Yi Fan, MD/PhD

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Description of Research Expertise

Research Interests: Angiogenesis; Myeloid cells; Immunotherapy; Cardiac repair; Radiotherapy.

We investigate how the tissue microenvironment governs disease progression and therapeutic response in cancer and regenerative medicine. Our central objective is to reprogram the microenvironment to suppress tumor growth, potentiate anti-tumor immunity, and promote tissue repair following injury.

Vascular regulation of tissue immunity
The vasculature is increasingly recognized not merely as a conduit for oxygen and nutrient delivery, but as a dynamic regulator of tissue immunity and repair. In cancer, aberrant endothelial states actively drive disease progression through paracrine signaling and direct cellular interactions within specialized vascular niches. We have shown that tumor-associated endothelial cells undergo mesenchymal transformation, a process that promotes pathological vascular remodeling and therapeutic resistance (JCI 2016; Science Translational Medicine 2020) and induces tumor resistance to anti-VEGF therapy (Liu et al., Nature Communications 2018a). Using integrated kinome-, genome-, and metabolome-wide screening platforms, we identified PAK4 and PHGDH as central regulators of endothelial plasticity and vasculature-mediated immune control, defining actionable targets to enhance CAR-T cell efficacy (Nature Cancer 2021; Cell Metabolism 2023). Collectively, this work establishes the conceptual framework for “vascular de-transformation” as a next-generation anti-cancer strategy (Trends in Cancer 2019) and motivates the development of combinatorial vasculoimmunotherapy approaches (Trends in Molecular Medicine 2024).

Tumor immune suppression
The efficacy of T cell–based immunotherapies in solid tumors remains fundamentally constrained by the immunosuppressive tumor microenvironment (TME), which restricts T cell infiltration and effector function. Our work seeks to overcome this barrier by systematically reprogramming TME-resident cell populations, including macrophages, myeloid-derived suppressor cells (MDSCs), dendritic cells, and fibroblasts (Nature Reviews Immunology 2025). We identified IL-6 and osteopontin as key drivers of macrophage-mediated immunosuppression in glioblastoma (Nature Communications 2018b; 2021; Science Advances 2024), delineating a cytokine network that enforces immune evasion. Building on this, we discovered toosendanin as a small-molecule agent capable of reversing macrophage immunosuppression and restoring tumor sensitivity to immunotherapy (Science Translational Medicine 2023). Extending these principles beyond oncology, we are applying immune reprogramming strategies to cardiovascular disease, with the goal of harnessing immune modulation for tissue repair (Circulation 2024).

FLASH radiation
FLASH radiotherapy, characterized by ultra-high dose-rate radiation delivery, represents a paradigm shift in radiation oncology. We are investigating the mechanisms underlying its dual capacity to spare normal tissue while reshaping tumor immunity. Our studies show that FLASH reprograms tumor-associated macrophages through modulation of lipid metabolism, thereby enhancing the efficacy of CAR-T cell therapy in brain tumors (Nature Cancer 2025).

