---
title: "CREBBP loss drives immune evasion in small cell lung cancer via STING and MHC-I silencing"
id: "pubmed-42905834"
canonical_url: "https://medichelpline.com/clinical-feed/pubmed-42905834"
content_type: "clinical_feed_article"
specialty: "Critical Care"
source_name: "PubMed / NCBI"
source_url: "https://pubmed.ncbi.nlm.nih.gov/42905834/"
doi: "10.1126/sciadv.aef1693"
published_at: "2026-10-23T00:00:00.000Z"
evidence_level: "Journal Article"
license: "CC-BY-NC-4.0 / Informational Use"
---
# CREBBP loss drives immune evasion in small cell lung cancer via STING and MHC-I silencing
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/pubmed-42905834
- **Specialty:** [Critical Care](https://medichelpline.com/clinical-feed/critical-care.md)
- **Primary Source:** PubMed / NCBI
- **Source URL:** [Original Journal Publication](https://pubmed.ncbi.nlm.nih.gov/42905834/)
- **DOI:** [10.1126/sciadv.aef1693](https://doi.org/10.1126%2Fsciadv.aef1693)
- **Published At:** 2026-10-23T00:00:00.000Z
- **Evidence Rating:** Journal Article
## Executive GIST (TL;DR)
- Most small cell lung cancers show low immunogenicity and resistance to immunotherapy, a clinical problem the investigators sought to explain. - The study team identified loss of **CREBBP**, a recurrent genetic alteration in SCLC, as a driver of tumor cell–intrinsic immune suppression in mouse models. - In Rb1/Trp53-driven autochthonous models, **Crebbp** deletion produced an immune-cold tumor microenvironment, the cohort showed reduced immune infiltration compared with controls. - Syngeneic tumor models confirmed that **Crebbp** loss promoted immune escape, indicating effects beyond a single model system. - Mechanistic data indicated that **Crebbp** loss reduced histone H3 acetylation, and this epigenetic change suppressed expression of **STING** and **MHC-I** genes in tumor cells. - The authors reported that pharmacologic inhibition of **HDAC** restored histone acetylation and reactivated these silenced immune genes, producing tumor cell–intrinsic immune responses. - Investigators observed that **HDAC** inhibition plus immune checkpoint blockade suppressed tumor growth in both **Crebbp**-mutant and wild-type SCLC models, with a larger effect in **Crebbp**-mutant tumors. - The study team concluded that **CREBBP** loss is a key mechanism of immune evasion and immunotherapy resistance in SCLC and proposed **HDAC** inhibition as a potential strategy to enhance immunotherapy efficacy. - The abstract notes that underlying mechanisms of low SCLC immunogenicity remain poorly understood, leaving open specific mechanistic questions for follow-up work.
