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

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机构： [1]Department of Thoracic Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China. [2]Northern Jiangsu People’s Hospital/Northern Jiangsu People’s Hospital of Jiangsu Province, Yangzhou, China. [3]The Yangzhou School of Clinical Medicine of Nanjing Medical University, Yangzhou, China. [4]Department of Thoracic Surgery, The Affiliated Qingdao Third People’s Hospital of Qingdao University, Qingdao 266071, China. [5]Shanghai Tenth People’s Hospital Chongming Branch, Shanghai 202157, China. [6]School of Public Health, Gansu University of Traditional Chinese Medicine, Lanzhou, China. [7]Department of Pulmonary and Critical Care Medicine, The Ninth People’s Hospital of Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China. [8]Beijing Key Laboratory of Diabetes Research and Care, Department of Endocrinology, Beijing Diabetes Institute, Beijing Tongren Hospital, Capital Medical University, Beijing 100730, China. [9]Department of Thoracic Surgery, The First Affiliated Hospital of Shaoyang University, Shaoyang 422000, China. [10]Department of Biochemistry and Molecular Biology, Basic Medical College, Qingdao University, Qingdao, Shandong Province, China. [11]Affiliated Hospital of Youjiang Medical University for Nationalities, Baise 533000, China. [12]Key Laboratory of Tumor Molecular Pathology of Baise, Baise 533000, China. [13]Center of Interventional Radiology & Vascular Surgery, Department of Radiology, Zhongda Hospital, Medical School, Southeast University, Nanjing, China.

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关键词： Tumor microenvironment CAR-T therapy Lung cancer

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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, GOLM1, and TK1 are functionally relevant molecular coordinators for tumor cell autonomous proliferation and TME mediated immunosuppression. Their membrane expression (notable in the case of PD-L1) and functional roles in immune modulation, make them reasonable targets of CAR T-cell immunotherapy. We posit that a combined strategy targeting KPNA2, GOLM1 and TK1 with or without PD-1/PD-L1 axis inhibitors could provide a better strategy to treat patients with ICI resistant LUAD and generate prolonged and stable immune remodeling.© 2025. The Author(s).

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出版当年[2025]版：

大类 | 3 区医学

小类 | 4 区医学：研究与实验

最新[2025]版：

大类 | 3 区医学

小类 | 4 区医学：研究与实验

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第一作者机构： [1]Department of Thoracic Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China.

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通讯机构： [1]Department of Thoracic Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China. [11]Affiliated Hospital of Youjiang Medical University for Nationalities, Baise 533000, China. [12]Key Laboratory of Tumor Molecular Pathology of Baise, Baise 533000, China. [13]Center of Interventional Radiology & Vascular Surgery, Department of Radiology, Zhongda Hospital, Medical School, Southeast University, Nanjing, China.

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

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