---
title: "TNG917: A Selective EHMT1/2 Inhibitor That Boosts Antitumor Immunity and Checkpoint Therapy"
id: "pubmed-42268285"
canonical_url: "https://medichelpline.com/clinical-feed/pubmed-42268285"
content_type: "clinical_feed_article"
specialty: "Pharmacology"
source_name: "PubMed / NCBI"
source_url: "https://pubmed.ncbi.nlm.nih.gov/42268285/"
doi: "10.1158/0008-5472.CAN-25-4720"
published_at: "2026-09-02T00:00:00.000Z"
evidence_level: "Journal Article"
license: "CC-BY-NC-4.0 / Informational Use"
---
# TNG917: A Selective EHMT1/2 Inhibitor That Boosts Antitumor Immunity and Checkpoint Therapy
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/pubmed-42268285
- **Specialty:** [Pharmacology](https://medichelpline.com/clinical-feed/pharmacology.md)
- **Primary Source:** PubMed / NCBI
- **Source URL:** [Original Journal Publication](https://pubmed.ncbi.nlm.nih.gov/42268285/)
- **DOI:** [10.1158/0008-5472.CAN-25-4720](https://doi.org/10.1158%2F0008-5472.CAN-25-4720)
- **Published At:** 2026-09-02T00:00:00.000Z
- **Evidence Rating:** Journal Article
## Executive GIST (TL;DR)
- A FACS-based CRISPR-Cas9 screen identified the histone lysine methyltransferases **EHMT1** and **EHMT2** as tumor-intrinsic suppressors of PD-L1 surface expression and interferon (IFN) signaling. - TNG917 was developed as a histone substrate–competitive dual inhibitor of **EHMT1/2**, with low nanomolar cellular potency and high selectivity over other methyltransferases. - In cancer cell lines, TNG917 relieved **H3K9**-mediated transcriptional repression, restored IFN-stimulated gene expression, and induced secretion of T-cell chemoattractant cytokines such as **CXCL10**. - Oral TNG917 monotherapy produced marked tumor growth inhibition in both syngeneic and humanized mouse models. - Combination of TNG917 with anti–**PD-1** therapy yielded complete, durable tumor regressions and established protective immune memory in preclinical models. - Early pharmacokinetic and toxicology evaluations indicated favorable exposure and a wide safety margin, supporting clinical advancement. - The study positions EHMT1/2 inhibition by TNG917 as a strategy to convert immune-cold tumors into T cell–inflamed lesions and to potentiate immune checkpoint blockade efficacy. - Details on specific potency values, dosing regimens, numerical efficacy endpoints, and full toxicology data were not reported in the abstract and require consultation of the full text for granular data.
## Clinical Analysis & Structured Key Points
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TNG917 is a Potent and Selective Inhibitor of Histone Lysine Methyltransferases EHMT1/2 that Enhances Antitumor Immunity and Immunotherapy Efficacy [Alvin Ziying Lu](https://pubmed.ncbi.nlm.nih.gov/?term=Lu+AZ&cauthor_id=42268285)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42268285/#full-view-affiliation-1 "Tango Therapeutics, Boston, Massachusetts."), [Brian B Haines](https://pubmed.ncbi.nlm.nih.gov/?term=Haines+BB&cauthor_id=42268285)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42268285/#full-view-affiliation-1 "Tango Therapeutics, Boston, Massachusetts."), [Wenhai Zhang](https://pubmed.ncbi.nlm.nih.gov/?term=Zhang+W&cauthor_id=42268285)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42268285/#full-view-affiliation-1 "Tango Therapeutics, Boston, Massachusetts."), [Minjie Zhang](https://pubmed.ncbi.nlm.nih.gov/?term=Zhang+M&cauthor_id=42268285)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42268285/#full-view-affiliation-1 "Tango Therapeutics, Boston, Massachusetts."), [Douglas A Whittington](https://pubmed.ncbi.nlm.nih.gov/?term=Whittington+DA&cauthor_id=42268285)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42268285/#full-view-affiliation-1 "Tango Therapeutics, Boston, Massachusetts."), [Lei Ji](https://pubmed.ncbi.nlm.nih.gov/?term=Ji+L&cauthor_id=42268285)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42268285/#full-view-affiliation-1 "Tango Therapeutics, Boston, Massachusetts."), [Teng Teng](https://pubmed.ncbi.nlm.nih.gov/?term=Teng+T&cauthor_id=42268285)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42268285/#full-view-affiliation-1 "Tango Therapeutics, Boston, Massachusetts."), [Maria Dam Ferdinez](https://pubmed.ncbi.nlm.nih.gov/?term=Dam+Ferdinez+M&cauthor_id=42268285)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42268285/#full-view-affiliation-1 "Tango Therapeutics, Boston, Massachusetts."), [Yi Yu](https://pubmed.ncbi.nlm.nih.gov/?term=Yu+Y&cauthor_id=42268285)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42268285/#full-view-affiliation-1 "Tango Therapeutics, Boston, Massachusetts."), [Hongxiang Zhang](https://pubmed.ncbi.nlm.nih.gov/?term=Zhang+H&cauthor_id=42268285)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42268285/#full-view-affiliation-1 "Tango Therapeutics, Boston, Massachusetts."), [Lina Gu](https://pubmed.ncbi.nlm.nih.gov/?term=Gu+L&cauthor_id=42268285)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42268285/#full-view-affiliation-1 "Tango Therapeutics, Boston, Massachusetts."), [Alice W Tsai](https://pubmed.ncbi.nlm.nih.gov/?term=Tsai+AW&cauthor_id=42268285)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42268285/#full-view-affiliation-1 "Tango Therapeutics, Boston, Massachusetts."), [Sirimas Sudsakorn](https://pubmed.ncbi.nlm.nih.gov/?term=Sudsakorn+S&cauthor_id=42268285)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42268285/#full-view-affiliation-1 "Tango Therapeutics, Boston, Massachusetts."), [William D Mallender](https://pubmed.ncbi.nlm.nih.gov/?term=Mallender+WD&cauthor_id=42268285)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42268285/#full-view-affiliation-1 "Tango Therapeutics, Boston, Massachusetts."), [Brett D Williams](https://pubmed.ncbi.nlm.nih.gov/?term=Williams+BD&cauthor_id=42268285)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42268285/#full-view-affiliation-1 "Tango Therapeutics, Boston, Massachusetts."), [Jon H Come](https://pubmed.ncbi.nlm.nih.gov/?term=Come+JH&cauthor_id=42268285)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42268285/#full-view-affiliation-1 "Tango Therapeutics, Boston, Massachusetts."), [Scott Throner](https://pubmed.ncbi.nlm.nih.gov/?term=Throner+S&cauthor_id=42268285)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42268285/#full-view-affiliation-1 "Tango Therapeutics, Boston, Massachusetts."), [Joseph P Vacca](https://pubmed.ncbi.nlm.nih.gov/?term=Vacca+JP&cauthor_id=42268285)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42268285/#full-view-affiliation-1 "Tango Therapeutics, Boston, Massachusetts."), [Alan Huang](https://pubmed.ncbi.nlm.nih.gov/?term=Huang+A&cauthor_id=42268285)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42268285/#full-view-affiliation-1 "Tango Therapeutics, Boston, Massachusetts."), [Chengyin Min](https://pubmed.ncbi.nlm.nih.gov/?term=Min+C&cauthor_id=42268285)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42268285/#full-view-affiliation-1 "Tango Therapeutics, Boston, Massachusetts."), [John P Maxwell](https://pubmed.ncbi.nlm.nih.gov/?term=Maxwell+JP&cauthor_id=42268285)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42268285/#full-view-affiliation-1 "Tango Therapeutics, Boston, Massachusetts."), [Jannik N Andersen](https://pubmed.ncbi.nlm.nih.gov/?term=Andersen+JN&cauthor_id=42268285)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42268285/#full-view-affiliation-1 "Tango Therapeutics, Boston, Massachusetts."), [Ying-Nan P Chen](https://pubmed.ncbi.nlm.nih.gov/?term=Chen+YP&cauthor_id=42268285)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42268285/#full-view-affiliation-1 "Tango Therapeutics, Boston, Massachusetts.") Affiliations Expand ### Affiliation * 1 Tango Therapeutics, Boston, Massachusetts. * PMID: **42268285** * DOI: [ 10.1158/0008-5472.CAN-25-4720 ](https://doi.org/10.1158/0008-5472.can-25-4720) Item in Clipboard # TNG917 is a Potent and Selective Inhibitor of Histone Lysine Methyltransferases EHMT1/2 that Enhances Antitumor Immunity and Immunotherapy Efficacy Alvin Ziying Lu et al. Cancer Res. 2026. Show details Display options Display options Format Abstract PubMed PMID Cancer Res Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22Cancer+Res%22%5Bjour%5D&sort=date&sort_order=desc) * [ Search in NLM Catalog ](https://www.ncbi.nlm.nih.gov/nlmcatalog?term=%22Cancer+Res%22%5BTitle+Abbreviation%5D) * [ Add to Search ](https://pubmed.ncbi.nlm.nih.gov/42268285/) . 