## Clinical Analysis & Structured Key Points
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Epub 2026 Oct 21. # CREBBP loss drives immune evasion by epigenetically silencing STING and MHC-I in small cell lung cancer [Qing Gao](https://pubmed.ncbi.nlm.nih.gov/?term=Gao+Q&cauthor_id=42905834)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42905834/#full-view-affiliation-1 "Department of Thoracic Surgery, Institute of Clinical Research, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China."), [Kehong Wei](https://pubmed.ncbi.nlm.nih.gov/?term=Wei+K&cauthor_id=42905834)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42905834/#full-view-affiliation-1 "Department of Thoracic Surgery, Institute of Clinical Research, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China."), [Deshen Pan](https://pubmed.ncbi.nlm.nih.gov/?term=Pan+D&cauthor_id=42905834)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42905834/#full-view-affiliation-1 "Department of Thoracic Surgery, Institute of Clinical Research, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China."), [Chaoliang Xu](https://pubmed.ncbi.nlm.nih.gov/?term=Xu+C&cauthor_id=42905834)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42905834/#full-view-affiliation-1 "Department of Thoracic Surgery, Institute of Clinical Research, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China."), [Yufei Xi](https://pubmed.ncbi.nlm.nih.gov/?term=Xi+Y&cauthor_id=42905834)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42905834/#full-view-affiliation-1 "Department of Thoracic Surgery, Institute of Clinical Research, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China."), [Yan Zhang](https://pubmed.ncbi.nlm.nih.gov/?term=Zhang+Y&cauthor_id=42905834)[ 2 ](https://pubmed.ncbi.nlm.nih.gov/42905834/#full-view-affiliation-2 "Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China.")[ 3 ](https://pubmed.ncbi.nlm.nih.gov/42905834/#full-view-affiliation-3 "Lung Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China."), [Arnaud Augert](https://pubmed.ncbi.nlm.nih.gov/?term=Augert+A&cauthor_id=42905834)[ 4 ](https://pubmed.ncbi.nlm.nih.gov/42905834/#full-view-affiliation-4 "Department of Pathology, Yale School of Medicine, Yale University, New Haven, CT, USA.")[ 5 ](https://pubmed.ncbi.nlm.nih.gov/42905834/#full-view-affiliation-5 "Yale Cancer Center, Yale School of Medicine, Yale University, New Haven, CT, USA."), [David MacPherson](https://pubmed.ncbi.nlm.nih.gov/?term=MacPherson+D&cauthor_id=42905834)[ 6 ](https://pubmed.ncbi.nlm.nih.gov/42905834/#full-view-affiliation-6 "Division of Human Biology, Fred Hutchinson Cancer Center, Seattle, WA, USA."), [Deshui Jia](https://pubmed.ncbi.nlm.nih.gov/?term=Jia+D&cauthor_id=42905834)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42905834/#full-view-affiliation-1 "Department of Thoracic Surgery, Institute of Clinical Research, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.") Affiliations Expand ### Affiliations * 1 Department of Thoracic Surgery, Institute of Clinical Research, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. * 2 Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China. * 3 Lung Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China. * 4 Department of Pathology, Yale School of Medicine, Yale University, New Haven, CT, USA. * 5 Yale Cancer Center, Yale School of Medicine, Yale University, New Haven, CT, USA. * 6 Division of Human Biology, Fred Hutchinson Cancer Center, Seattle, WA, USA. * PMID: **42905834** * DOI: [ 10.1126/sciadv.aef1693 ](https://doi.org/10.1126/sciadv.aef1693) Item in Clipboard # CREBBP loss drives immune evasion by epigenetically silencing STING and MHC-I in small cell lung cancer Qing Gao et al. Sci Adv. 2026. Show details Display options Display options Format Abstract PubMed PMID Sci Adv Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22Sci+Adv%22%5Bjour%5D&sort=date&sort_order=desc) * [ Search in NLM Catalog ](https://www.ncbi.nlm.nih.gov/nlmcatalog?term=%22Sci+Adv%22%5BTitle+Abbreviation%5D) * [ Add to Search ](https://pubmed.ncbi.nlm.nih.gov/42905834/) . 