ArticleCancer discovery2022
Enhancing PD-L1 Degradation by ITCH during MAPK Inhibitor Therapy Suppresses Acquired Resistance.
Article in Cancer discovery, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers, 1 of them a synthesis that pooled it.
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
22 citing papers in PubMed, 1 synthesis or guideline pooled it, 38 citations in OpenAlex.
- Correlation between PD-L1 expression and clinical pathology, immunobiological markers, and prognosis in gastroenteropancreatic neuroendocrine neoplasms: a systematic review and meta-analysis.Frontiers in immunology · 2026Pooled it
- Cancer immunoediting in the melanoma tumor microenvironment: from immune elimination to therapeutic resistance.Frontiers in immunology · 2026Review
- PARG inhibition suppresses breast cancer progression and potentiates immunoresponse through MTDH degradation mediated by E3 ligase ITCH-dependent ubiquitination.NPJ breast cancer · 2025Article
- Molecular mechanisms and potential targeting strategies of ubiquitin‑proteasome system‑mediated PD‑1/PD‑L1 ubiquitination in tumor immune suppression (Review).Oncology reports · 2025Review
- Biochemical analysis of PD-L1 ubiquitination by CRL3Structure (London, England : 1993) · 2025Article
- E3 ligase TRIM22 promotes melanoma proliferation by regulating cell cycle progression through K63-linked ubiquitination of p21.Scientific reports · 2025Article
- Polymorphic tandem repeats influence cell type-specific gene expression across the human immune landscape.bioRxiv : the preprint server for biology · 2025Article
- Gene Signature-Based Drug Screening Reveals Ponatinib Enhances Immunotherapy Efficacy in Triple-Negative Breast Cancer by Reversing MDSC-Mediated Immunosuppressive Tumor Microenvironment.Research (Washington, D.C.) · 2025Article
- LKB1 dictates sensitivity to immunotherapy through Skp2-mediated ubiquitination of PD-L1 protein in non-small cell lung cancer.Journal for immunotherapy of cancer · 2024Article
- Syndecan-1 inhibition promotes antitumor immune response and facilitates the efficacy of anti-PD1 checkpoint immunotherapy.Science advances · 2024Article
- Posttranslational regulatory mechanism of PD-L1 in cancers and associated opportunities for novel small-molecule therapeutics.Acta biochimica et biophysica Sinica · 2024Review
- The evolving treatment landscape for BRAF-mutated non-small cell lung cancer.Translational lung cancer research · 2024Article
- Beyond inhibition against the PD-1/PD-L1 pathway: development of PD-L1 inhibitors targeting internalization and degradation of PD-L1.RSC medicinal chemistry · 2024Review
- N6-methyladenosine-modified circSLCO1B3 promotes intrahepatic cholangiocarcinoma progression via regulating HOXC8 and PD-L1.Journal of experimental & clinical cancer research : CR · 2024Article
- Challenges Coexist with Opportunities: Spatial Heterogeneity Expression of PD-L1 in Cancer Therapy.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2024Review
- Current knowledge about immunotherapy resistance for melanoma and potential predictive and prognostic biomarkers.Cancer drug resistance (Alhambra, Calif.) · 2024Review
- Inhibition of CK2/ING4 Pathway Facilitates Non-Small Cell Lung Cancer Immunotherapy.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2023Article
- PD-L1 translocation to the plasma membrane enables tumor immune evasion through MIB2 ubiquitination.The Journal of clinical investigation · 2023Article
- Identification of novel urine proteomic biomarkers for high stamina in high-altitude adaptation.Frontiers in physiology · 2023Article
- Role of regulation of PD-1 and PD-L1 expression in sepsis.Frontiers in immunology · 2023Review
Corrections and comments
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Authors and funding
9 authors at 1 institution in 1 country.
Funding
Abstract
MAPK inhibitor (MAPKi) therapy in melanoma leads to the accumulation of tumor-surface PD-L1/L2, which may evade antitumor immunity and accelerate acquired resistance. Here, we discover that the E3 ligase ITCH binds, ubiquitinates, and downregulates tumor-surface PD-L1/L2 in MAPKi-treated human melanoma cells, thereby promoting T-cell activation. During MAPKi therapy in vivo, melanoma cell-intrinsic ITCH knockdown induced tumor-surface PD-L1, reduced intratumoral cytolytic CD8+ T cells, and accelerated acquired resistance only in immune-competent mice. Conversely, tumor cell-intrinsic ITCH overexpression reduced MAPKi-elicited PD-L1 accumulation, augmented intratumoral cytolytic CD8+ T cells, and suppressed acquired resistance in BrafV600MUT, NrasMUT, or Nf1MUT melanoma and KrasMUT-driven cancers. CD8+ T-cell depletion and tumor cell-intrinsic PD-L1 overexpression nullified the phenotype of ITCH overexpression, thereby supporting an in vivo ITCH-PD-L1-T-cell regulatory axis. Moreover, we identify a small-molecular ITCH activator that suppresses acquired MAPKi resistance in vivo. Thus, MAPKi-induced PD-L1 accelerates resistance, and a PD-L1-degrading ITCH activator prolongs antitumor response. SIGNIFICANCE: MAPKi induces tumor cell-surface PD-L1 accumulation, which promotes immune evasion and therapy resistance. ITCH degrades PD-L1, optimizing antitumor T-cell immunity. We propose degrading tumor cell-surface PD-L1 and/or activating tumor-intrinsic ITCH as strategies to overcome MAPKi resistance. This article is highlighted in the In This Issue feature, p. 1825.
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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.