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<p>Small Ubiquitin-like Modifier modification (SUMOylation), a critical post-translational modification, plays a dual role in cancer by regulating both tumor cell-intrinsic properties and the tumor immune microenvironment (TIME). Based on a synthesis of direct mechanistic, functional/preclinical, and correlative evidence, it promotes immune evasion through multiple mechanisms: suppressing antigen presentation, limiting immunopeptidome diversity, regulating immune checkpoint molecules (with direct evidence for PD-L1 and TIGIT, while support for other checkpoints remains indirect), and modulating immune cell differentiation and function. Pharmacological inhibition of SUMOylation (e.g., TAK-981, ML792) reverses these immunosuppressive effects by restoring antigen presentation, activating type I interferon responses, enhancing CD8 + T cell cytotoxicity, and reducing regulatory T cells. Notably, while prospective validation is still lacking, SUMOylation-related gene signatures hold promise as prognostic markers and correlative candidate indicators of immunotherapy response. Furthermore, preclinical models demonstrate that SUMOylation inhibitors synergize with immune checkpoint blockade to enhance anti-tumor efficacy, although this synergistic effect has not yet been validated in clinical settings. This review consolidates current knowledge on the immunologic and translational dimensions of SUMOylation—from molecular mechanisms to therapeutic implications—into a single narrative focused on how SUMOylation shapes the TIME and its implications for cancer immunotherapy.</p>

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SUMOylation in cancer: molecular mechanisms and therapeutic implications

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年5月25日

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  • Yu Ding,
  • Fei Li,
  • Jia-Mei Wang

摘要

Small Ubiquitin-like Modifier modification (SUMOylation), a critical post-translational modification, plays a dual role in cancer by regulating both tumor cell-intrinsic properties and the tumor immune microenvironment (TIME). Based on a synthesis of direct mechanistic, functional/preclinical, and correlative evidence, it promotes immune evasion through multiple mechanisms: suppressing antigen presentation, limiting immunopeptidome diversity, regulating immune checkpoint molecules (with direct evidence for PD-L1 and TIGIT, while support for other checkpoints remains indirect), and modulating immune cell differentiation and function. Pharmacological inhibition of SUMOylation (e.g., TAK-981, ML792) reverses these immunosuppressive effects by restoring antigen presentation, activating type I interferon responses, enhancing CD8 + T cell cytotoxicity, and reducing regulatory T cells. Notably, while prospective validation is still lacking, SUMOylation-related gene signatures hold promise as prognostic markers and correlative candidate indicators of immunotherapy response. Furthermore, preclinical models demonstrate that SUMOylation inhibitors synergize with immune checkpoint blockade to enhance anti-tumor efficacy, although this synergistic effect has not yet been validated in clinical settings. This review consolidates current knowledge on the immunologic and translational dimensions of SUMOylation—from molecular mechanisms to therapeutic implications—into a single narrative focused on how SUMOylation shapes the TIME and its implications for cancer immunotherapy.