ArticleCellular & molecular immunology2024
4-1BB-encoding CAR causes cell death via sequestration of the ubiquitin-modifying enzyme A20.
Article in Cellular & molecular immunology, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed.
- Preclinical advances and mechanistic insights of CAR-T therapy for acute myeloid leukemia: from target iteration to microenvironment regulation.Annals of medicine · 2026Review
- The ubiquitin-editing enzyme A20 (TNFAIP3): mechanisms of activation, biological function, diseases and therapeutic targets.Molecular biomedicine · 2026Review
- Enhancing persistence while managing cytokine release syndrome to embrace next-generation CAR-T cell therapy.Journal of translational medicine · 2026Review
- The race between 4-1BB- and CD28-based CD19 CAR-T products in the therapy of B-cell malignancies.Biochimica et biophysica acta. Reviews on cancer · 2026Review
- Decoding signaling architectures: CAR versus TCR dynamics in solid tumor immunotherapy.Acta biochimica et biophysica Sinica · 2026Review
- Enhancement of CAR-T cell efficacy and persistence via CD30 costimulation and NF-κB signaling.Molecular cancer · 2025Article
- Base-editing a single missense mutation in A20 enhances CAR-T cell efficacy.bioRxiv : the preprint server for biology · 2025Article
- Necroptosis in cancer: insight from epigenetic, post-transcriptional and post-translational modifications.Journal of hematology & oncology · 2025Review
- The landscape of CAR-engineered innate immune cells for cancer immunotherapy.Nature cancer · 2025Review
- Optimization of lentiviral delivery of barcoded anti-CD20 chimeric antigen receptors into rhesus macaque and human natural killer cells.Molecular therapy. Methods & clinical development · 2025Article
- Immunomodulatory Effects of Curcumin on CAR T-Cell Therapy.Antioxidants (Basel, Switzerland) · 2025Article
- The Role of Post-Translational Modifications in Necroptosis.Biomolecules · 2025Review
- CAR-γδ T cells: a new paradigm of programmable innate immune sentinels and their systemic applications in cancer and beyond.Frontiers in immunology · 2025Review
- Revolution in Cell Therapy: In Vivo Chimeric-Antigen-Receptor-T-Cell Therapy Breakthroughs and Promises for the Future.Research (Washington, D.C.) · 2025Review
- From innate-like to innate: the next wave of off-the-shelf CAR immunotherapies.Frontiers in immunology · 2025Review
- The Impact of the Intracellular Domains of Chimeric Antigenic Receptors on the Properties of CAR T-cells.Acta naturaeArticle
Corrections and comments
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Authors and funding
14 authors.
Funding
Abstract
CD28 and 4-1BB costimulatory endodomains included in chimeric antigen receptor (CAR) molecules play a critical role in promoting sustained antitumor activity of CAR-T cells. However, the molecular events associated with the ectopic and constitutive display of either CD28 or 4-1BB in CAR-T cells have been only partially explored. In the current study, we demonstrated that 4-1BB incorporated within the CAR leads to cell cluster formation and cell death in the forms of both apoptosis and necroptosis in the absence of CAR tonic signaling. Mechanistic studies illustrate that 4-1BB sequesters A20 to the cell membrane in a TRAF-dependent manner causing A20 functional deficiency that in turn leads to NF-κB hyperactivity, cell aggregation via ICAM-1 overexpression, and cell death including necroptosis via RIPK1/RIPK3/MLKL pathway. Genetic modulations obtained by either overexpressing A20 or releasing A20 from 4-1BB by deleting the TRAF-binding motifs of 4-1BB rescue cell cluster formation and cell death and enhance the antitumor ability of 4-1BB-costimulated CAR-T cells.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.