Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

In vivo CRISPR screens identify dual functions of DNMT3A in mediating tumor immune evasion

ABSTRACT: Cancer immunotherapy has achieved remarkable clinical efficacy across multiple cancers, but it remains ineffective for most patients and the resistance mechanisms remain elusive. Epigenetic regulators play pivotal roles in both tumorigenesis and the modulation of antitumor immunity. Here, we performed in vivo CRISPR-Cas9 screens targeting epigenetic regulators and identified DNMT3A as a key driver of tumor immune evasion, exerting its effects through both methyltransferase activity-dependent and -independent mechanisms. Mechanistically, DNMT3A repressed the expression of TNFRSF1A and TNFRSF1B in a methyltransferase activity-dependent manner, enabling tumor cells to evade TNFα-induced killing. Importantly, DNMT3A exerted an additional noncanonical function by interacting with NFYA to activate cholesterol biosynthesis-related genes. This led to the accumulation of zymosterol in the tumor interstitial fluid, which directly impaired SREBP2 cleavage and enhanced HMGCR degradation in CD8⁺ T cells. Consequently, zymosterol-mediated suppression of cholesterol biosynthesis in CD8⁺ T cells compromised their activation and antitumor effector functions. Targeting DNMT3A’s multifaceted functions with antisense oligonucleotides (ASOs) effectively overcame resistance to immune checkpoint blockade (ICB) therapy. Collectively, our findings uncover a dual role of DNMT3A in tumor immune evasion and establish it as an integrated epigenetic and metabolic checkpoint, thus providing a potential target for immunotherapy.

ORGANISM(S): Mus musculus

PROVIDER: GSE338899 | GEO | 2026/07/31

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

tRNA m1A modification regulates cholesterol biosynthesis to promote antitumor immunity of CD8+ T cells

Project description:Activation of CD8+ T cells necessitates rapid metabolic reprogramming to fulfill the substantial biosynthetic demands of their effector functions. However, the post-transcriptional mechanisms underpinning this process remain obscure. The tRNA N1-methyladenine (m1A) modification, which plays a role in maintaining tRNA stability and modulating protein translation, has an undefined physiological function in CD8+ T cells, particularly in antitumor responses. Here, we demonstrate that the tRNA m1A 'writer' gene Trmt61a enhances the tumor-killing capacity of CD8+ T cells by regulating cholesterol biosynthesis. We find that Trmt61a expression in CD8+ T cells is upregulated upon activation and correlates positively with T cell-mediated cytotoxicity within the tumor microenvironment of colorectal cancer (CRC) patients. Deletion of Trmt61a in CD8+ T cells leads to a compromised tumor-killing function in both in vivo and in vitro assays, which is dependent on the m1A catalytic activity of TRMT61A. Mechanistically, tRNA m1A promotes antitumor immunity in CD8+ T cells by enhancing the translation of ATP citrate lyase (ACLY), a key enzyme for cholesterol biosynthesis. Supplementation with cholesterol can rescue the impaired tumor-killing function and proliferation of TRMT61A-deficient CD8+ T cells. Our findings underscore the significance of tRNA m1A modification as a regulatory checkpoint in cholesterol metabolism in CD8+ T cells, suggesting potential novel strategies for cancer immunotherapy.

2025-01-07 | GSE275602 | GEO

Tumor-secreted FGF21 acts as an immune suppressor by rewiring cholesterol metabolism of CD8+ T cells

Project description:Tumors use various strategies for immune evasion. Understanding the mechanisms by which tumors suppress anti-tumor immunity facilitates the development of immunotherapies. Here we have identified tumor-secreted fibroblast growth factor 21 (FGF21) as an essential immune suppressor. We show that FGF21 is upregulated in multiple types of tumors and promotes tumor progression. FGF21 significantly disrupts CD8+T anti-tumor immune response by rewiring cholesterol metabolism of CD8+ T cells. We further reveal that FGF21 activates AKT-mTORC1- sterolregulatoryelementbindingprotein 1 (SREBP1) signal axis to enhance cholesterol biosynthesis in CD8+T cells. FGF21 knockdown or blockade of FGF21 by a neutralizing antibody attenuates AKT-mTORC1 signaling and subsequently decreases cholesterol content in CD8+T cells, thus restoring CD8+T cytotoxic function and robustly suppressing tumor growth. Our findings uncover FGF21 as a “secreted immune checkpoint” to restrict anti-tumor immunity and suggest its inhibition is a useful strategy for improving the efficacy of cancer immunotherapy.

