研究领域与方向
癌症是严重威胁人类健康并制约经济社会发展的重大疾病，其治疗仍面临多重挑战。相比于传统疗法，肿瘤免疫疗法近年来取得了突破性进展，但仅有少数患者能够得到持久获益。治疗响应率有限及免疫耐药的发生是制约其临床应用的关键瓶颈。围绕这些问题，本课题组综合运用小鼠模型、抗体工程、高通量筛选等技术手段，系统研究肿瘤微环境中髓系免疫细胞的功能调控机制，并探索开发新型免疫治疗策略。主要研究方向包括：1）筛选与鉴定肿瘤相关树突状细胞的关键功能调控因子，研发增强抗肿瘤免疫应答的新策略；2）解析肿瘤微环境中免疫抑制与免疫激活信号网络的分子调控机制，阐明其在肿瘤治疗响应及耐药形成中的作用；3）设计与开发面向肿瘤免疫治疗的下一代抗体药物。
研究成果与贡献
1. 传统观点认为，肿瘤细胞表达的PD-L1通过与T细胞表面的PD-1结合，抑制T细胞效应功能并促进肿瘤免疫逃逸。我们的研究发现，在部分肿瘤中，髓系细胞、尤其是树突状细胞表达的PD-L1，在调控抗肿瘤免疫中发挥了更关键的作用；相比阻断肿瘤细胞PD-L1，靶向树突状细胞PD-L1信号对免疫治疗的疗效更为重要（Nat Commun, 2020; J Clin Invest, 2018）。临床研究进一步证实，肿瘤患者髓系细胞PD-L1表达水平可作为预测免疫检查点阻断治疗疗效及患者预后的潜在生物标志物。
2. 作为经典免疫检查点分子，PD-L1在树突状细胞自身生物学功能中的作用尚不明确。我们的研究发现，PD-L1通过调控铁死亡相关分子，保护树突状细胞免受化疗诱导的铁死亡，从而维持其抗原递呈功能并增强抗肿瘤免疫应答（Cell Reports, 2024）。进一步研究发现，氧化应激诱导的DNA损伤可激活cGAS/STING信号通路，增强树突状细胞免疫活性；靶向DNA损伤修复通路可进一步放大树突状细胞介导的抗肿瘤免疫效应（Cell Reports, 2025）。这些研究揭示了树突状细胞功能调控的新机制，为优化肿瘤免疫治疗联合策略提供了新的理论依据和干预靶点。
3. 当前针对肿瘤相关树突状细胞的治疗靶点及药物仍较为有限。我们建立了结合计算生物学预测与实验验证的靶点筛选体系，系统发掘可增强树突状细胞抗原递呈功能的治疗靶点及候选药物。基于该策略，我们发现部分老药具有增强树突状细胞介导抗肿瘤免疫反应的新功能，为老药新用提供了理论依据（J Immunother Cancer, 2024；PLoS Comput Biol, 2024）。这些研究为树突状细胞靶向药物研发及肿瘤免疫治疗策略优化提供了新的思路。
荣誉和奖项
2019年Bayer Investigator Award
2014年Irvington Postdoctoral Fellowship, Cancer Research Institute (New York)
2012年北京生命科学研究院和赛诺菲巴斯德生物医学杰出研究生奖
代表性论文
(#co-first author, *corresponding author)
1. Ng I-I, Zhang Z, Xiao K, Ye M, Tian T, Zhu Y, He Y, Chu L, Tang H*. Targeting WEE1 in tumor-associated dendritic cells potentiates antitumor immunity via the cGAS/STING pathway. Cell Rep, 2025, 44 (6): 115733.
2. Cheng JN, Jin Z, Su C, Jiang T, Zheng X, Guo J, Li X, Chu H, Jia J, Zhou Q, Ding X, Zhang Y, Xu S, Dong F, Zhang Q, Yang X, Yang T, Cheng X, Zha H, Chen D, Wan YY, Liu X, Ye L, Tang H, Symonds ALJ, Li QJ, Jia Q, Zhu B. Bone metastases dimmish extraosseous response to checkpoint blockade immunotherapy through osteopontin-producing osteoclasts. Cancer Cell, 2025, 43: 1-15.
3. Xiao K#, Zhang S#, Peng Q#, Du Y#, Yao X, Ng I-I, Tang H*. PD-L1 protects tumor-associated dendritic cells from ferroptosis during immunogenic chemotherapy, Cell Rep, 2024, 43 (11): 114868.
