Established cancer treatments are harnessing the SUMO–StUbL system to degrade or inactivate the oncoproteins PML-RARα and estrogen receptor alpha (ERα), which are associated with acute promyelocytic leukemia and breast cancer, respectively. StUbL-based PROTACs and SUMO-targeting chimeras (SUTACs), hold promise to selectively inactivate oncogenic transcription factors to rewire cancer-associated transcriptional programs. Proximity-based drugs which induce SUMOylation and SUMO-primed ubiquitylation through target specific ligase recruitment could act as dual-hit compounds that combine transcriptional repression with targeted degradation of oncoproteins.

In neurodegeneration, redirecting SUMOylation and StUbL activity by recruiting aggregation-prone proteins like TDP-43 to PML nuclear bodies offers a potential strategy to reprogram proteostasis networks to limiting toxic aggregates in ALS, Alzheimer’s disease and related disorders.

While many new insights on StUbL-based therapeutics and SUMO–StUbL signaling have emerged, more work remains to be done regarding the definition of optimal SUMO–StUbL signatures and the identification of specific binders of SUMO-ligases, StUbLs and target proteins as prerequisites for the development of SUTACs and StUbL-based PROTACs.