Cullin-g the Brakes on T-cell Persistence

Adoptive T-cell therapies require T cells to sustain cytotoxic function for as long as tumor persists. In this issue, two independent studies converge on a ubiquitin-dependent pathway, centered on the cullin-5 (CUL5)-RING E3 ubiquitin ligase (CRL5) complex, as an intrinsic brake on T-cell function under repetitive antigen stimulation. Genetic disruption of individual CRL5 components preserves cytotoxicity during repeated tumor challenge. Saco and colleagues demonstrate similar benefits with pharmacologic inhibition of CRL5 and related ubiquitin ligase complexes, whereas Bachl and colleagues extend the genetic benefit across multiple antigens and receptor architectures. Targeting this pathway offers a strategy to improve T-cell functional persistence and therapeutic durability. See related article by Bachl et al., p. XXX . See related article by Saco et al., p. XXX .