2024-06-29 | GSE236180 | GEO

Ceramide Disrupts TM9SF2-PGK1 Axis to Redirect PD-L1 Trafficking and Enhance Antitumor Immunity

Project description:<p>The PD-1/PD-L1 axis represents a cornerstone of cancer immunotherapy, yet the dynamic shuttling of PD-L1 between endosomal recycling and lysosomal degradation routes limits durable responses. Using a CRISPR screen targeting glycosphingolipid metabolism, we identify TM9SF2 as a key regulator of PD-L1 levels. TM9SF2 orchestrates a dual mechanism: it recruits PGK1 to promote PD-L1 recycling to the plasma membrane while dismantling the HIP1R-mediated lysosomal degradation pathway. Genetic or pharmacological disruption of the TM9SF2-PGK1 complex depletes PD-L1 levels and boosts antitumor immunity. Further, the endogenous ceramide species Cer(d18:1/26:0) destabilizes this complex, triggering PD-L1 lysosomal destruction and potentiating antitumor immunity. These findings delineate a ceramide-gated sorting mechanism within the endosomal network, revealing a druggable metabolic switch to disrupt immune evasion and amplify checkpoint blockade efficacy.</p>

2026-02-05 | MTBLS13838 | MetaboLights

Epigenetic Silencing by SETDB1 Suppresses Tumor-cell Intrinsic Immunogenicity

Project description:Griffin GK, Wu J, Iracheta-Vellve A, Patti JC, Hsu J, Davis T, Dele-Oni D, Du PP, Halawi A, Ishizuka JJ, Kim S, Klaeger S, Knudsen NH, Miller BC, Nguyen T, Olander K, Papanastasiou M, Rachimi S, Robitschek EJ, Schneider EM, Yeary M, Zimmer M, Jaffe JD, Carr SA, Doench JG, Haining WN, Yates KB, Manguso RT, Bernstein BE. 2020. Epigenetic dysregulation is a defining feature of tumorigenesis and has been implicated in immune escape, yet mechanisms that drive immune evasion are poorly understood. To systematically identify epigenetic factors that modulate the immune sensitivity of tumor cells, we performed in vivo CRISPR-Cas9 screens targeting 936 chromatin regulators in mouse tumor models treated with immune checkpoint blockade. We identified the H3K9-methyltransferase SETDB1 and other members of the HUSH and KAP1 complexes as cell-intrinsic mediators of immune escape in tumor cells. We also found that amplification of SETDB1 (1q21) in human tumors is associated with reduced cytotoxic T-cell infiltration and resistance to immune checkpoint blockade. Mechanistically, we demonstrate that SETDB1 represses broad domains, hundreds of kilobases in size, many of which reside within the open genome compartment. These SETDB1 domains are enriched for transposable elements (TEs) and immune gene clusters associated with segmental duplication events, a central mechanism of mammalian genome evolution. SETDB1 loss derepresses latent TE-encoded regulatory elements and proximal immune genes within these repetitive regions, including canonical co-stimulatory ligands, and induces hundreds of putative TE-encoded viral antigens. Our study establishes SETDB1 as an epigenetic checkpoint that suppresses intrinsic immunogenicity in cancer cells, and thus represents a candidate target for immunotherapy.

2020-12-11 | MSV000086580 | MassIVE

RNA N6-methyladenosine methyltransferase METTL3 drives NAFLD-HCC and is a therapeutic target for boosting immunotherapy [RNA-Seq]

Project description:Non-alcoholic fatty liver disease (NAFLD) is an emerging risk factor of hepatocellular carcinoma (HCC). However, the mechanism and target therapy on NAFLD-HCC are still unclear. Here, we identify that the N6-methyladenosine (m6A) methyltransferase METTL3 promotes NAFLD-HCC. Hepatocyte-specific Mettl3 knockin exacerbated NAFLD-HCC formation while Mettl3 knockout exerted an opposite effect in mice. Single-cell RNA-seq revealed that METTL3 suppressed antitumor immune response by reducing infiltration of Gzmb+ and IFN-γ+ CD8+ T-cell, thereby facilitating immune escape. Mechanistically, METTL3 mediates SCAP mRNA m6A to promote its translation, leading to the activation of cholesterol biosynthesis. This enhanced secretion of cholesterol and cholesteryl esters, lipotoxins that impaired CD8+ T cell function in tumor microenvironment. Targeting of METTL3 by sgRNA, nanoparticle-siRNA, or pharmacological inhibitor (STM2457) in combination with anti-PD1 synergized to reinvigorate cytotoxic CD8+ T cells and mediate tumor regression. Together, METTL3 is a therapeutic target in NAFLD-HCC, especially in conjunction with immune checkpoint blockade (ICB) therapy.