2026 Sep 2;86(17):4315-4333. doi: 10.1158/0008-5472.CAN-25-4720. ### Authors [Alvin Ziying Lu](https://pubmed.ncbi.nlm.nih.gov/?term=Lu+AZ&cauthor_id=42268285)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42268285/#short-view-affiliation-1 "Tango Therapeutics, Boston, Massachusetts."), [Brian B Haines](https://pubmed.ncbi.nlm.nih.gov/?term=Haines+BB&cauthor_id=42268285)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42268285/#short-view-affiliation-1 "Tango Therapeutics, Boston, Massachusetts."), [Wenhai Zhang](https://pubmed.ncbi.nlm.nih.gov/?term=Zhang+W&cauthor_id=42268285)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42268285/#short-view-affiliation-1 "Tango Therapeutics, Boston, Massachusetts."), [Minjie Zhang](https://pubmed.ncbi.nlm.nih.gov/?term=Zhang+M&cauthor_id=42268285)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42268285/#short-view-affiliation-1 "Tango Therapeutics, Boston, Massachusetts."), [Douglas A Whittington](https://pubmed.ncbi.nlm.nih.gov/?term=Whittington+DA&cauthor_id=42268285)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42268285/#short-view-affiliation-1 "Tango Therapeutics, Boston, Massachusetts."), [Lei Ji](https://pubmed.ncbi.nlm.nih.gov/?term=Ji+L&cauthor_id=42268285)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42268285/#short-view-affiliation-1 "Tango Therapeutics, Boston, Massachusetts."), [Teng Teng](https://pubmed.ncbi.nlm.nih.gov/?term=Teng+T&cauthor_id=42268285)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42268285/#short-view-affiliation-1 "Tango Therapeutics, Boston, Massachusetts."), [Maria Dam Ferdinez](https://pubmed.ncbi.nlm.nih.gov/?term=Dam+Ferdinez+M&cauthor_id=42268285)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42268285/#short-view-affiliation-1 "Tango Therapeutics, Boston, Massachusetts."), [Yi Yu](https://pubmed.ncbi.nlm.nih.gov/?term=Yu+Y&cauthor_id=42268285)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42268285/#short-view-affiliation-1 "Tango Therapeutics, Boston, Massachusetts."), [Hongxiang Zhang](https://pubmed.ncbi.nlm.nih.gov/?term=Zhang+H&cauthor_id=42268285)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42268285/#short-view-affiliation-1 "Tango Therapeutics, Boston, Massachusetts."), [Lina Gu](https://pubmed.ncbi.nlm.nih.gov/?term=Gu+L&cauthor_id=42268285)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42268285/#short-view-affiliation-1 "Tango Therapeutics, Boston, Massachusetts."), [Alice W Tsai](https://pubmed.ncbi.nlm.nih.gov/?term=Tsai+AW&cauthor_id=42268285)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42268285/#short-view-affiliation-1 "Tango Therapeutics, Boston, Massachusetts."), [Sirimas Sudsakorn](https://pubmed.ncbi.nlm.nih.gov/?term=Sudsakorn+S&cauthor_id=42268285)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42268285/#short-view-affiliation-1 "Tango Therapeutics, Boston, Massachusetts."), [William D Mallender](https://pubmed.ncbi.nlm.nih.gov/?term=Mallender+WD&cauthor_id=42268285)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42268285/#short-view-affiliation-1 "Tango Therapeutics, Boston, Massachusetts."), [Brett D Williams](https://pubmed.ncbi.nlm.nih.gov/?term=Williams+BD&cauthor_id=42268285)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42268285/#short-view-affiliation-1 "Tango Therapeutics, Boston, Massachusetts."), [Jon H Come](https://pubmed.ncbi.nlm.nih.gov/?term=Come+JH&cauthor_id=42268285)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42268285/#short-view-affiliation-1 "Tango Therapeutics, Boston, Massachusetts."), [Scott Throner](https://pubmed.ncbi.nlm.nih.gov/?term=Throner+S&cauthor_id=42268285)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42268285/#short-view-affiliation-1 "Tango Therapeutics, Boston, Massachusetts."), [Joseph P Vacca](https://pubmed.ncbi.nlm.nih.gov/?term=Vacca+JP&cauthor_id=42268285)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42268285/#short-view-affiliation-1 "Tango