A new immuno-oncology target – SUMOylation

Chen, Yuan

doi:10.1016/j.trecan.2023.04.010

Cited by 10 publications

(4 citation statements)

References 15 publications

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“…1 H, J, Figure S7). SUMOylation has been reported to down-regulate the IFN-1 signaling [ 30 ]. ELISA testing of IFN-1 in tumor tissue also revealed impaired IFN-1 secretion following iRFA treatment (Figure S8).…”

Section: Results Smentioning

confidence: 99%

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Targeting SUMOylation with an injectable nanocomposite hydrogel to optimize radiofrequency ablation therapy for hepatocellular carcinoma

Liu,

Li,

Chen

et al. 2024

J Nanobiotechnol

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Background Incomplete radiofrequency ablation (iRFA) in hepatocellular carcinoma (HCC) often leads to local recurrence and distant metastasis of the residual tumor. This is closely linked to the development of a tumor immunosuppressive environment (TIME). In this study, underlying mechanisms and potential therapeutic targets involved in the formation of TIME in residual tumors following iRFA were explored. Then, TAK-981-loaded nanocomposite hydrogel was constructed, and its therapeutic effects on residual tumors were investigated. Results This study reveals that the upregulation of small ubiquitin-like modifier 2 (Sumo2) and activated SUMOylation is intricately tied to immunosuppression in residual tumors post-iRFA. Both knockdown of Sumo2 and inhibiting SUMOylation with TAK-981 activate IFN-1 signaling in HCC cells, thereby promoting dendritic cell maturation. Herein, we propose an injectable PDLLA-PEG-PDLLA (PLEL) nanocomposite hydrogel which incorporates self-assembled TAK-981 and BSA nanoparticles for complementary localized treatment of residual tumor after iRFA. The sustained release of TAK-981 from this hydrogel curbs the expansion of residual tumors and notably stimulates the dendritic cell and cytotoxic lymphocyte-mediated antitumor immune response in residual tumors while maintaining biosafety. Furthermore, the treatment with TAK-981 nanocomposite hydrogel resulted in a widespread elevation in PD-L1 levels. Combining TAK-981 nanocomposite hydrogel with PD-L1 blockade therapy synergistically eradicates residual tumors and suppresses distant tumors. Conclusions These findings underscore the potential of the TAK-981-based strategy as an effective therapy to enhance RFA therapy for HCC. Graphic Abstract

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Section: Results Smentioning

confidence: 99%

“…SUMOylation has previously been identified as suppressing the IFN-1 signal by modifying several targets within the cell [ 30 ]. In this study, we further investigated if knocking down Sumo2 and inhibiting SUMOylation could stimulate the IFN-1 signal in HCC cells.…”

Section: Results Smentioning

confidence: 99%

Targeting SUMOylation with an injectable nanocomposite hydrogel to optimize radiofrequency ablation therapy for hepatocellular carcinoma

Liu,

Li,

Chen

et al. 2024

J Nanobiotechnol

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“…Nonetheless, parallel analysis with thiolutin treatment can serve as an effective control for confirming that any effects of 1,10-phenanthroline are specific to inhibition of sumoylation, since thiolutin also impairs transcription but has no effect on SUMO conjugation levels. Sumoylation has recently been identified as a promising target for cancer immunotherapy because inhibiting sumoylation potentiates antitumour immunity (Chen, 2023 ; Gabellier et al, 2023 ). As such, it may be worthwhile to further explore the mechanisms and efficacy of SUMO inhibition in human cells by 1,10-phenanthroline and related compounds.…”

Section: Resultsmentioning

confidence: 99%

1,10-phenanthroline inhibits sumoylation and reveals that yeast SUMO modifications are highly transient

McNeil,

Lee,

Oliinyk

et al. 2024

EMBO Rep

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The steady-state levels of protein sumoylation depend on relative rates of conjugation and desumoylation. Whether SUMO modifications are generally long-lasting or short-lived is unknown. Here we show that treating budding yeast cultures with 1,10-phenanthroline abolishes most SUMO conjugations within one minute, without impacting ubiquitination, an analogous post-translational modification. 1,10-phenanthroline inhibits the formation of the E1~SUMO thioester intermediate, demonstrating that it targets the first step in the sumoylation pathway. SUMO conjugations are retained after treatment with 1,10-phenanthroline in yeast that express a defective form of the desumoylase Ulp1, indicating that Ulp1 is responsible for eliminating existing SUMO modifications almost instantly when de novo sumoylation is inhibited. This reveals that SUMO modifications are normally extremely transient because of continuous desumoylation by Ulp1. Supporting our findings, we demonstrate that sumoylation of two specific targets, Sko1 and Tfg1, virtually disappears within one minute of impairing de novo sumoylation. Altogether, we have identified an extremely rapid and potent inhibitor of sumoylation, and our work reveals that SUMO modifications are remarkably short-lived.

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“…The function of the SUMO pathway as a means of modulating the immune response makes it a potentially potent method of augmenting other immunotherapeutic treatment strategies ( Chen, 2023 ). Methods such as CAR-T cells and cancer vaccines that have represented advances in the management of other cancers are thought to have faltered against glial malignancies due to the “cold” immunologic microenvironment and relative dearth of neoepitopes for activation of anti-tumoral immunity ( Bagley et al, 2018 ; Maggs et al, 2021 ).…”

Section: Opportunities For Sumo-augmented Oncolytic Viral Immunothera...mentioning

confidence: 99%

Positioning SUMO as an immunological facilitator of oncolytic viruses for high-grade glioma

Karandikar,

Suh,

Gerstl

et al. 2023

Front. Cell Dev. Biol.

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Oncolytic viral (OV) therapies are promising novel treatment modalities for cancers refractory to conventional treatment, such as glioblastoma, within the central nervous system (CNS). Although OVs have received regulatory approval for use in the CNS, efficacy is hampered by obstacles related to delivery, under-/over-active immune responses, and the “immune-cold” nature of most CNS malignancies. SUMO, the Small Ubiquitin-like Modifier, is a family of proteins that serve as a high-level regulator of a large variety of key physiologic processes including the host immune response. The SUMO pathway has also been implicated in the pathogenesis of both wild-type viruses and CNS malignancies. As such, the intersection of OV biology with the SUMO pathway makes SUMOtherapeutics particularly interesting as adjuvant therapies for the enhancement of OV efficacy alone and in concert with other immunotherapeutic agents. Accordingly, the authors herein provide: 1) an overview of the SUMO pathway and its role in CNS malignancies; 2) describe the current state of CNS-targeted OVs; and 3) describe the interplay between the SUMO pathway and the viral lifecycle and host immune response.

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A new immuno-oncology target – SUMOylation

Cited by 10 publications

References 15 publications

Targeting SUMOylation with an injectable nanocomposite hydrogel to optimize radiofrequency ablation therapy for hepatocellular carcinoma

Targeting SUMOylation with an injectable nanocomposite hydrogel to optimize radiofrequency ablation therapy for hepatocellular carcinoma

1,10-phenanthroline inhibits sumoylation and reveals that yeast SUMO modifications are highly transient

Positioning SUMO as an immunological facilitator of oncolytic viruses for high-grade glioma

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