Skip to content
DraconiticResearch
Search Sources API
186,541 studies31 sourcesUpdated 3 min ago
Peer-reviewedCC BY-NCScience Advances

CREBBP loss drives immune evasion by epigenetically silencing STING and MHC-I in small cell lung cancer

  • Qing Gao1
  • Kehong Wei1
  • Deshen Pan1
  • Chaoliang Xu1
  • Yufei Xi1
  • Yan Zhang2,3
  • Arnaud Augert4,5
  • David MacPherson6
  • Deshui Jia1
6 affiliations
  1. 1Department of Thoracic Surgery, Institute of Clinical Research, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  2. 2Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
  3. 3Lung Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
  4. 4Department of Pathology, Yale School of Medicine, Yale University, New Haven, CT, USA.
  5. 5Yale Cancer Center, Yale School of Medicine, Yale University, New Haven, CT, USA.
  6. 6Division of Human Biology, Fred Hutchinson Cancer Center, Seattle, WA, USA.
Read full textPDFDOICite

Abstract

Most small cell lung cancers (SCLCs) exhibit low immunogenicity and intrinsic resistance to immunotherapy, yet the underlying mechanisms remain poorly understood. Here, we identify CREBBP loss, a frequent genetic alteration in SCLC, as a key suppressor of tumor cell-intrinsic immune responses that drives an immune-cold tumor microenvironment in Rb1/Trp53-driven autochthonous mouse models. Consistently, Crebbp deletion promotes immune escape in syngeneic SCLC models. Mechanistically, Crebbp loss suppresses Sting and major histocompatibility complex class-I expression by reducing histone H3 acetylation. Notably, HDAC inhibition restores histone acetylation, reactivates these silenced genes, and induces tumor cell-intrinsic immune responses. Moreover, pharmacological HDAC inhibition synergizes with immune checkpoint blockade to suppress tumor growth in both Crebbp-mutant and Crebbp-wild-type SCLCs, with a more prominent effect in Crebbp-mutant tumors. Collectively, these findings establish CREBBP loss as a key mechanism of immune evasion and immunotherapy resistance in SCLC, highlighting HDAC inhibition as a promising strategy to enhance immunotherapy efficacy.

Related

  1. RhoA Y42C drives cell plasticity and PD-1-mediated immune evasion of diffuse gastric cancer
    Kyung-Pil Ko, Sangmin Kim, Jinho Jang +11
    Nature CommunicationsPeer-reviewedCC BY-NC-ND 4.0Full textOncologyCrossrefEurope PMC
  2. CGRP–RAMP1/CALCRL Signaling Drives TGF-β2-Mediated Immune Evasion and Pancreatic Cancer Progression
    Biyu Zhang, Yaxin Li, Simiao Fan +15
    International Journal of Molecular SciencesPeer-reviewedCC BY 4.0Full textPsychiatry & mental healthCrossrefEurope PMC
  3. An Epigenetically Remodeled EMT–Inflammatory Clone Associated with Spatial Immune Exclusion in Clear Cell Renal Cell Carcinoma
    Rifang Lan, Lixia Weng, Bingbing Cao +5
    International Journal of Molecular SciencesPeer-reviewedCC BY 4.0General medicineCrossref
  4. Fungal Pathogenesis at the Host–Pathogen Interface: Immune Recognition, Evasion, Antifungal Resistance, and Emerging Therapies
    Tropical medicine and infectious diseasePeer-reviewedCC BYFull textGeneral medicineEurope PMC
  5. Editorial: Immunology of human fungal pathogens: host-pathogen interactions, immune evasion, and therapeutic strategies
    Iván Martínez-Duncker, Andrea Regina de Souza Baptista, Héctor M. Mora Montes
    Frontiers in ImmunologyPeer-reviewedCC BY 4.0Full textInfectious diseaseCrossref

Cite

BibTeXRIS
BibTeX
@article{gao2026crebbp,
  title = {{CREBBP loss drives immune evasion by epigenetically silencing STING and MHC-I in small cell lung cancer}},
  author = {Qing Gao and Kehong Wei and Deshen Pan and Chaoliang Xu and Yufei Xi and Yan Zhang and Arnaud Augert and David MacPherson and Deshui Jia},
  journal = {Science Advances},
  year = {2026},
  month = oct,
  doi = {10.1126/sciadv.aef1693},
  url = {https://www.science.org/doi/10.1126/sciadv.aef1693},
  note = {CC BY-NC},
}
RIS
TY  - JOUR
TI  - CREBBP loss drives immune evasion by epigenetically silencing STING and MHC-I in small cell lung cancer
AU  - Qing Gao
AU  - Kehong Wei
AU  - Deshen Pan
AU  - Chaoliang Xu
AU  - Yufei Xi
AU  - Yan Zhang
AU  - Arnaud Augert
AU  - David MacPherson
AU  - Deshui Jia
PY  - 2026
DA  - 2026/10/21
JO  - Science Advances
DO  - 10.1126/sciadv.aef1693
UR  - https://www.science.org/doi/10.1126/sciadv.aef1693
AB  - Most small cell lung cancers (SCLCs) exhibit low immunogenicity and intrinsic resistance to immunotherapy, yet the underlying mechanisms remain poorly understood. Here, we identify CREBBP loss, a frequent genetic alteration in SCLC, as a key suppressor of tumor cell-intrinsic immune responses that drives an immune-cold tumor microenvironment in Rb1/Trp53-driven autochthonous mouse models. Consistently, Crebbp deletion promotes immune escape in syngeneic SCLC models. Mechanistically, Crebbp loss suppresses Sting and major histocompatibility complex class-I expression by reducing histone H3 acetylation. Notably, HDAC inhibition restores histone acetylation, reactivates these silenced genes, and induces tumor cell-intrinsic immune responses. Moreover, pharmacological HDAC inhibition synergizes with immune checkpoint blockade to suppress tumor growth in both Crebbp-mutant and Crebbp-wild-type SCLCs, with a more prominent effect in Crebbp-mutant tumors. Collectively, these findings establish CREBBP loss as a key mechanism of immune evasion and immunotherapy resistance in SCLC, highlighting HDAC inhibition as a promising strategy to enhance immunotherapy efficacy.
SN  - 2375-2548
ER  -