). Furthermore, functional interrogation using RNAi-mediated gene silencing in LUAD cell lines (NCI-H1650, A549), demonstrated their essential roles in mediating protumorigenic pathways. Specifically, CRISPR interference of KPNA2 or TK1 inhibited cellular proliferation and invasion while also phenocopying a pro-apoptotic effect with cisplatin. GOLM1 depletion inhibited PD-L1 upregulation and restored CD8 + T-cell cytotoxicity in co-culture. Mechanistically, dual knockdown targets, KPNA2 and TK1, were shown to restore deregulated STAT3 signaling that promotes cell survival and also enhance MHC class I antigen presentation implicating functional roles for KPNA2 and TK1 in linked processes of intrinsic oncogenesis and immunoediting by immune evasion and suppression. In summary, KPNA2, G...