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<p>UFMylation, a recently identified ubiquitin-like modification, is essential for cellular stress homeostasis, particularly endoplasmic reticulum (ER) stress regulation. However, its biological and therapeutic exploration has been hindered by the absence of potent small-molecule inhibitors. Here, we report the first discovery of two compounds targeting the UFMylation E3 ligase complex core protein DDRGK1: Osimertinib, originally designed as an EGFR T790M selective inhibitor, acting through a previously unrecognized covalent mechanism, and CP-24, a novel non-covalent inhibitor. Both compounds disrupt the DDRGK1-UFL1 interaction, globally suppress UFMylation, inhibit ER-phagy, and induce ER stress. In glioblastoma (GBM), pharmacological UFMylation inhibition markedly reduces tumor cell viability and sensitizes cells to Temozolomide and radiotherapy. Both compounds also exert strong immunomodulatory activity, promoting macrophage polarization toward an anti-tumor M1 state. In vivo, Osimertinib, benefiting from superior pharmacokinetics, significantly suppresses tumor growth in immunodeficient models and achieves tumor-free outcomes in 65% of immunocompetent mice. These tumor-free mice develop durable anti-GBM immune memory, rapidly clearing tumors upon rechallenge, an outcome unattainable by previous GBM treatments. Mechanistically, Osimertinib enhances anti-tumor immunity by promoting macrophage M1 polarization, T cell expansion, and reducing PD-1 protein levels. Collectively, our study introduces Osimertinib and CP-24 as valuable chemical probes for dissecting UFMylation biology and highlights Osimertinib’s potential for off-label use in EGFR-wildtype GBM. More broadly, we establish UFMylation inhibition as a dual-targeting therapeutic strategy that disrupts tumor survival pathways and reprograms the immune microenvironment, offering a promising avenue for durable GBM control.</p>

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Dual-targeting pharmacological UFMylation inhibition reprograms tumor and immune microenvironments to achieve long-term glioblastoma regression

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月20日

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  • Pengcheng Tan,
  • Zhimin Liu,
  • Xiaodan Hu,
  • Yuxia Zhang,
  • Hedi Chen,
  • Baoliang Lan,
  • Tianhua Ma,
  • Sheng Ding

摘要

UFMylation, a recently identified ubiquitin-like modification, is essential for cellular stress homeostasis, particularly endoplasmic reticulum (ER) stress regulation. However, its biological and therapeutic exploration has been hindered by the absence of potent small-molecule inhibitors. Here, we report the first discovery of two compounds targeting the UFMylation E3 ligase complex core protein DDRGK1: Osimertinib, originally designed as an EGFR T790M selective inhibitor, acting through a previously unrecognized covalent mechanism, and CP-24, a novel non-covalent inhibitor. Both compounds disrupt the DDRGK1-UFL1 interaction, globally suppress UFMylation, inhibit ER-phagy, and induce ER stress. In glioblastoma (GBM), pharmacological UFMylation inhibition markedly reduces tumor cell viability and sensitizes cells to Temozolomide and radiotherapy. Both compounds also exert strong immunomodulatory activity, promoting macrophage polarization toward an anti-tumor M1 state. In vivo, Osimertinib, benefiting from superior pharmacokinetics, significantly suppresses tumor growth in immunodeficient models and achieves tumor-free outcomes in 65% of immunocompetent mice. These tumor-free mice develop durable anti-GBM immune memory, rapidly clearing tumors upon rechallenge, an outcome unattainable by previous GBM treatments. Mechanistically, Osimertinib enhances anti-tumor immunity by promoting macrophage M1 polarization, T cell expansion, and reducing PD-1 protein levels. Collectively, our study introduces Osimertinib and CP-24 as valuable chemical probes for dissecting UFMylation biology and highlights Osimertinib’s potential for off-label use in EGFR-wildtype GBM. More broadly, we establish UFMylation inhibition as a dual-targeting therapeutic strategy that disrupts tumor survival pathways and reprograms the immune microenvironment, offering a promising avenue for durable GBM control.