我们课题组聚焦肿瘤边界微环境的空间特征及其调控机制研究，围绕“肿瘤空间特征解析-免疫逃逸机制-潜在靶点发现”层层递进开展系统研究。原创性建立系列空间组学算法与数据库解析肿瘤微环境的空间特征；揭示肿瘤边界微环境调控免疫逃逸的分子机制；挖掘潜在靶点并构建免疫治疗疗效预测模型与分析工具，旨在系统阐明肿瘤边界微环境在肿瘤发生发展及治疗响应中的关键作用。围绕上述目标，开展以下三个方向研究：

（i）开发系列单细胞空间组学算法与数据库，解析肿瘤微环境空间特征

单细胞与空间多组学技术的发展极大推动了复杂生物系统中细胞异质性的研究。为更高效利用相关技术，本团队建立系列算法与数据库以系统解析肿瘤微环境的空间特征。如Cottrazm用于精准鉴定肿瘤边界、多尺度预测空间细胞组成并重构近单细胞分辨率的空间基因表达图谱（Nat Commun 2023a）；HiST融合空间转录组与病理图像的多尺度深度学习模型，可预测病理切片空间表达谱，实现HE图像中的肿瘤定位、预后评估及临床分型（Adv Sci 2026）。

在资源建设方面，构建多层级数据库体系，包括泛癌肿瘤空间微环境数据库SpatialTME（Can Res 2024a）、泛癌间质细胞图谱数据库scPanStroma（Can Res 2024b）、免疫治疗前后肿瘤免疫微环境动态分子图谱数据库CTTIME（GPB 2025），以及整合空间转录组技术、分析算法与数据库的可视化平台SpatialToolDB（Sci Bull 2026）。上述算法与数据库显著提升了单细胞空间组学数据的解析与应用能力，并为生理与病理条件下细胞表型的计算建模奠定基础。课题组持续在肿瘤空间微环境解析方法上开展研究，重点推进跨模态融合与跨样本整合算法的发展。

（ii）肿瘤边界微环境参与免疫逃逸的机制研究

课题组聚焦肿瘤边界区域在免疫调控中的关键作用，系统解析其对T细胞功能异常及免疫逃逸的调控机制。基于单细胞与空间多组学技术，研究揭示肿瘤微环境中的低氧异质性影响细胞空间分布，并通过“低氧–ALCAM^high巨噬细胞–耗竭性T细胞”轴介导免疫治疗抵抗（Nat Metab 2019；Adv Sci 2024）。进一步研究发现，肿瘤与癌旁交互区中SPP1⁺巨噬细胞与FAP⁺肿瘤相关成纤维细胞（CAF）通过细胞互作促进细胞外基质沉积，形成免疫屏障并限制T细胞浸润；靶向SPP1干预可破坏该互作、促进T细胞浸润并增强免疫治疗疗效（J Hepatol 2023；Nat Commun 2022）。同时，揭示交互区CAF可诱导肿瘤边界CD8⁺ T细胞功能耗竭，导致免疫治疗不响应（Cancer Res 2024b；Adv Sci 2025）。此外，联合研究发现代谢重编程在T细胞免疫调控中发挥关键作用：“果糖–脂肪细胞–瘦素–CD8⁺ T细胞”轴增强抗肿瘤免疫功能，“乳酸–Foxp3–USP39–CTLA-4”信号轴抑制免疫治疗疗效（Cell Metab 2023；Immunity 2024a, 2024b）。总体上，课题组从空间结构、细胞互作及代谢调控等多维度系统揭示肿瘤边界微环境调控T细胞迁移与功能异常的机制，为理解肿瘤免疫逃逸及优化免疫治疗策略提供重要理论基础。

