Endoplasmic reticulum stress-induced histone lactylation mediating immune escape of gastric cancer via PDIA6 overexpression in dendritic cells.

Gastric cancer is one of the most prevalent cancers worldwide and is associated with a high mortality rate. Although immunotherapy has achieved some success for many tumor types, the limited response of gastric cancer to immunotherapy poses a challenge. Lactylation is a recently proposed post-translational modification derived from lactate that plays a key role in many physiological processes. In this study, we found that endoplasmic reticulum stress (ERS)-induced histone lactylation attenuated the immune response of dendritic cells (DC), decreased the ability of T cells to kill tumor cells, and enhanced tumor growth. Interestingly, ERS-induced H4K12 lactylation promoted the expression of PDIA6 in DC, leading to weakened immune activity of DC and decreased anti-tumor ability of T cells, thereby promoting gastric cancer immune evasion. Collectively, our work provides new insights into how ERS-induced lactylation modification attenuates the stability of DC to drive immune escape in gastric cancer and provides a promising biomarker for the efficacy of immunotherapy in gastric cancer.