4. Ng I-I#, Zhang J#, Tian T#, Peng Q#, Huang Z, Xiao K, Yao X, Ng L*, Zeng J*, Tang H*. Network-based screening identifies sitagliptin as an antitumor drug targeting dendritic cells, J Immunother Cancer, 2024, 12 (3): e008254.
5. Liu C#, Xiao K#, Yu C#, Lei Y#, Lyu K, Tian T, Zhao D*, Zhou F*, Tang H*, Zeng J*. A probabilistic knowledge graph for target identification. PLoS Comput Biol, 2024, 20 (4): e1011945.
6. Zhang Y, Song Q, Cassady K, Lee M, Tang H, Zheng M, Wang B, Schones DE, Fu Y-X, Riggs AD, Martin PJ, Feng R. Zeng D. Blockade of trans PD-L1 interaction with CD80 augments anti-tumor immunity. PNAS, 2023, 120 (16): e2205085120.
7. Ni L#*, Chen J#, Deng M#, Tang H#, Bao M#. Editorial: Involvement of Dendritic Cells in Gastrointestinal Cancer. Front Immunol, 2023, 14: 1178075.
8. Miao Y, Liu Y, Tang H, Zhang Z. Dendritic cell maturation in the tumor microenvironment. National Science Open, 2023, 2: 20220053.
9. Sun S, Cai Y, Song T, Pu Y, Cheng L, Xu H, Sun J, Meng C, Lin Y, Huang H, Zhao F, Zhang S, Gao Y, Han J, Feng X, Yu D, Zhu Y, Gao P, Tang H, Zhao J, Zhang Z, Yang J, Hu Z, Fu Y-X, Zheng Y, Peng H. Interferon-armed RBD dimer enhances the immunogenicity of RBD for sterilizing immunity against SARS-CoV-2. Cell Res. 2021, 31 (9): 1011-1023.
10. Peng Q, Qiu X, Zhang Z, Zhang S, Zhang Y, Liang Y, Guo J, Peng H, Chen M, Fu Y-X, Tang H*. PD-L1 on dendritic cells attenuates T cell activation and regulates response to immune checkpoint blockade. Nat Commun. 2020, 11 (1): 4835.
11. Liang Y#, Tang H#*, Guo J#, Qiu X, Yang Z, Ren Z, Sun Z, Bian Y, Xu L, Xu H, Shen J, Han Y, Dong H, Peng H*, Fu Y-X*. Targeting IFNa to tumor by anti-PD-L1 creates feedforward antitumor responses to overcome checkpoint blockade resistance. Nat Commun. 2018, 9 (1): 4586.
12. Tang H, Fu Y-X. Immune Evasion in Tumor’s Own Sweet Way. Cell Metab. 2018, 27 (5): 945-946.
13. Tang H*, Qiu X, Timmerman C, Fu Y-X. Targeting tertiary lymphoid structures for tumor immunotherapy. Methods Mol Biol. 2018, 1845: 275-286.
14. Tang H#, Liang Y#, Anders R, Taube J, Qiu X, Mulgaonkar A, Liu X, Harrington S, Guo J, Xin Y, Xiong Y, Nham K, Silvers W, Hao G, Sun X, Chen M, Hannan R, Qiao J, Peng H, Dong H, Fu Y-X. PD-L1 on host cells is essential for tumor regression mediated by PD-L1 blockade. J Clin Invest. 2018, 128 (2): 580-588.
15. Tang H*, Zhu M, Qiao J, Fu Y-X*. Lymphotoxin signaling in tertiary lymphoid structures and immunotherapy. Cell Mol Immunol. 2017, 14 (10): 809-818.
16. Tang H, Wang Y, Chlewicki L, Zhang Y, Guo J, Liang W, Wang J, Wang X, Fu Y-X. Facilitating T cell infiltration in tumor microenvironment overcomes resistance to PD-L1 blockade. Cancer Cell. 2016, 29 (3): 285-296.
17. Tang H, Qiao J, Fu Y-X. Immunotherapy and tumor microenvironment. Cancer Lett. 2016, 370 (1): 85-90.
18. Tang H, Li C, Wang L, Zhang H, Fan Z. Granzyme H of cytotoxic lymphocytes is required for clearance of the hepatitis B virus through cleavage of the hepatitis B virus X protein. J Immunol. 2012, 188 (2): 824-831.
