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

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.