2023-08-23 | GSE233806 | GEO

RNA N6-methyladenosine methyltransferase METTL3 drives NAFLD-HCC and is a therapeutic target for boosting immunotherapy [m6A-seq]

2023-08-23 | GSE233807 | GEO

Splice switching of SULT1C2 mRNA to lncRNA elicits tumor progression and immune evasion through triggering cholesterol biosynthesis

Project description:Emerging evidence shows that protein-coding genes can produce noncoding splice forms in addition to their canonical mRNA transcripts. However, the coding-to-noncoding transformation of mRNA and its pathological significance in cancer remain poorly understood. Here, we explored the noncoding variants of protein-coding genes in hepatocellular carcinoma (HCC), and identified a novel sulfotransferase 1C2 (SULT1C2) noncoding variant, lncSULT1C2, as a driver of hepatic tumorigenesis. Polypyrimidine tract-binding protein 1 (PTBP1) mediates the splice switching of SULT1C2 pre-mRNA to lncSULT1C2. Increased lncSULT1C2 expression accelerated the tumorigenicity of HCC cells by reprogramming cholesterol biosynthesis. LncSULT1C2-induced cholesterol accumulation activated mTORC1 signaling and drove the PD-L1-mediated antitumor immune response. High lncSULT1C2 expression decreased the efficacy of anti-PD-1 immunotherapy in mice. GalNAc-conjugated antisense oligonucleotide (ASO) against lncSULT1C2 elicited robust antitumor effects. This study unravels lncSULT1C2 as a previously unrecognized oncogenic noncoding variant of SULT1C2 and highlight the relevance of lncSULT1C2 in cholesterol metabolism reprogramming and tumor immune evasion.

2025-09-23 | PXD068724 |

Epigenetic Silencing by SETDB1 Suppresses Tumor-cell Intrinsic Immunogenicity

Project description:Epigenetic dysregulation is a defining feature of tumorigenesis and has been implicated in immune escape. However, the epigenetic mechanisms that drive immune evasion in cancer are poorly understood. To systematically identify epigenetic factors that modulate the immune sensitivity of tumor cells, we performed in vivo loss of function screens targeting 936 chromatin regulators in mouse tumor models treated with immune checkpoint blockade. We identified the H3K9-methyltransferase SETDB1 and other members of the HUSH and KAP1 complexes as cell-intrinsic mediators of immune escape in tumor cells. We also found that amplification of SETDB1 (1q21) in human tumors is associated with reduced cytotoxic T-cell infiltration and resistance to immune checkpoint blockade. Mechanistically, we demonstrate that SETDB1 targets broad domains, hundreds of kilobases in size, many of which reside within the open genome compartment. These SETDB1 domains are enriched for transposable elements (TEs) and immune gene clusters associated with segmental duplication events, a central mechanism of mammalian genome evolution. SETDB1 loss derepresses latent TE-encoded regulatory elements and proximal immune genes within these repetitive regions, including canonical NKG2D ligands, and induces hundreds of putative TE-encoded viral antigens. Our study establishes SETDB1 as an epigenetic checkpoint that suppresses intrinsic immunogenicity in cancer cells, and thus represents a candidate target for immunotherapy.

2021-03-18 | GSE155972 | GEO

TMT proteomics analysis of B16/F10

Project description:The recently described role of RNA methylation in regulating immune cell infiltration into tumors has attracted interest, given its potential impact on immunotherapy response. YTHDF1 is a versatile and powerful m6A reader, but the understanding of its impact on immune evasion is limited. Here, we revealed that tumor-intrinsic Ythdf1 drives immune evasion and immune checkpoint inhibitor (ICI) resistance. TMT proteomics analysis was performed to identify the altered protein.

2022-12-06 | PXD036938 | Pride

Targeting secreted MDK-mediated tryptophan/kynurenine metabolism enhances DLL3 CAR T therapy for SCLC

Project description:<p>Small cell lung cancer (SCLC) exhibits profound immunometabolic suppression that impairs antigen presentation and constrains immunotherapy efficacy. Through integrated multi-omics analyses of primary human SCLC tumors, we identified midkine (MDK) as a dominant tumor-secreted driver of immune evasion. Mechanistically, MDK activates STAT3 to induce indoleamine 2,3-dioxygenase 1 (IDO1), driving tryptophan-kynurenine metabolic reprogramming. This axis suppresses myeloid antigen presentation, reduces HLA class I expression, and impairs CD8+ T cell function, establishing a immunosuppressive tumor microenvironment (TME). We engineered DLL3-targeted CAR T cells secreting anti-MDK scFv. These dual-functional CAR T cells neutralize MDK within the TME, restore antigen presentation, alleviate metabolic suppression, and reinvigorate CD8+ T cell responses. In SCLC models, they exhibited markedly enhanced antitumor activity, improved metabolic fitness, and durable immune activation without systemic toxicity. Collectively, our findings identify MDK as a key immunometabolic regulator and support sMDK-DLL3 CAR T cells as a targeted immunotherapy for SCLC.</p>

2026-03-23 | MTBLS14116 | MetaboLights

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data