（iii）基于临床治疗队列构建疗效预测模型并挖掘空间相关潜在靶点

免疫治疗疗效预测仍面临重要挑战，传统基于肿瘤突变负荷及PD-L1表达的指标难以全面评估患者响应。课题组基于临床治疗队列开展系统研究，构建了基于治疗早期血浆细胞因子动态变化的免疫激活预测模型（Innovation 2022），以及基于选择性多聚腺苷酸化和circRNA特征的疗效预测模型（Can Res 2022；Nat Commun 2023b）。进一步整合多癌种空间多模态数据与免疫治疗结局信息，发展智能体引导的空间预测模型，以提高免疫治疗疗效预测的准确性与泛化能力。在潜在靶点挖掘方面，研究发现化疗过程中肿瘤细胞可由中间状态向耐药性基底样表型转化，并与SPP1⁺巨噬细胞及耗竭CD8⁺ T细胞共同构建免疫抑制性耐药生态位；机制研究表明免疫检查点分子CD276在其中发挥双重调控作用，一方面促进肿瘤细胞基底样转化，另一方面增强免疫抑制信号（Gastroenterology 2026）。本方向旨在识别具有空间特征的关键调控分子，并推动其向潜在治疗靶点转化，以提升肿瘤治疗效果与患者获益。

本课题组更多研究方向和科研成果讯息详见实验室网站：http://www.yelab.site/

代表性论文

以*（共同）一作/#共同通讯发表的期刊

2026

1. Li W, Zhang D, Peng E, Shen S, Alinejad-Rokny H, Liu Y*, Zheng J*, Jiang C*, Ye Y*. HiST: Histological Images Reconstruct Tumor Spatial Transcriptomics via MultiScale Fusion Deep Learning. Adv Sci (Weinh). 2026 Mar;13(13):e14351. doi: 10.1002/advs.202514351. Epub 2026 Jan 5.

2. Guo ZZ, Wu R, Li W, Yang K, Ying X, Alinejad-Rokny H*, Ye Y*. Mapping biology in space: from spatial transcriptomics platforms to analytical tools and databases. Sci Bull (Beijing). 2026 Feb 28;71(4):921-945. doi: 10.1016/j.scib.2026.01.034. Epub 2026 Jan 20.

3. Zhang Y, Du Y, Wang J, Wang D, Li J, Zhang J, Zhao Y, Sun S, Sun H, Qi J, Bao R, Shao C, Zhang M, He X, Zhang L, Zhou C, Wang D, Su B*, Zou D*, Ye Y*. Single-Cell Analysis of Chemotherapy-induced Remodeling Reveals CD276-driven Basal-like Chemoresistance in Pancreatic Cancer. Gastroenterology. 2026 Apr;170(4):769-786.

2025

1. Miao S#, Li H#, Song X#, Liu Y, Wang G, Kan C, Ye Y*, Liu RJ*, Li HB*. tRNA m1A modification regulates cholesterol biosynthesis to promote antitumor immunity of CD8+ T cells. J Exp Med. 2025 Mar 3;222(3):e20240559. 

2. Ding X#, Wu Q#, Du Y, Ji MM, Yang H*, Hu Q*, Ye Y*. CDK16+ Luminal Progenitor Cell-Like Tumor Cells Interacted with POSTN+ Cancer-Associated Fibroblasts Associate with Chemo-Resistance In Breast Cancer. Small Methods. 2025 May;9(5):e2401192.

3. Du Y, Zhao Y, Li J, Wang J, You S, Zhang Y, Zhang L, Yang J, Alinejad-Rokny H, Cheng S, Shao C, Zou D *, Ye Y *. PLXDC1+ Tumor-Associated Pancreatic Stellate Cells Promote Desmoplastic and Immunosuppressive Niche in Pancreatic Ductal Adenocarcinoma. Adv Sci (Weinh). 2025 May;12(18):e2415756.

4. Wang F#, Bao R#, Xu S#, Li W#, Huang H#, Li R#, Ding X, Zhang Y, Yu X, Han Q, Du X, Wan J, Li S, Xiao Y, Zhao R, Cui X, Ye Y*, Sun J*, Zheng J*, Chen GQ*, Zou Q*. An age-related decrease in leptin contributes to CD8+ T cell aging in the tumor microenvironment. Cell Rep Med. 2025 Sep 16;6(9):102310.

5. Zhang C#, Dong Y#, Liu Y#, Shi J, Han L *, Ye Y *. CTTIME: A Database for Analyzing Cancer Therapy's Impact on Tumor Immune Microenvironment. Genomics Proteomics Bioinformatics. 2025 Sep 22:qzaf086.

