NIPAL1 Drives a Metabolic‐Epigenetic Feedback Loop to Promote Lactate‐Mediated Immune Evasion in Esophageal Cancer

ABSTRACT Metabolic reprogramming is a hallmark of cancer that promotes tumor progression and immune evasion. Here, we identify a NIPAL1‐driven metabolic‐epigenetic circuit in esophageal squamous cell carcinoma (ESCC) that facilitates tumor growth and suppresses antitumor immunity. Mechanistically, NIPAL1 recruits the tyrosine kinase HCK to phosphorylate LDHA at Y10, enhancing glycolysis and lactate production. Lactate accumulation promotes p300‐mediated histone H3K18 lactylation (H3K18la), which transcriptionally activates NIPAL1 expression, establishing a self‐sustaining NIPAL1‐HCK‐p‐LDHA‐lactate‐p300‐H3K18la loop. This axis functions independently of NIPAL1's canonical magnesium transporter activity and promotes immune escape by impairing CD8 + T cell function. Pharmacological inhibition of HCK or p300 disrupts this loop and restores antitumor immunity, sensitizing tumors to anti‐PD‐1 therapy. Clinically, expression of NIPAL1, p‐LDHA (Y10), and H3K18la correlates with response to immune checkpoint blockade. Our findings reveal a previously unrecognized NIPAL1‐HCK‐H3K18la signaling loop that integrates tumor metabolism to immune regulation, offering promising targets to improve immunotherapy efficacy in ESCC.