肿瘤免疫药物设计研究组

Laboratory of Immuno-oncology Drug Design

研究成果
1. 免疫受体信号调控与治疗性生物大分子开发

      课题组围绕肿瘤免疫与炎症反应中的关键免疫受体,结合结构生物学、蛋白质工程和细胞功能研究,解析受体聚集、膜相互作用及信号转导的分子机制,发展精准调控受体功能的干预策略。代表性成果包括:揭示DR5配体结合前的自抑制性聚集机制,提出通过单价纳米抗体重排受体预聚集体、激活死亡信号的新策略(Cell Research, 2023);发现OX40膜近端富碱性基序通过膜锚定协同募集TRAF2,揭示其在4-1BB和CD40中的保守调控作用(EMBO Journal, 2026);开发选择性人源化TNFR1纳米抗体,阐明其结合表位与拮抗机制,实现对炎症和坏死性凋亡信号的抑制(Communications Biology, 2026)。在此基础上,进一步探索免疫受体的精准激动与拮抗机制,推进共刺激信号模块优化及治疗性抗体开发。


2. 肿瘤抗原呈递调控与pMHC靶向免疫治疗

课题组聚焦肿瘤抗原的有效呈递与T细胞识别,研究MHC-I膜转运、抗原复合物稳定性及TCR识别特征,探索增强肿瘤免疫识别的干预路径。代表性成果包括:发现HLA-A胞质尾360–365区段是调控内吞和表面驻留的关键模块,通过序列突变或细胞穿透肽干预降低内吞、维持HLA-I表面表达,为改善肿瘤抗原展示提供新的切入点(Cell Reports, 2026);围绕HLA-A*11:01呈递的KRAS共享新抗原,阐明G12突变及肽长度对pMHC稳定性和TCR识别的影响,揭示G12D 10肽相较9肽更有利于稳定呈递和免疫识别(Communications Biology, 2026)。后续将结合肿瘤抗原鉴定、MHC-I表面驻留调控与TCR分子设计,发展pMHC靶向治疗策略,并探索其与抗原呈递增强策略的协同应用。

3. 膜蛋白构象动态与跨膜转运调控机制

课题组围绕膜蛋白与底物、小分子配体及磷脂的相互作用,研究构象动态与跨膜转运功能之间的联系。结合顺磁弛豫增强核磁共振、脂质体功能实验及分子动力学模拟,建立了从分子相互作用、构象变化到转运功能的综合研究体系。以线粒体解偶联蛋白(UCP1)和ATP/ADP转运蛋白(AAC)为代表,阐明其底物结合与配体调控机制,为理解线粒体载体蛋白的转运功能及膜蛋白的动态调控提供了机制依据与研究方法(Nature Structural & Molecular Biology, 2018;Structure, 2017;Protein & Cell, 2016)。



代表性论文列表:

1. Xu, X.#, Wang, Y.#, Wu, Y., Cai, Z., Zhu, J., Wu, H., ... & Zhao, L.* (2026). Membrane engagement by the HLA-A cytoplasmic tail regulates endocytosis and surface retention. Cell Reports, 45(9).

2. Zhu, J.#, Xu, X.#, Liu, P., Wu, H., Wang, Y., Xu, B., ... & Zhao, L.* (2026). A conserved basic motif mediates membrane anchoring and TRAF2 recruitment across costimulatory TNFRs. The EMBO Journal, 1-24.

3. Liu, P.#, Zhao, Y.#, Cai, Z., Wu, H., Wang, S., Jiang, L., ... & Zhao, L.* (2026). A humanized anti-TNFR1 nanobody antagonist targeting the CRD3 region suppresses inflammation and necroptosis in vitro. Communications Biology.

4. Wu, Y., Hu, W., Zhao, L.* (2026). From Prediction to Design: A Paradigm Shift in AI-Driven Protein–Protein Interaction Research. Health and Metabolism.
5. Zhu, J.#, Chen, Z.#, Xu, X., Wang, Y., Liu, P., Wen, M., ... & Zhao, L.* (2025). Structure guided analysis of KRAS G12 mutants in HLA-A* 11: 01 reveals a length encoded immunogenic advantage in G12D. Communications Biology, 9(1), 26.

6. Ahmad, S.#, Zou, T.#, Hwang, J.#, Zhao, L.#, Wang, X., Davydenko, A., ... & Hur, S.* (2025). PACT prevents aberrant activation of PKR by endogenous dsRNA without sequestration. Nature Communications, 16(1), 3325.

7. Du, G.#, Zhao, L.#, Zheng, Y., Belfetmi, A., Cai, T., Xu, B., ... & Chou, J. J.* (2023). Autoinhibitory structure of preligand association state implicates a new strategy to attain effective DR5 receptor activation. Cell Research, 33(2), 131-146.

8. Zhao L, Fu Q, Pan L, Piai A, Chou JJ.* (2020). The diversity and similarity of transmembrane trimerization of TNF receptors. Frontier Cell Dev Biol, 8, 1096.

9. Pan, L.#, Fu, T. M.#, Zhao, W.#, Zhao, L.#, Chen, W., Qiu, C., ... & Chen, S.* (2019). Higher-order clustering of the transmembrane anchor of DR5 drives signaling. Cell, 176(6), 1477-1489.

10. Fu, T., Pan, L., Zhao, L., Wu, H., & Chou, J.* (2019). Higher‐Order Clustering of the Transmembrane Anchor of DR5 Drives Signaling. The FASEB Journal, 33(S1), 792-3.

11. Yang, Q., Brüschweiler, S., Zhao, L., & Chou, J. J.* (2018). Reply to ‘Concerns with yeast mitochondrial ADP/ATP carrier’s integrity in DPC’and ‘Dynamics and interactions of AAC3 in DPC are not functionally relevant’. Nature structural & molecular biology, 25(9), 749-750.
12. Zhao, L., Wang, S., Zhu, Q., Wu, B., Liu, Z., OuYang, B., & Chou, J. J.* (2017). Specific interaction of the human mitochondrial uncoupling protein 1 with free long-chain fatty acid. Structure, 25(9), 1371-1379.
13. Zhao, L.#, Wang, S.#, Run, C., OuYang, B., & Chou, J. J.* (2016). Specific lipid binding of membrane proteins in detergent micelles characterized by NMR and molecular dynamics. Biochemistry, 55(38), 5317-5320.
14. Zhao, L., Wang, S., Du, L., Dev, J., Zhou, L., Liu, Z., ... & OuYang, B.* (2016). Structural basis of interaction between the hepatitis C virus p7 channel and its blocker hexamethylene amiloride. Protein & cell, 7(4), 300-304.

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