SUMOylation in cancer: molecular mechanisms and therapeutic implications

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.