# Targeting Mettl8-Tcf1 axis promotes CD8+ TPEX differentiation and antitumor immunity

## TL;DR

A new study shows that targeting Mettl8 helps convert exhausted T cells into more effective forms, improving cancer immunotherapy.

## Contribution

The study identifies Mettl8 as a novel regulator of TPEX cell differentiation through m3C modification and chromatin looping.

## Key findings

- Mettl8 deletion or inhibition promotes TPEX differentiation into Int-TEX cells, reducing tumor growth.
- Mettl8 stabilizes Tcf7 mRNA and enhances Tcf1 protein expression to maintain TPEX stemness.
- Pharmacological Mettl8 inhibition synergizes with anti–PD-1 therapy to improve antitumor immunity.

## Abstract

The study reveals that Mettl8 maintains stem-like TPEX cells by stabilizing Tcf1 via m3C modification and facilitating chromatin looping at the Tox locus. Its deletion or inhibition drives TPEX differentiation into effective Int-TEX cells, restraining tumor growth and synergizing with anti–PD-1 therapy, thus presenting a promising immunotherapeutic target.

CD8+ T cell exhaustion represents a major obstacle to effective cancer immunotherapy. While stem-like progenitor exhausted T (TPEX) cells can differentiate into intermediate (Int-TEX) and terminally exhausted (TEX) subsets, the epigenetic regulation of this process is unclear. We identify the RNA methyltransferase Mettl8 as a critical regulator, with expression significantly higher in TPEX than in TEX subsets. In anti–PD-1 responding non-small cell lung cancer patients, Mettl8 and the stemness factor TCF7 were downregulated. In murine models, Mettl8 deletion restrained tumor progression by driving TPEX differentiation into effective Int-TEX cells. Mechanistically, Mettl8 stabilizes Tcf7 mRNA via m3C modification and enhances Tcf1 protein expression. Additionally, Mettl8 interacts with Tcf1 to facilitate chromatin looping at the Tox locus, maintaining TPEX stemness. Pharmacological Mettl8 inhibition promoted TPEX-to-Int-TEX differentiation and tumor control. Combining this inhibition with anti–PD-1 therapy yielded synergistic efficacy. Our findings establish Mettl8 as a pivotal regulator of TPEX fate and a promising therapeutic target for enhancing immunotherapy.