The double-edged sword of TOX: orchestrating T cell exhaustion and epigenetic remodeling in the tumor microenvironment
- 1Immunology and Molecular Oncology Diagnostics, Veneto Institute of Oncology IOV-IRCCS
- 2Department of Surgery, Oncology and Gastroenterology, University of Padua
Abstract
The capacity to profoundly change chromatin domains and in turn drive or inhibit gene expression makes chromatin modulators a powerful tool adopted to regulate crucial steps during development and cell lineage specification. These proteins can however be as well engaged to irreversibly reprogram cells toward pathological outcomes such as cancer. An example of such chromatin remodelers is the family of Thymocyte-selection associated high mobility box proteins (TOX), which has rather pleiotropic functions during development and in cancer. In light of the most recent findings, this review gives an overview on the many different roles played by TOX family of proteins in physiological processes, and of the context-dependent effects that TOX induces in a variety of tumors. A particular attention is given to the contribution of TOX to the mechanism of T cell-exhaustion and to the “exhaustion lock” - no longer viewed as a dysfunctional immunological program but rather as a sophisticated strategy evolved by the immune system to keep control during events of chronic stress. The therapeutic potentials of TOX as valuable biomarker and target in cancer and immunotherapy as well as in adoptive cell therapies are also discussed.
Related
- Metabolic Dysfunction and T-Cell Exhaustion in Colorectal Cancer: Mechanisms, Microenvironment Remodeling, and Therapeutic Opportunities
- Deep Immunophenotyping Unravels the Double Negative T cells and PD-1-Mediated Inflammatory Exhaustion in Ankylosing Spondylitis.
- Perinatal insults, genetic susceptibility, and the pathogenesis of neurodevelopmental disorders: from epigenetic remodeling to neural circuit dysfunction—a narrative review
- 683 Single-cell RNA-seq analysis of 9464D-GD2 neuroblastoma reveals immune remodeling after anti-CD40 and epigenetic modifier inhibitor therapy
- Selenium metabolism-related gene TXNRD1 drives tumor progression and microenvironment remodeling in oral squamous cell carcinoma
BibTeX
@article{zuccolotto2026doubleedged,
title = {{The double-edged sword of TOX: orchestrating T cell exhaustion and epigenetic remodeling in the tumor microenvironment}},
author = {Gaia Zuccolotto and Lodovica Borghese and Alessia Rebuli and Antonio Rosato and Anna Tosi},
journal = {Frontiers in Immunology},
year = {2026},
month = oct,
doi = {10.3389/fimmu.2026.1957165},
url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1957165/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - The double-edged sword of TOX: orchestrating T cell exhaustion and epigenetic remodeling in the tumor microenvironment
AU - Gaia Zuccolotto
AU - Lodovica Borghese
AU - Alessia Rebuli
AU - Antonio Rosato
AU - Anna Tosi
PY - 2026
DA - 2026/10/13
JO - Frontiers in Immunology
DO - 10.3389/fimmu.2026.1957165
UR - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1957165/full
AB - The capacity to profoundly change chromatin domains and in turn drive or inhibit gene expression makes chromatin modulators a powerful tool adopted to regulate crucial steps during development and cell lineage specification. These proteins can however be as well engaged to irreversibly reprogram cells toward pathological outcomes such as cancer. An example of such chromatin remodelers is the family of Thymocyte-selection associated high mobility box proteins (TOX), which has rather pleiotropic functions during development and in cancer. In light of the most recent findings, this review gives an overview on the many different roles played by TOX family of proteins in physiological processes, and of the context-dependent effects that TOX induces in a variety of tumors. A particular attention is given to the contribution of TOX to the mechanism of T cell-exhaustion and to the “exhaustion lock” - no longer viewed as a dysfunctional immunological program but rather as a sophisticated strategy evolved by the immune system to keep control during events of chronic stress. The therapeutic potentials of TOX as valuable biomarker and target in cancer and immunotherapy as well as in adoptive cell therapies are also discussed.
SN - 1664-3224
ER -