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journal article·2026-05Open access

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

Ri‐Xin Chen, Xiao‐Dan Ma, Shui‐Dan Xu, Ao‐Tian Mo, Min‐Hua Deng, Jun‐Han Wu, Wei‐Tao Zhuang, Jin‐Ling Duan, Shu‐Huan Xie, Jin‐Long Lin, Peng Lin, Ji‐Ming Tang, Hai‐Yu Zhou, Xiao‐Song Ben, Gui‐Bin Qiao, Dan Xie

Advanced Science· Volume 13· Issue 29
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Source abstract

Abstract

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.
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Research context

OpenAlex topics: Cancer, