The LDH‐H3K18La‐Nur77 Axis Potentiates Immune Escape in Small Cell Lung Cancer

Abstract Small cell lung cancer (SCLC) remains a therapeutic challenge due to its aggressive nature and limited response to immunotherapy. This study identifies lactate‐induced histone lactylation as a novel epigenetic mechanism in SCLC, contributing to immune escape and poor therapeutic outcomes. By identifying the LDH‐H3K18La‐Nur77 axis, new insights into the metabolic regulation of immune responses in SCLC are offered. Multi‐omics analysis, including metabolomics and TCR sequencing, is used to compare serum samples and immune cell profiles from SCLC patients. Data from Shanzhong cohort (n = 222), along with a validation cohort from the IMpower133 study (n = 264), demonstrates that LDH levels are associated with poorer outcomes following immunotherapy. ChIP‐qPCR and luciferase reporter assays reveal that lactate‐induced histone lactylation at H3K18La induces transcriptional activation of Nur77 in naïve CD8 ⁺ T cells, leading to tonic TCR signaling, which impairs antigen recognition and prevents effective anti‐tumor activity. In preclinical SCLC models, lactate inhibition reduces Nur77 expression, restores T cell function, and enhances the efficacy of PD‐1 blockade, leading to a decreased tumor burden and improved survival. This study uncovers a novel mechanism of immune escape in SCLC through lactate‐driven histone lactylation and provides the first evidence that targeting lactate metabolism can enhance immunotherapy effectiveness.