固有免疫调控与胸部慢性疾病免疫微环境研究; The regulation of innate immunity and the immune microenvironment of chronic thoracic diseases.
聚焦于固有免疫调控与胸部慢性疾病免疫微环境研究，综合运用生物化学与分子生物学、细胞生物学、免疫学、生物信息学手段和疾病动物模型，研究固有免疫信号转导通路的新功能与新机制，阐释固有免疫信号通路在自身免疫性疾病、胸部慢性疾病以及肺癌免疫微环境中的功能与分子调控机理。近5年作为第一作者或通讯作者在Cancer Research、Genome Medicine、PLoS Pathogens等期刊发表研究论文多篇。
主要研究成果：
1．固有免疫调控方向，
①发现并鉴定出肿瘤抑制因子CYLD通过抑制STING蛋白酶体依赖的降解途径进而促进固有免疫应答。这一发现阐释了CYLD通过正反馈途径调控STING的去泛素化的机制，为以CYLD为靶点的肿瘤治疗提供了新的思路（PLoS Pathogens, 2018）。
②发现内质网蛋白SCAP可以竞争性抑制登革病毒NS3蛋白的K27链型的多聚泛素化修饰，抑制其NS2B3蛋白酶的活力，增强宿主抗病毒反应（Journal of virology, 2017）；
③鉴定RNF111介导的neddylation修饰增强cGAS-STING信号通路依赖的固有免疫激活，为cGAS分子的功能调控提供了新视角，有望为相关药物靶点的发掘提供了新的策略（PLoS Pathogens, 2021）。
2．胸部慢性疾病与肺癌免疫微环境调控方向，
①依托非小细胞肺癌（NSCLC）免疫治疗队列，系统刻画新辅助免疫治疗NSCLC的TME动态变化，鉴定出新的生物标志物并提出潜在的耐药机制（Genome Medicine, 2023），该研究入选ESI高被引论文；
②阐释ASS1酶介导的代谢重塑促进NSCLC铁死亡抵抗的功能与机制，并初步揭示铁死亡诱导联合精氨酸剥夺这一新型治疗方案可以显著抑制ASS1 缺乏型NSCLC 进展（Cancer Research, 2023）；
③整合新辅助免疫治疗队列的多组学数据，探索了驱动基因突变在非小细胞肺癌新辅助免疫治疗中对免疫浸润以及疗效的影响（Cancer Immunology, Immunotherapy, 2023）。
Research Focus: The regulation of innate immunity and the immune microenvironment of chronic thoracic diseases. Our research utilizes a combination of biochemical and molecular biology, cell biology, immunology, bioinformatics, and disease animal models to investigate the novel functions and mechanisms of innate immune signal transduction pathways. The aim is to elucidate the roles and molecular regulatory mechanisms of innate immune signaling pathways in autoimmune diseases, chronic thoracic diseases, and the immune microenvironment of lung cancer. Over the past five years, several research papers have been published in journals such as Cancer Research, Genome Medicine, and PLoS Pathogens.
Main Research Achievements:
Innate Immune Regulation:
①We identified that the tumor suppressor CYLD promotes innate immune response by inhibiting the proteasome-dependent degradation of the STING protein. This finding elucidates the mechanism by which CYLD regulates the deubiquitination of STING through a positive feedback pathway, providing new insights for tumor therapy targeting CYLD (PLoS Pathogens, 2018).
②We found that the endoplasmic reticulum protein SCAP can competitively inhibit the K27-linked polyubiquitination of Dengue virus NS3 protein, thereby suppressing the activity of the NS2B3 protease and enhancing the host's antiviral response (Journal of Virology, 2017).
③We identified that RNF111-mediated neddylation modification enhances cGAS-STING pathway-dependent innate immune activation, offering a new perspective on the functional regulation of cGAS and potential strategies for discovering related drug targets (PLoS Pathogens, 2021).
Regulation of the Immune Microenvironment in Chronic Thoracic Diseases and Lung Cancer:
①Based on the non-small cell lung cancer (NSCLC) immunotherapy cohort, we systematically characterized the dynamic changes in the tumor microenvironment (TME) during neoadjuvant immunotherapy for NSCLC, identified novel biomarkers, and proposed potential mechanisms of resistance (Genome Medicine, 2023). This study was selected as an ESI Highly Cited Paper.
