SUMO2 deletion changes chromatin accessibility and enhances cytotoxic T cell activation and tumor infiltration
6 affiliations
- 1School of Medicine, University of California, San Diego, La Jolla, CA 92037, USA.
- 2Department of Bioengineering, University of California, San Diego, La Jolla, CA 92037, USA.
- 3Department of Chemistry, University of California, San Diego, La Jolla, CA 92037, USA.
- 4New York Genome Institute, New York, NY 10013, USA.
- 5La Jolla Institute for Immunology, La Jolla, CA 92037, USA.
- 6Salk Institute for Biological Sciences, La Jolla, CA 92037, USA.
Abstract
Cytotoxic T cells (CTL) are crucial for adaptive immunity that leads to prolonged survival and potential cures for cancer. Recent clinical data has shown that pharmacological inhibition of SUMOylation (SUMOi) profoundly modifies tumor microenvironment (TME) and activates CTL, although the mechanism is not well described. In this study, we found that T cell specific knock out (KO) of the most dominant SUMO paralog, Sumo2 / SUMO2 , in both mouse and human CD8 + T cells significantly enhanced CD8 + T cell activation that is independent of the known mechanism – inducing type I IFN (IFN-I) expression by myeloid cells. Sumo2 / SUMO2 KO in CD8 + T cells increased chromatin accessibility for transcription factors BATF, JunB, ATF3, FRA1, FRA2, and AP1 that are known to promote T cell activation and proliferation. Using antigen-specific T cell models, OT1 and Chimeric Antigen Receptor (CAR)-T cells, we found that Sumo2 KO CD8 + T cells had significantly higher tumor infiltration as revealed by flow cytometry, immuno-fluorescence (IF) staining, and single nuclei RNA-sequencing (snRNA-seq) and conferred greater tumor growth inhibition than wildtype (WT) control T cells. snRNA-seq also revealed Sumo2 KO CD8 + T cells increased the expression of Tumor Necrosis Factor-Related Apoptosis-inducing Ligand (TRAIL), induced apoptosis genes in tumor cells and activated IFN-I and IFN-γ responsive genes in all cell types in the TME. These findings elucidate a novel mechanism regarding how SUMOylation can directly control CTL activation and tumor infiltration that activate anti-tumor immunity in the TME. SUMO2 KO can also be a potential strategy to enhance adoptive T cell therapies of solid tumors by enhancing their activity, tumor infiltration and their ability to after the TME.
Related
- HDAC inhibitor treatment restores transcriptome, chromatin accessibility, and memory deficits in a mouse model for Down syndrome
- FHL1 Downregulation Is Specific to Cancer-Associated Fibroblasts and Linked to Reduced Chromatin Accessibility in Colorectal Cancer.
- Genetic regulation of cell type–specific chromatin accessibility contributes to migraine etiology
- Latexin deletion in the bone marrow niche suppresses leukemia via LIFR downregulation and immune activation
- Dynamic Changes in Macrophage Infiltration and Polarization During Oral Carcinogenesis and Tumor Progression
BibTeX
@article{tharuka2026sumo2,
title = {{SUMO2 deletion changes chromatin accessibility and enhances cytotoxic T cell activation and tumor infiltration}},
author = {Mohottige D. Neranjan Tharuka and Dai-Hua Chen and Maria Luisa Jurgensen Amaral and Tianchen Ren and Yixuan Kuang and Shih-Ting Huang and Nikhil Chilakapati and Bing Ren and Stephen P. Schoenberger and Ye Zheng and Yuan Chen},
journal = {Science Advances},
year = {2026},
month = oct,
doi = {10.1126/sciadv.aef2217},
url = {https://www.science.org/doi/10.1126/sciadv.aef2217},
note = {CC BY-NC},
}
RIS
TY - JOUR
TI - SUMO2 deletion changes chromatin accessibility and enhances cytotoxic T cell activation and tumor infiltration
AU - Mohottige D. Neranjan Tharuka
AU - Dai-Hua Chen
AU - Maria Luisa Jurgensen Amaral
AU - Tianchen Ren
AU - Yixuan Kuang
AU - Shih-Ting Huang
AU - Nikhil Chilakapati
AU - Bing Ren
AU - Stephen P. Schoenberger
AU - Ye Zheng
AU - Yuan Chen
PY - 2026
DA - 2026/10/09
JO - Science Advances
DO - 10.1126/sciadv.aef2217
UR - https://www.science.org/doi/10.1126/sciadv.aef2217
AB - Cytotoxic T cells (CTL) are crucial for adaptive immunity that leads to prolonged survival and potential cures for cancer. Recent clinical data has shown that pharmacological inhibition of SUMOylation (SUMOi) profoundly modifies tumor microenvironment (TME) and activates CTL, although the mechanism is not well described. In this study, we found that T cell specific knock out (KO) of the most dominant SUMO paralog, Sumo2 / SUMO2 , in both mouse and human CD8 + T cells significantly enhanced CD8 + T cell activation that is independent of the known mechanism – inducing type I IFN (IFN-I) expression by myeloid cells. Sumo2 / SUMO2 KO in CD8 + T cells increased chromatin accessibility for transcription factors BATF, JunB, ATF3, FRA1, FRA2, and AP1 that are known to promote T cell activation and proliferation. Using antigen-specific T cell models, OT1 and Chimeric Antigen Receptor (CAR)-T cells, we found that Sumo2 KO CD8 + T cells had significantly higher tumor infiltration as revealed by flow cytometry, immuno-fluorescence (IF) staining, and single nuclei RNA-sequencing (snRNA-seq) and conferred greater tumor growth inhibition than wildtype (WT) control T cells. snRNA-seq also revealed Sumo2 KO CD8 + T cells increased the expression of Tumor Necrosis Factor-Related Apoptosis-inducing Ligand (TRAIL), induced apoptosis genes in tumor cells and activated IFN-I and IFN-γ responsive genes in all cell types in the TME. These findings elucidate a novel mechanism regarding how SUMOylation can directly control CTL activation and tumor infiltration that activate anti-tumor immunity in the TME. SUMO2 KO can also be a potential strategy to enhance adoptive T cell therapies of solid tumors by enhancing their activity, tumor infiltration and their ability to after the TME.
SN - 2375-2548
ER -