Therapeutics, Boston, Massachusetts."), [Alan Huang](https://pubmed.ncbi.nlm.nih.gov/?term=Huang+A&cauthor_id=42268285)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42268285/#short-view-affiliation-1 "Tango Therapeutics, Boston, Massachusetts."), [Chengyin Min](https://pubmed.ncbi.nlm.nih.gov/?term=Min+C&cauthor_id=42268285)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42268285/#short-view-affiliation-1 "Tango Therapeutics, Boston, Massachusetts."), [John P Maxwell](https://pubmed.ncbi.nlm.nih.gov/?term=Maxwell+JP&cauthor_id=42268285)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42268285/#short-view-affiliation-1 "Tango Therapeutics, Boston, Massachusetts."), [Jannik N Andersen](https://pubmed.ncbi.nlm.nih.gov/?term=Andersen+JN&cauthor_id=42268285)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42268285/#short-view-affiliation-1 "Tango Therapeutics, Boston, Massachusetts."), [Ying-Nan P Chen](https://pubmed.ncbi.nlm.nih.gov/?term=Chen+YP&cauthor_id=42268285)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42268285/#short-view-affiliation-1 "Tango Therapeutics, Boston, Massachusetts.") ### Affiliation * 1 Tango Therapeutics, Boston, Massachusetts. * PMID: **42268285** * DOI: [ 10.1158/0008-5472.CAN-25-4720 ](https://doi.org/10.1158/0008-5472.can-25-4720) Item in Clipboard Full text links Cite Display options Display options Format Abstract PubMed PMID ## Abstract Epigenetic silencing of interferon (IFN) signaling contributes to the resistance of tumors to programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) immune checkpoint blockade. In this study, we conducted a fluorescence-activated cell sorting (FACS)-based CRISPR-Cas9 screen to identify tumor-intrinsic regulators of PD-L1 surface expression and identified the histone-lysine methyltransferases EHMT1 and EHMT2 as key suppressors of IFN signaling. TNG917 was developed as a histone substrate-competitive dual-inhibitor of EHMT1/2 with low nanomolar potency in cells and high selectivity over other methyltransferases. In cancer cell lines, TNG917 relieved H3K9-mediated repression, restored IFN-stimulated gene expression, and triggered secretion of T-cell chemoattractant cytokines, including CXCL10. When dosed orally in both syngeneic and humanized mouse models, TNG917 monotherapy led to marked tumor growth inhibition, whereas combination with anti-PD-1 therapy produced complete, durable regressions and established protective immune memory. Early pharmacokinetic and toxicology assessments revealed favorable exposure profiles and a wide safety margin. These findings establish EHMT1/2 inhibition by TNG917 as a strategy to convert immune-cold tumors into T cell-inflamed lesions and potentiate checkpoint blockade efficacy, supporting its advancement into clinical development in combination with immunotherapy. **Significance:** By reversing EHMT1/2-dependent repression of interferon signaling, TNG917 enhances tumor immunogenicity and T-cell infiltration, identifying EHMT1/2 as key epigenetic drivers of immune evasion and actionable targets to restore immune checkpoint blockade responsiveness. ©2026 American Association for Cancer Research. [PubMed Disclaimer](https://pubmed.ncbi.nlm.nih.gov/disclaimer/) ## Similar articles * [ ILT4 inhibition prevents TAM- and dysfunctional T cell-mediated immunosuppression and enhances the efficacy of anti-PD-L1 therapy in NSCLC with EGFR activation. ](https://pubmed.ncbi.nlm.nih.gov/33537094/) Chen X, Gao A, Zhang F, Yang Z, Wang S, Fang Y, Li J, Wang J, Shi W, Wang L, Zheng Y, Sun Y.Chen X, et al.Theranostics. 2021 Jan 19;11(7):3392-3416. doi: 10.7150/thno.52435. eCollection 2021.Theranostics. 2021.PMID: 33537094Free PMC article. * [ Targeting PKMYT1 enhances antitumor immune responses to PD-L1 blockade in castration-resistant prostate cancer. ](https://pubmed.ncbi.nlm.nih.gov/41617394/) Gao L, Wang B, Liu H, Liu P, Liu L, Han J, Wang X, Dou B, Sun F, Liu W, Wang X, Feng T, Zhao R, Yang X, Chen W, Hu J, Han B.Gao L, et al.J Immunother Cancer. 2026 Jan 30;14(1):e013247. doi: 10.1136/jitc-2025-013247.J Immunother Cancer. 20
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