2024

1. Du Y#, Shi J#, Wang J, Xun Z, Yu Z, Sun H, Bao R, Zheng J, Li Z, Ye, Y. Integration of Pan-Cancer Single-Cell and Spatial Transcriptomics Reveals Stromal Cell Features and Therapeutic Targets in Tumor Microenvironment. Cancer Res 2024 Jan 16;84(2):192-210.

2. Shi J#, Wei X#, Xun Z, Ding X, Liu Y, Liu L, Ye, Y. The Web-Based Portal SpatialTME Integrates Histological Images with Single-Cell and Spatial Transcriptomics to Explore the Tumor Microenvironment Cancer Res 2024 Apr 15;84(8):1210-1220.

3. Chen W, He Y, Zhou G, Chen X *, Ye, Y *, Zhang G *, Liu H *. Multiomics characterization of pyroptosis in the tumor microenvironment and therapeutic relevance in metastatic melanoma. BMC Med 2024 Jan 17;22(1):24.

4. Ding R, Yu X, Hu Z, Dong Y, Huang H, Zhang Y, Han Q, Ni ZY *, Zhao R *, Ye, Y *, Zou Q *. Lactate modulates RNA splicing to promote CTLA-4 expression in tumor-infiltrating regulatory T cells. Immunity 2024 Mar 12;57(3):528-540.e6.

5. Xiao J, Wang S, Chen L, Ding X, Dang Y, Han M, Zheng Y, Shen H, Wu S, Wang M, Yang D, Li N, Dong C, Hu M, Su C, Li W, Hui L, Ye, Y *, Tang H *, Wei B *, Wang H *. 25-Hydroxycholesterol regulates lysosome AMP kinase activation and metabolic reprogramming to educate immunosuppressive macrophages. Immunity 2024 Apr 12:S1074-7613(24)00142-0.

2023

1. Dong Y, Gao Q, Chen Y, Zhang Z, Du Y, Liu Y, Zhang G, Li S, Wang G, Chen X*, Liu H*, Han L*, Ye Y*. Identification of CircRNA signature associated with tumor immune infiltration to predict therapeutic efficacy of immunotherapy. Nature Communications(2023) 14(1):2540.

2. Xun, Z., Ding, X., Yao Zhang, Zhang, B., Lai, S., Zou, D., Zheng, J., Chen, G., Su, B., Han, L.* & Ye, Y.* Reconstruction of the tumor spatial microenvironment along the malignant- boundary-nonmalignant axis. Nature Communications(2023) 14: 933.
   

3. Sun, C. *, Ye, Y. *, Tan, Z., Liu, Y., Li, Y., Hu, W., Liang, K., Egranov, S. D., Huang, L. A., Zhang, Z., Zhang, Y., Yao, J., Nguyen, T. K., Zhao, Z., Wu, A., Marks, J. R., Caudle, A. S., Sahin, A. A., Gao, J., et al. Tumor-associated nonmyelinating Schwann cell - expressed PVT1 promotes pancreatic cancer kynurenine pathway and tumor immune exclusion. Science Advances 6995, 1–17 (2023).
   

4. Liu Y., Xun Z., Ma K.,Liang S., Li X., Zhou S., Sun L., Liu Y., Du Y., Guo X., Cui T., Zhou H., Wang J., Yin D., Song R., Zhang S., Cai W., Meng F., Guo H., Zhang B., Yang D., Bao R., Hu Q., Wang J., Ye, Y#., Liu L#. Identification of a tumour immune barrier in the HCC microenvironment that determines the efficacy of immunotherapy. Journal of hepatology S0168-8278(23)00023-5. doi: 10.1016/j.jhep.2023.01.011.

2022

1. Mo J., Tan K., Dong Y., Lu W., Liu F., Mei Y., Huang H., Zhao K., Lv Z.#, Ye Y.#, Tang Y.#. Therapeutic targeting the oncogenic driver EWSR1::FLI1 in Ewing sarcoma through inhibition of the FACT complex. Oncogene(2022) 42(1):11-25.

2. Zhang, C., Wang, H., Yang, X., Fu, Z., Ji, X., Shi, Y., Zhong, J., Hu, W., Ye Y.#, Wang, Z.# & Ni, D#. Oral zero-valent-molybdenum nanodots for inflammatory bowel disease therapy. Science Advances8, 1–12 (2022).

