ArticleSignal transduction and targeted therapy2024
MEK inhibition prevents CAR-T cell exhaustion and differentiation via downregulation of c-Fos and JunB.
Article in Signal transduction and targeted therapy, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 36 papers.
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Who cites it
36 citing papers in PubMed.
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- BMP4 cocktail promotes utricular progenitor reprogramming and vestibular functional recovery in adult mice.Journal of advanced research · 2026Article
- Linperlisib enhances MUC1-Tn CAR T cell efficacy by inhibiting EGR1/DUSP2 axis to prevent CAR T cell exhaustion.Leukemia · 2026Article
- TGF-β1 drives neutrophil extracellular traps formation to promote CD8Journal for immunotherapy of cancer · 2026Article
- Redifferentiation-enabled TSHRCART cells overcome antigen loss in aggressive thyroid cancers.Molecular cancer · 2026Article
- Implications of Rho GTPase signaling in cancer immunotherapy.Biochemical Society transactions · 2026Review
- Soluble Uric Acid Drives CD8+ T-cell Exhaustion by Inducing KSR1-Mediated MAPK Hyperactivation.Cancer research · 2026Article
- Mechanobiology of CAR-T cell therapy: regulatory mechanisms and strategies for enhanced antitumor immunity.Journal of translational medicine · 2026Review
- Ginkgolide A enhances cardiomyocyte differentiation from pluripotent stem cells by targeting cytochrome c to attenuate intrinsic apoptosis.The Journal of biological chemistry · 2026Article
- T Cell Exhaustion in Cancer Immunotherapy: Heterogeneity, Mechanisms, and Therapeutic Opportunities.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Review
- Enhancing persistence while managing cytokine release syndrome to embrace next-generation CAR-T cell therapy.Journal of translational medicine · 2026Review
- KLF4 overexpression in CAR T cells enhances antitumor potency by preventing exhaustion.Journal for immunotherapy of cancer · 2026Article
- Engineered dCas12f1-SAM enables robust transcriptional activation and gain-of-function screening in primary human cells.Nature communications · 2026Article
- Combining Small-Molecular Compounds With CAR T-Cell Therapy: Novel Strategies for Enhanced Cancer Immunotherapy.Cancer innovation · 2026Review
- DUSP6 ablation restores CAR T-cell fitness impaired by tumor CD58 loss through invigoration of AP-1 signaling.Signal transduction and targeted therapy · 2026Article
- M2-like GAMs secreting CSTA drive glioblastoma progression via the ITGB4-TGFB1 feedback axis.Journal of translational medicine · 2026Article
- A fungi-derived cyclic peptide enhances Th9-mediated antitumor immunity by targeting ZAP70 and SREBP1.The Journal of clinical investigation · 2026Article
- SLC46A1 deficiency-mediated folate restriction suppresses colorectal cancer progression through epigenetic-transcriptional reprogramming.Cell death & disease · 2026Article
- Decoding signaling architectures: CAR versus TCR dynamics in solid tumor immunotherapy.Acta biochimica et biophysica Sinica · 2026Review
Corrections and comments
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Authors and funding
28 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Clinical evidence supports the notion that T cell exhaustion and terminal differentiation pose challenges to the persistence and effectiveness of chimeric antigen receptor-T (CAR-T) cells. MEK1/2 inhibitors (MEKIs), widely used in cancer treatment due to their ability to inhibit aberrant MAPK signaling, have shown potential synergistic effects when combined with immunotherapy. However, the impact and mechanisms of MEKIs on CAR-T cells remain uncertain and controversial. To address this, we conducted a comprehensive investigation to determine whether MEKIs enhance or impair the efficacy of CAR-T cells. Our findings revealed that MEKIs attenuated CAR-T cell exhaustion and terminal differentiation induced by tonic signaling and antigen stimulation, thereby improving CAR-T cell efficacy against hematological and solid tumors. Remarkably, these effects were independent of the specific scFvs and costimulatory domains utilized in CARs. Mechanistically, analysis of bulk and single-cell transcriptional profiles demonstrates that the effect of MEK inhibition was related to diminish anabolic metabolism and downregulation of c-Fos and JunB. Additionally, the overexpression of c-Fos or JunB in CAR-T cells counteracted the effects of MEK inhibition. Furthermore, our Cut-and-Tag assay revealed that MEK inhibition downregulated the JunB-driven gene profiles associated with exhaustion, differentiation, anergy, glycolysis, and apoptosis. In summary, our research unveil the critical role of the MAPK-c-Fos-JunB axis in driving CAR-T cell exhaustion and terminal differentiation. These mechanistic insights significantly broaden the potential application of MEKIs to enhance the effectiveness of CAR-T therapy.
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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 Socratic graph.