Reshaping tumor immunity by targeting SUMOylation: A novel immunotherapeutic strategy

SUMOylation, a reversible post-translational modification mediated by Small Ubiquitin-like Modifier (SUMO) proteins, is fundamental to regulating transcriptional programs, particularly within the nucleus. Accumulating evidence indicates that SUMOylation is a critical modulator of immune signaling and inflammatory responses, with profound implications for infections, autoimmune disorders, and oncogenesis. In the context of the tumor immune microenvironment(TIME), aberrant SUMOylation activity orchestrates an immunosuppressive landscape by directly altering the function of key transcription factors in both innate and adaptive immune cells. Consequently, pharmacological inhibition of the SUMO pathway, exemplified by the first-in-class inhibitor TAK-981, has emerged as a promising therapeutic strategy. Such inhibitors can reverse immune suppression by enhancing type I interferon signaling, augmenting antigen presentation, and reinvigorating anti-tumor immunity. In this review, we synthesize current understanding of how SUMOylation governs the function and polarization of critical immune cells within the TIME, and explore the therapeutic potential of SUMO-targeting inhibitors in cancer treatment, aiming to provide novel theoretical insights and innovative strategies to advance cancer therapy.