3. Wang G., Xie Z., Su J., Chen M., Du Y., Gao Q., Zhang G., Zhang H., Chen X.#, Liu H.#, Han L.# & Ye Y#. Characterization of immune-related alternative polyadenylation events in cancer immunotherapy. Cancer Research CAN-22-1417 (2022) doi:10.1158/0008-5472.CAN-22-1417.

4. He, Y., Dong, Y., Chen, Y., Zhang, G., Zhang, H., Lei, G., Du, Y., Chen, X.#, Ye, Y#. & Liu, H#. Multi-omics characterization and therapeutic liability of ferroptosis in melanoma. Signal Transduction and Targeted Therapy. 7, (2022).

5. Qi J., Sun H., Zhang Y., Wang Z., Xun Z., Li, Z., Ding X., Bao R., Hong L., Ji W., Fang, F., Li H., Chen L., Zhong J., Zou D., Liu L., Han L., Ginhoux F., Ye, Y.# (lead contact), Su, B.#. Single-cell and spatial analysis reveal interaction of FAP+ fibroblasts and SPP1+ macrophages in colorectal cancer. Nature Communications (2022) 13:1742.

6. Shen M., Du Y.#, Ye Y.# . Tumor-associated macrophages, dendritic cells, and neutrophils: biological roles, crosstalk, and therapeutic relevance. Medical Review 2022;4710:1-22Liu Z.*, Ye Y.# , Liu Y., Liu Y., Chen H., Shen M., Wang Z., Huang S., Han L., Chen Z., He X. RNA helicase DHX37 facilitates liver cancer progression by cooperating with PLRG1 to drive super enhancer-mediated transcription of cyclin D1. Cancer Research (2022)

7. Ye Y.* , Zhang Y. *, Yang N. *, Gao Q. *, Ding X., Kuang X., Bao R., Zhang Z., Sun C., Zhou B., Wang L., Hu Q., Lin C., Gao J., Lou Y., Lin S.H., Diao L., Liu H., Chen X., Mills G.B., Han L. Profiling of immune features to predict immunotherapy efficacy. The Innovation (2022) 3 (1) 100194.

8. Wang F; Zhang Y; Yu X; Teng X-L; Ding R; Hu Z; Wang A; Wang Z; Ye Y.# , Zou Q#. ZFP91 disturbs metabolic fitness and antitumor activity of tumor-infiltrating T cells. Journal of Clinical Investigation (2021) 131.

9. Chen, H., Yao, J., Bao, R., Dong, Y., Zhang, T., Du, Y., Wang, G., Ni, D., Xun, Z., Niu, X., Ye Y.#, Li H#. Cross-talk of four types of RNA modification writers defines tumor microenvironment and pharmacogenomic landscape in colorectal cancer. Molecular Cancer (2021) 20, 1-21.

10. Shen L#, Ye Y#, Sun H#, Su B. ILC3 plasticity in microbiome-mediated tumor progression and immunotherapy. Cancer Cell (2021) 39, 10:1308-1310.

2021

1. Ye Y. *#, Kuang X. *, Xie Z. *, Liang L., Zhang Z., Zhang Y., Ma F., Gao, Q., Chang R., Zhao S., Su J., Li, H., Peng, J., Chen H., Yin M., Peng C., Yang N., Liu J., Liu H.#, Han L.#, Chen X#. Small-molecule MMP2/MMP9 inhibitor SB-3CT modulates tumor immune surveillance by regulating PD-L1. Genome Medicine (2020) 12:83.

2. Ye Y., Jing Y., Li L., Mills G.B., Diao L., Liu H., Han L. Sex-associated molecular differences for cancer immunotherapy. Nature Communications (2020). 11.

3. Chang G. *, Shi L. *, Ye Y. *, Shi H., Zeng L, Tiwary S., Chang G., Huse J.T., Huo L., Ma L., Ma Y., Zeng L., Zhang S., Zhu J., Han L., He C. & Huang S. Genetic and Epigenetic Changes in YTHDF3 Promote Multiple Steps of Breast Cancer Brain Metastasis. Cancer Cell (2020) 38:1-15

4. Ye Y.*, Zhang Z.*, Liu Y., Han L. A multi-omics perspective for quantitative trait loci in precision medicine. Trends in Genetics (2020). 318-336.

