# Lactylation stabilizes PD-L1 to promote tumor immune evasion and cell growth

## TL;DR

Lactylation of PD-L1 by lactate stabilizes the protein, helping tumors evade the immune system and grow, suggesting a new target for cancer immunotherapy.

## Contribution

Discovery of lactylation as a novel regulatory mechanism of PD-L1 stability and tumor immune evasion.

## Key findings

- Lactylation at PD-L1 K280 inhibits HUWE1 binding and proteasomal degradation, stabilizing PD-L1.
- AARS1 acts as the lactyltransferase using lactate to lactylate PD-L1.
- PD-L1 lactylation correlates with advanced lung cancer stages and poor survival, indicating its clinical relevance.

## Abstract

Programmed death-ligand 1 (PD-L1) plays a critical role in tumor immune evasion, yet the mechanisms that regulate its expression, specifically the metabolic control of its stability and function, remain elusive. In this study, we demonstrate that lactate, a key metabolite in the tumor microenvironment, upregulates PD-L1 expression via lysine lactylation (Kla) of PD-L1 at residue K280 within its intracellular domain. This modification stabilizes PD-L1 by inhibiting E3 ligase HUWE1 binding, ubiquitination, and subsequent proteasomal degradation. We identified alanyl-tRNA synthetase 1 (AARS1) as the lactyltransferase that utilizes lactate as a lactyl-donor and is responsible for PD-L1 K280 lactylation. Functionally, PD-L1 lactylation promotes tumor immune evasion by impairing CD8 + T cell-mediated cytotoxicity and accelerates tumor growth in vivo. Furthermore, sodium lactate (NaLa) administration enhances the efficacy of anti-PD-L1 immunotherapy in preclinical models. Clinically, PD-L1 K280 lactylation correlates with advanced non-small cell lung cancer stages and poor patient survival, highlighting its potential as a diagnostic biomarker. Our findings unveil a novel lactate-PD-L1 regulatory axis and propose lactylation as a therapeutic target to augment the efficacy of the immune checkpoint blockade.