Boosting CAR T-cell efficacy by blocking proteasomal degradation of membrane antigens.

ABSTRACT:

Abstract

Chimeric antigen receptor (CAR) T cells exhibit high response rates in B-cell malignancies, but most patients eventually relapse. A key mechanism of treatment failure is the loss or downregulation of tumor antigen expression, yet strategies to modulate cell surface levels of CAR T-cell targets remain largely unexplored. Here, we identify B-cell maturation antigen (BCMA), a central CAR T-cell target in multiple myeloma (MM), as a highly short-lived protein that undergoes K48-linked polyubiquitylation at the plasma membrane, leading to its p97-dependent degradation via the ubiquitin-proteasome system (UPS). This previously unprecedented mechanism of plasma membrane protein regulation enables significant enhancement of BCMA expression via proteasome inhibitors (PIs). The clin

SUBMITTER: Rieger L 

PROVIDER: S-EPMC12883852 | biostudies-literature | 2026 Jan

REPOSITORIES: biostudies-literature