5. Hui L.*, Kuang X. *, Liang, L. *,Ye Y. *, Zhang Y, Li J., Ma F., Tao J., Lei G., Zhao S., Su J., Yang N., Peng C., Xu X., Hung.-C., Han., Liu H., Liu J., & Chen X. The beneficial role of Sunitinib in tumor immune surveillance by regulating tumor PD-L1. Advanced Science (2020)6, 1-16.

Before

1. Ye Y.*, Hu Q.*, Chen H., Liang K., Yuan Y., Xiang Y., Ruan H., Zhang Z., Song A., Zhang H., Liu L., Diao L., Lou Y., Zhou B., Wang L., Zhou S., Gao J., Jonasch E., Lin S.H. et al. Characterization of hypoxia-associated molecular features to aid hypoxia-targeted therapy. Nature Metabolism (2019). 1, 431-444. (Featured as Cover Story) (Included in Nature Research Collection on "Nobel Prize in Physiology or Medicine 2019")

2. Hu Q.*, Ye Y.*, Chan L.-C., Li Y., Liang K., Lin A., Egranov S.D., Zhang Y., Xia W., Gong J., Pan Y., Chatterjee S.S., Yao J., Evans K.W., Nguyen T.K., Park P.K., Liu J., Coarfa C., Donepudi S.R. et al. Oncogenic lncRNA downregulates cancer cell antigen presentation and intrinsic tumor suppression. Nature Immunology (2019). 20, 835-851.

3. Xiang Y.*, Ye Y.*, Lou Y., Yang Y., Cai C., Zhang Z., Mills T., Chen N., Kim Y., Ozguc F.M., Diao L., Karmouty-quintana H., Xia Y., Kellems R., Chen Z., Yoo S., Shyu A., Mills G.B. & Han L. Comprehensive characterization of alternative polyadenylation in human cancer. Journal of the National Cancer Institute (2018). 110, 379-389.

4. Ye Y., Xiang Y., Ozguc F.M., Kim Y., Liu C.J., Park P.K., Hu Q., Diao L., Lou Y., Lin C., Guo A.Y., Zhou B., Wang L., Chen Z., Takahashi J.S., Mills G.B., Yoo S.H. & Han L. The Genomic Landscape and Pharmacogenomic Interactions of Clock Genes in Cancer Chronotherapy. Cell Systems (2018). 6, 314-328.E2. (Highlighted by preview from Cell Systems)

5. Xiang Y.*, Ye Y.*, Zhang Z. & Han L. Maximizing the utility of cancer transcriptomic data. Trends Cancer (2018). 4, 823-837.

6. Zhang Z.*, Ye Y.*, Gong J., Ruan H., Liu C., Xiang Y., Cai C., Guo A., Ling J., Diao L., Weinstein J.N. & Han L. Global analysis of tRNA and translation factor expression reveals a dynamic landscape of translational regulation in human cancers. Communications Biology (2018). 1, 234.

7. Ye Y.*, Li M.*, Gu L., Chen X., Shi J., Zhang X. & Jiang C. Chromatin remodeling during in vivo neural stem cells differentiating to neurons in early Drosophila embryos. Cell Death and Differentiation (2017). 24, 409-420.

专著章节(#: 共同通讯)

1. Tan P.#, Ye Y.#, Mao J., He L: Autophagy- and Immune-Related Diseases. In: Cui J Ed. Autophagy Regulation of Innate Immunity, Advances in Experimental Medicine and Biology. 2019.

2. Liu Y., Ye Y., Gong J., Han L: Expression Quantitative Trait Loci (eQTL) Analysis in Cancer. In Walker J Ed. Methods in Molecular Biology ISSN: 1064-3745. 2019.

办公室地址： 上海市重庆南路280号5号楼607室

办公室电话： 021-63846590-776772

实验室地址： 上海市重庆南路280号5号楼607室

实验室电话： 021-63846590-776772

邮           箱： youqiong.ye@shsmu.edu.cn