2026 Oct 23;12(43):eaef1693. doi: 10.1126/sciadv.aef1693. Epub 2026 Oct 21. ### Authors [Qing Gao](https://pubmed.ncbi.nlm.nih.gov/?term=Gao+Q&cauthor_id=42905834)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42905834/#short-view-affiliation-1 "Department of Thoracic Surgery, Institute of Clinical Research, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China."), [Kehong Wei](https://pubmed.ncbi.nlm.nih.gov/?term=Wei+K&cauthor_id=42905834)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42905834/#short-view-affiliation-1 "Department of Thoracic Surgery, Institute of Clinical Research, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China."), [Deshen Pan](https://pubmed.ncbi.nlm.nih.gov/?term=Pan+D&cauthor_id=42905834)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42905834/#short-view-affiliation-1 "Department of Thoracic Surgery, Institute of Clinical Research, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China."), [Chaoliang Xu](https://pubmed.ncbi.nlm.nih.gov/?term=Xu+C&cauthor_id=42905834)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42905834/#short-view-affiliation-1 "Department of Thoracic Surgery, Institute of Clinical Research, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China."), [Yufei Xi](https://pubmed.ncbi.nlm.nih.gov/?term=Xi+Y&cauthor_id=42905834)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42905834/#short-view-affiliation-1 "Department of Thoracic Surgery, Institute of Clinical Research, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China."), [Yan Zhang](https://pubmed.ncbi.nlm.nih.gov/?term=Zhang+Y&cauthor_id=42905834)[ 2 ](https://pubmed.ncbi.nlm.nih.gov/42905834/#short-view-affiliation-2 "Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China.")[ 3 ](https://pubmed.ncbi.nlm.nih.gov/42905834/#short-view-affiliation-3 "Lung Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China."), [Arnaud Augert](https://pubmed.ncbi.nlm.nih.gov/?term=Augert+A&cauthor_id=42905834)[ 4 ](https://pubmed.ncbi.nlm.nih.gov/42905834/#short-view-affiliation-4 "Department of Pathology, Yale School of Medicine, Yale University, New Haven, CT, USA.")[ 5 ](https://pubmed.ncbi.nlm.nih.gov/42905834/#short-view-affiliation-5 "Yale Cancer Center, Yale School of Medicine, Yale University, New Haven, CT, USA."), [David MacPherson](https://pubmed.ncbi.nlm.nih.gov/?term=MacPherson+D&cauthor_id=42905834)[ 6 ](https://pubmed.ncbi.nlm.nih.gov/42905834/#short-view-affiliation-6 "Division of Human Biology, Fred Hutchinson Cancer Center, Seattle, WA, USA."), [Deshui Jia](https://pubmed.ncbi.nlm.nih.gov/?term=Jia+D&cauthor_id=42905834)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42905834/#short-view-affiliation-1 "Department of Thoracic Surgery, Institute of Clinical Research, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.") ### Affiliations * 1 Department of Thoracic Surgery, Institute of Clinical Research, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. * 2 Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China. * 3 Lung Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China. * 4 Department of Pathology, Yale School of Medicine, Yale University, New Haven, CT, USA. * 5 Yale Cancer Center, Yale School of Medicine, Yale University, New Haven, CT, USA. * 6 Division of Human Biology, Fred Hutchinson Cancer Center, Seattle, WA, USA. * PMID: **42905834** * DOI: [ 10.1126/sciadv.aef1693 ](https://doi.org/10.1126/sciadv.aef1693) Item in Clipboard Cite Display options Display options Format Abstract PubMed PMID Linked Discoveries ## 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. [PubMed Disclaimer](https://pubmed.ncbi.nlm.nih.gov/disclaimer/) ## MeSH terms * Acetylation Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22Acetylation%22%5BMeSH%5D&sort=date&sort_order=desc) * [ Search in MeSH ](https://www.ncbi.nlm.nih.gov/mesh?term=Acetylation) * [ Add to Search ](https://pubmed.ncbi.nlm.nih.gov/42905834/) * Animals Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22Animals%22%5BMeSH%5D&sort=date&sort_order=desc) * [ Search in MeSH ](https://www.ncbi.nlm.nih.gov/mesh?term=Animals) * [ Add to Search ](https://pubmed.ncbi.nlm.nih.gov/42905834/) * CREB-Binding Protein* / deficiency Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22CREB-Binding+Protein%2Fdeficiency%22%5BMAJR%5D&sort=date&sort_order=desc) * [ Search in MeSH ](https://www.ncbi.nlm.nih.gov/mesh?term=CREB-Binding+Protein) * [ Add to Search ](https://pubmed.ncbi.nlm.nih.gov/42905834/) * CREB-Binding Protein* / genetics Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22CREB-Binding+Protein%2Fgenetics%22%5BMAJR%5D&sort=date&sort_order=desc) * [ Search in MeSH ](https://www.ncbi.nlm.nih.gov/mesh?term=CREB-Binding+Protein) * [ Add to Search ](https://pubmed.ncbi.nlm.nih.gov/42905834/) * CREB-Binding Protein* / metabolism Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22CREB-Binding+Protein%2Fmetabolism%22%5BMAJR%5D&sort=date&sort_order=desc) * [ Search in MeSH ](https://www.ncbi.nlm.nih.gov/mesh?term=CREB-Binding+Protein) * [ Add to Search ](https://pubmed.ncbi.nlm.nih.gov/42905834/) * Cell Line, Tumor Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22Cell+Line%2C+Tumor%22%5BMeSH%5D&sort=date&sort_order=desc) * [ Search in MeSH ](https://www.ncbi.nlm.nih.gov/mesh?term=Cell+Line%2C+Tumor) * [ Add to Search ](https://pubmed.ncbi.nlm.nih.gov/42905834/) * Epigenesis, Genetic* Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22Epigenesis%2C+Genetic%22%5BMAJR%5D&sort=date&sort_order=desc) * [ Search in MeSH ](https://www.ncbi.nlm.nih.gov/mesh?term=Epigenesis%2C+Genetic) * [ Add to Search ](https://pubmed.ncbi.nlm.nih.gov/42905834/) * Gene Expression Regulation, Neoplastic Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22Gene+Expression+Regulation%2C+Neoplastic%22%5BMeSH%5D&sort=date&sort_order=desc) * [ Search in MeSH ](https://www.ncbi.nlm.nih.gov/mesh?term=Gene+Expression+Regulation%2C+Neoplastic) * [ Add to Search ](https://pubmed.ncbi.nlm.nih.gov/42905834/) * Gene Silencing Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22Gene+Silencing%22%5BMeSH%5D&sort=date&sort_order=desc) * [ Search in MeSH ](https://www.ncbi.nlm.nih.gov/mesh?term=Gene+Silencing) * [ Add to Search ](https://pubmed.ncbi.nlm.nih.gov/42905834/) * Histone Deacetylase Inhibitors / pharmacology Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22Histone+Deacetylase+Inhibitors%2Fpharmacology%22%5BMeSH%5D&sort=date&sort_order=desc) * [ Search in MeSH ](https://www.ncbi.nlm.nih.gov/mesh?term=Histone+Deacetylase+Inhibitors) * [ Add to Search ](https://pubmed.ncbi.nlm.nih.gov/42905834/) * Histones / metabolism Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22Histones%2Fmetabolism%22%5BMeSH%5D&sort=date&sort_order=desc) * [ Search in MeSH ](https://www.ncbi.nlm.nih.gov/mesh?term=Histones) * [ Add to Search ](https://pubmed.ncbi.nlm.nih.gov/42905834/) * Humans Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22Humans%22%5BMeSH%5D&sort=date&sort_order=desc) * [ Search in MeSH ](https://www.ncbi.nlm.nih.gov/mesh?term=Humans) * [ Add to Search ](https://pubmed.ncbi.nlm.nih.gov/42905834/) * Immunoediting, Cancer Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22Immunoediting%2C+Cancer%22%5BMeSH%5D&sort=date&sort_order=desc) * [ Search in MeSH ](https://www.ncbi.nlm.nih.gov/mesh?term=Immunoediting%2C+Cancer) * [ Add to Search ](https://pubmed.ncbi.nlm.nih.gov/42905834/) * Lung Neoplasms* / drug therapy Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22Lung+Neoplasms%2Fdrug+therapy%22%5BMAJR%5D&sort=date&sort_order=desc) * [ Search in MeSH ](https://www.ncbi.nlm.nih.gov/mesh?term=Lung+Neoplasms) * [ Add to Search ](https://pubmed.ncbi.nlm.nih.gov/42905834/) * Lung Neoplasms* / genetics Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%2
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