Coordinating oncogenesis and immune evasion: KPNA2, GOLM1, and TK1 as novel CAR T-cell targets in lung adenocarcinoma
Abstract 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 n...
Saved in:
| Main Authors: | , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2025-08-01
|
| Series: | European Journal of Medical Research |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s40001-025-02955-z |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849226494435393536 |
|---|---|
| author | Wangrui Liu Hui Zou Lei Guo Zhonghua Zhou Yahui Xie Huaqi Guo Gang Wei Kai Zhang Hui Yin Shiyin Wei Jiachang Chi |
| author_facet | Wangrui Liu Hui Zou Lei Guo Zhonghua Zhou Yahui Xie Huaqi Guo Gang Wei Kai Zhang Hui Yin Shiyin Wei Jiachang Chi |
| author_sort | Wangrui Liu |
| collection | DOAJ |
| description | Abstract 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. |
| format | Article |
| id | doaj-art-52df8e534d0248fd83b61edd5330a177 |
| institution | Kabale University |
| issn | 2047-783X |
| language | English |
| publishDate | 2025-08-01 |
| publisher | BMC |
| record_format | Article |
| series | European Journal of Medical Research |
| spelling | doaj-art-52df8e534d0248fd83b61edd5330a1772025-08-24T11:15:08ZengBMCEuropean Journal of Medical Research2047-783X2025-08-0130111210.1186/s40001-025-02955-zCoordinating oncogenesis and immune evasion: KPNA2, GOLM1, and TK1 as novel CAR T-cell targets in lung adenocarcinomaWangrui Liu0Hui Zou1Lei Guo2Zhonghua Zhou3Yahui Xie4Huaqi Guo5Gang Wei6Kai Zhang7Hui Yin8Shiyin Wei9Jiachang Chi10Department of Thoracic Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong UniversityNorthern Jiangsu People’s Hospital/Northern Jiangsu People’s Hospital of Jiangsu ProvinceDepartment of Thoracic Surgery, The Affiliated Qingdao Third People’s Hospital of Qingdao UniversityShanghai Tenth People’s Hospital Chongming BranchSchool of Public Health, Gansu University of Traditional Chinese MedicineDepartment of Pulmonary and Critical Care Medicine, The Ninth People’s Hospital of Shanghai Jiao Tong University School of MedicineBeijing Key Laboratory of Diabetes Research and Care, Department of Endocrinology, Beijing Diabetes Institute, Beijing Tongren Hospital, Capital Medical UniversityDepartment of Pulmonary and Critical Care Medicine, The Ninth People’s Hospital of Shanghai Jiao Tong University School of MedicineDepartment of Thoracic Surgery, The First Affiliated Hospital of Shaoyang UniversityAffiliated Hospital of Youjiang Medical University for NationalitiesDepartment of Thoracic Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong UniversityAbstract 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.https://doi.org/10.1186/s40001-025-02955-zTumor microenvironmentCAR-T therapyLung cancer |
| spellingShingle | Wangrui Liu Hui Zou Lei Guo Zhonghua Zhou Yahui Xie Huaqi Guo Gang Wei Kai Zhang Hui Yin Shiyin Wei Jiachang Chi Coordinating oncogenesis and immune evasion: KPNA2, GOLM1, and TK1 as novel CAR T-cell targets in lung adenocarcinoma European Journal of Medical Research Tumor microenvironment CAR-T therapy Lung cancer |
| title | Coordinating oncogenesis and immune evasion: KPNA2, GOLM1, and TK1 as novel CAR T-cell targets in lung adenocarcinoma |
| title_full | Coordinating oncogenesis and immune evasion: KPNA2, GOLM1, and TK1 as novel CAR T-cell targets in lung adenocarcinoma |
| title_fullStr | Coordinating oncogenesis and immune evasion: KPNA2, GOLM1, and TK1 as novel CAR T-cell targets in lung adenocarcinoma |
| title_full_unstemmed | Coordinating oncogenesis and immune evasion: KPNA2, GOLM1, and TK1 as novel CAR T-cell targets in lung adenocarcinoma |
| title_short | Coordinating oncogenesis and immune evasion: KPNA2, GOLM1, and TK1 as novel CAR T-cell targets in lung adenocarcinoma |
| title_sort | coordinating oncogenesis and immune evasion kpna2 golm1 and tk1 as novel car t cell targets in lung adenocarcinoma |
| topic | Tumor microenvironment CAR-T therapy Lung cancer |
| url | https://doi.org/10.1186/s40001-025-02955-z |
| work_keys_str_mv | AT wangruiliu coordinatingoncogenesisandimmuneevasionkpna2golm1andtk1asnovelcartcelltargetsinlungadenocarcinoma AT huizou coordinatingoncogenesisandimmuneevasionkpna2golm1andtk1asnovelcartcelltargetsinlungadenocarcinoma AT leiguo coordinatingoncogenesisandimmuneevasionkpna2golm1andtk1asnovelcartcelltargetsinlungadenocarcinoma AT zhonghuazhou coordinatingoncogenesisandimmuneevasionkpna2golm1andtk1asnovelcartcelltargetsinlungadenocarcinoma AT yahuixie coordinatingoncogenesisandimmuneevasionkpna2golm1andtk1asnovelcartcelltargetsinlungadenocarcinoma AT huaqiguo coordinatingoncogenesisandimmuneevasionkpna2golm1andtk1asnovelcartcelltargetsinlungadenocarcinoma AT gangwei coordinatingoncogenesisandimmuneevasionkpna2golm1andtk1asnovelcartcelltargetsinlungadenocarcinoma AT kaizhang coordinatingoncogenesisandimmuneevasionkpna2golm1andtk1asnovelcartcelltargetsinlungadenocarcinoma AT huiyin coordinatingoncogenesisandimmuneevasionkpna2golm1andtk1asnovelcartcelltargetsinlungadenocarcinoma AT shiyinwei coordinatingoncogenesisandimmuneevasionkpna2golm1andtk1asnovelcartcelltargetsinlungadenocarcinoma AT jiachangchi coordinatingoncogenesisandimmuneevasionkpna2golm1andtk1asnovelcartcelltargetsinlungadenocarcinoma |