②We elucidated the function and mechanism by which ASS1 enzyme-mediated metabolic reprogramming promotes ferroptosis resistance in NSCLC, and preliminarily revealed that a novel therapeutic strategy combining ferroptosis induction with arginine deprivation could significantly inhibit the progression of ASS1-deficient NSCLC (Cancer Research, 2023).
③We integrated multi-omics data from the neoadjuvant immunotherapy cohort to explore the impact of driver gene mutations on immune infiltration and therapeutic efficacy in neoadjuvant immunotherapy for non-small cell lung cancer (Cancer Immunology, Immunotherapy, 2023).
SELECTED PUBLICATIONS
Hu Q#, Dai J,# Zhang Z#, Yu H, Zhang J, Zhu X, Qin Y, Zhang L*, Zhang P*. ASS1-Mediated Reductive Carboxylation of Cytosolic Glutamine Confers Ferroptosis Resistance in Cancer Cells. Cancer research 2023, 83(10): 1646-1665.
Hu J#, Zhang L#, Xia H#, Yan Y#, Zhu X, Sun F, Sun L, Li S, Li D, Wang J, Han Y, Zhang J, Bian D, Yu H, Chen Y, Fan P, Ma Q, Jiang G, Wang C*, Zhang P*. Tumor microenvironment remodeling after neoadjuvant immunotherapy in non-small cell lung cancer revealed by single-cell RNA sequencing. Genome Med 2023, 15(1): 14.
Shen Z#, Teng M#, Han L#, Bian D, Zhang J, Zhu X, Qing Y, Hu S, Chen Y, Yao W, Yu H, Zhang L*, Zhang P*. The impact of oncogenic driver mutations on neoadjuvant immunotherapy outcomes in patients with resectable non-small cell lung cancer. Cancer Immunol Immunother 2023, 72(12): 4235-4247.
Zhang J#, Zhang H#, Zhang L#, Li D#, Qi M#, Zhang L, Yu H, Wang D, Jiang G, Wang X*, Zhu X*, Zhang P*. Single‐Cell Transcriptome Identifies Drug‐Resistance Signature and Immunosuppressive Microenvironment in Metastatic Small Cell Lung Cancer. Advanced Genetics 2022, 3(2): 2100060.
Song J#, Zhang L#*, Li C#, Maimaiti M, Sun J, Hu J, Li L, Zhang X, Wang C*, Hu H*. m(6)A-mediated modulation coupled with transcriptional regulation shapes long noncoding RNA repertoire of the cGAS-STING signaling. Comput Struct Biotechnol J 2022, 20: 1785-1797.
Li D#, Yu H#, Hu J#, Li S, Yan Y, Li S, Sun L, Jiang G, Hou L*, Zhang L*, Zhang P*. Comparative profiling of single-cell transcriptome reveals heterogeneity of tumor microenvironment between solid and acinar lung adenocarcinoma. J Transl Med 2022, 20(1): 423.
Li C#, Zhang L#, Qian D#, Cheng M, Hu H, Hong Z, Cui Y, Yu H, Wang Q, Zhu J, Meng W, Xu JF, Sun Y*, Zhang P*, Wang C*. RNF111-facilitated neddylation potentiates cGAS-mediated antiviral innate immune response. PLoS pathogens 2021, 17(3): e1009401.
Zhang L#, Wei N#, Cui Y, Hong Z, Liu X, Wang Q, Li S, Liu H, Yu H, Cai Y, Wang Q, Zhu J, Meng W, Chen Z*, Wang C*. The deubiquitinase CYLD is a specific checkpoint of the STING antiviral signaling pathway. PLoS pathogens 2018, 14(11): e1007435.
Liu H#, Zhang L#, Sun J#, Chen W, Li S, Wang Q, Yu H, Xia Z, Jin X*, Wang C*. Endoplasmic Reticulum Protein SCAP Inhibits Dengue Virus NS2B3 Protease by Suppressing Its K27-Linked Polyubiquitylation. Journal of virology 2017, 91(9).
# First/Co-first author. * Corresponding/Co-corresponding author