Selected Publications

• Ni H, Reitman ZJ, Zou W, Akhtar MN, Paul R, Huang M, Zhang D, Zheng H, Zhang R, Ma R, Ngo G, Zhang L, Diffenderfer ES, Motlagh SAO, Kim MM, Minn AJ, Dorsey JF, Foster JB, Metz J, Koumenis C, Kirsch DG*, Gong Y*, Fan Y*. : FLASH radiation stimulates proinflammatory macrophage polarization and sensitizes medulloblastoma to CAR-T cell immunotherapy. Nature Cancer : doi.org/10.1038/s43018-025-00905-6, Feb 2025 Notes: *, co-corresponding authors.
• Lamplugh ZL, Wellhausen N, June CH, Fan Y. : Microenvironmental regulation of solid tumour resistance to CAR T cell therapy Nature Review Immunology 2025
• Cleveland AH, Fan Y. : Reprogramming endothelial cells to empower cancer immunotherapy. Trends in Molecular Medcine 30(2) : 126-135., Feb 2024 Notes: Peer reviewed opinion
• Zhang D, Cleveland AH, Krimitza E, Han K, Yi C, Stout AL, Zou W, Dorsey JF, Gong Y*, Fan Y*. : Spatial analysis of tissue immunity and vascularity by light sheet fluorescence microscopy Nature Protocols 19(4) : 1053-1082, Apr 2024 Notes: *Co-senior authors
• Yang F, Akhtar N, Zhang D, El-Mayta R, Shin J, Dorsey JF, Zhang L, Xu X, Guo W, Bagley SJ, Fuchs SY, Koumenis C, Lathia JD, Mitchell MJ, Gong Y*, & Fan Y*. : An immunosuppressive vascular niche drives macrophage polarization and immunotherapy resistance in glioblastoma Science Advances 10(9) : eadj4678, Mar 2024 Notes: *Co-senior authors
• Zhao X, Williamson T, Gong Y*, Epstein J*, Fan Y*. : Immunomodulatory therapy for ischemic heart disease. Circulation 150(13) : 1050-1058, Sept 2024 Notes: *Co-senior author. peer-reviewed opinion.
• Yang F, Zhang D, Jiang H, Ye J, Zhang L, Winkler J, Gong Y, & Fan Y. : Small-molecule reversal of macrophage-mediated immunosuppression overcomes glioblastoma resistance to immunotherapy. Science Translational Medicine 15 : eabq3558, Feb 2023
• Zhang D, Li A, Huang M, Yang F, Zhang L, Wellen KE, Xu X, Conn CS, Zou W, Kahn M, Rhoades SD, Weljie AM, Amankulor N, Yoshor D, Ye J, Koumenis C, Gong Y, & Fan Y. : PHGDH-mediated endothelial metabolism drives glioblastoma resistance to CAR T cell immunotherapy. Cell Metabolism 35 : 1-18, Feb 2023
• Huang M, Yang F, Zhang D, Lin M, Duan H, EI-Mayta R, Zhang L, Qin L, Shewale S, Pei L, Mitchell M, Rader D, Fan Y*, Gong Y*. : : Endothelial plasticity drives aberrant vascularization and impedes cardiac repair after myocardial infarction. Nature Cardiovascular Research 1(4) : 372–388, Apr 2022 Notes: *Co-senior author.
• Ma W, Wang Y, Zhang R, Yang F, Zhang D, Huang M, Zhang L, Dorsey JF, Binder ZA, O’Rourke DM, Fraietta JA, Gong Y*, Fan Y*. : Targeting PAK4 to reprogram vascular microenvironment and improve CAR T immunotherapy for glioblastoma. Nature Cancer 2 : 83–97, February 2021 Notes: *Co-corresponding authors.
• Yang F, He Z, Duan H, Zhang D, Li J, Yang H, Dorsey JF, Zou W, Nabavizadeh SA, Bagley SJ, Abdullah K, Brem S, Zhang L, Xu X, Byrne KT, Vonderheide RH*, Gong Y*, & Fan Y*. : Synergistic immunotherapy of glioblastoma by dual targeting of IL-6 and CD40. Nature Comm. 12(1) : 3424, June 2021 Notes: *Co-corresponding authors.
• Huang M, Zhang D, Wu JY, Xing K, Yeo E, Li C, Zhang L, Holland E, Yao L, Qin L, Binder ZA, O’Rourke DM, Brem S, Koumenis C, Gong Y, and Fan Y. : Wnt-mediated endothelial transformation into mesenchymal stem cell-like cells induces chemoresistance in glioblastoma. Science Transl Medicine 12(532) : eaay7522, Feb 2020
• Fan Y : Vascular Detransformation for Cancer Therapy. Trends in Cancer 5(8) : 460-463, August 2019
• Wang Q, He Z, Huang M, Liu T, Xu H, Ma P, Zhang L, Zamvil SS, Hidalgo J, Zhang Z, O’Rourke DM, Dahmane N, Brem S, Gong Y, & Fan Y : Vascular niche IL-6 induces macrophage M2 polarization in gliomblastoma through HIF-2α. Nature Comm 9(1) : 559, February 2018
• Liu T, Ma W, Xu H, Huang M, Zhang D, He Z, Zhang L, Brem S, O'Rourke DM, Gong Y, Mou Y, Zhang Z, and Fan Y : PDGF-mediated mesenchymal transformation renders endothelial resistance to anti-VEGF treatment in glioblastoma. Nature Comm 9(1) : 3439, August 2018
• Liu T, Xu H, Huang M, Ma W, Saxena D, Lustig RA, Alonso-Basanta M, Zhang Z, O’Rourke DM, Zhang L, Gong Y, Kao GD, Dorsey JF*, & Fan Y* : Circulating glioma cells exhibit stem cell-like properties. Cancer Res 78(23) : 6632-6642, December 2018 Notes: *corresponding authors.
• Wang Y, Xu H, Liu T, Huang M, Butter P, Li C, Zhang L, Kao G, Gong Y, Maity A, Koumenis C, & Fan Y : Temporal DNA-PK activation drives genomic instability and therapy resistance in glioma stem cells. JCI Insight 3(3) : pii98096, February 2018
• Huang M, T Liu, Ma P, Mitteer RA, Zhang Z, Kim HJ, Yeo E, Zhang D, Cai P, Li C, Zhang L, Zhao B, Roccograndi L, O’Rourke DM, Dahmane N, Gong Y, Koumenis C, Fan Y : c-Met-mediated endothelial plasticity drives aberrant vascularization and chemoresistance in glioblastoma. J Clin Invest 126(5) : 1801-14, May 2016