New opportunities to overcome T cell dysfunction: the role of transcription factors and how to target them

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Updated: Jun 13, 2025

Adenoviral Transduction of Naive CD4 T Cells to Study Treg Differentiation
15:33

Adenoviral Transduction of Naive CD4 T Cells to Study Treg Differentiation

Published on: August 13, 2013

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Bocheng Wu1, Angela N Koehler2, Peter M K Westcott3

  • 1Koch Institute for Integrative Cancer Research, Cambridge, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Trends in Biochemical Sciences
|September 14, 2024
PubMed

Insights

Immune checkpoint blockade (ICB) therapies can restore T cell function but often fail due to resistance. Targeting transcription factors (TFs) with small molecules offers a promising strategy to enhance anti-cancer immunity.

Area of Science:

  • Immunology
  • Cancer Biology
  • Molecular Biology

Background:

  • Immune checkpoint blockade (ICB) therapies reinvigorate T cell responses but face challenges with non-responders and acquired resistance.
  • Dysfunctional T cells are a major hurdle in achieving durable anti-cancer immunity.
  • Novel strategies are crucial to overcome resistance and broaden the efficacy of immunotherapies.

Purpose of the Study:

  • To review mechanisms underlying T cell dysfunction, with a focus on transcription factor (TF) networks.
  • To explore the dual roles of core TFs in both T cell function and dysfunction.
  • To discuss emerging strategies for targeting TFs to improve anti-cancer immunity.

Main Methods:

  • Literature review of T cell dysfunction mechanisms.
  • Analysis of key transcription factor networks in T cell biology.
  • Review of small molecule modulators targeting TFs for immunotherapy.

Main Results:

  • Identified key transcription factors (TFs) and their complex roles in T cell dysfunction.
  • Highlighted the potential of targeting TF networks to overcome immunotherapy resistance.
  • Emphasized the challenges and promise of small molecule TF modulators.

Conclusions:

  • Transcription factors play critical roles in regulating T cell function and dysfunction.
  • Targeting TFs offers a promising avenue to enhance the efficacy of immune checkpoint blockade therapies.
  • Small molecule modulators represent a challenging but potentially transformative approach to sustained anti-cancer immunity.
Keywords:
ICBNR4APROTAC degradersT cell dysfunctionTOXdisordered proteinsimmunotherapysmall molecule inhibitortranscriptional factor

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