# Targeting DAP5 Disrupts Alternate Mode of Translational Initiation in Tregs and Potentiates Antitumor Immunity

## TL;DR

This study shows that targeting DAP5 in regulatory T cells disrupts their survival in tumors, boosting the body's ability to fight cancer.

## Contribution

The study reveals that DAP5 enables Tregs to survive in tumors via alternate translation, offering a new therapeutic target for cancer immunotherapy.

## Key findings

- DAP5 expression correlates with tumor-infiltrating Treg frequencies in human and mouse cancers.
- Disrupting DAP5 in Tregs impairs their survival in tumors while preserving systemic immune tolerance.
- DAP5 supports Treg stability by enabling alternate translation of CD25 and MCL-1 transcripts.

## Abstract

Regulatory T cells (Tregs) can thrive in the harsh tumor microenvironment (TME) to dampen antitumor immunity. Chronic stresses within TME compromise canonical cap‐dependent translation (CDT), which compromises effector T cell function but not Treg persistence. Death‐associated protein 5 (DAP5/eIF4G2), a non‐classical translational scaffold, has been reported to support human Treg differentiation in vitro, but its functions in thymic Treg development, peripheral Treg homeostasis, and tumor‐infiltrating Treg (ti‐Treg) fitness remain unclear. Here, it is shown that DAP5 expression positively correlates with ti‐Treg frequencies in both colorectal cancer patients and murine subcutaneous tumors. Mice with homozygous Dap5 deletion in Tregs has intact thymic and peripheral Treg development but spontaneously developed typical scurfy symptoms. Haploinsufficiency of Dap5 in Tregs preserves peripheral immune homeostasis while suppressing tumor growth, with enhanced CD8+ T cell infiltration and effector function. Mechanistically, Dap5 mediates alternate mode of translation of transcripts encoding CD25 and MCL‐1 in Tregs, thereby sustaining Treg lineage stability and survival in the stressful TME. Overall, Tregs rely on DAP5‐driven alternate translation to maintain peripheral homeostasis and acquired fitness within the TME. Selective disruption of this pathway impairs ti‐Tregs while sparing systemic tolerance, offering a potential therapeutic strategy to enhance anti‐tumor immunity.

Regulatory T cells (Tregs) suppress antitumor immunity. This study identifies that the translation scaffold DAP5/eIF4G2 is upregulated in tumor‐infiltrating Tregs (ti‐Tregs). DAP5 mediates an alternate translation mode to sustain CD25 and MCL‐1 expression, which is critical for ti‐Treg stability and survival in the tumor microenvironment. Selective disruption of DAP5 impairs ti‐Tregs and potentiates antitumor immunity.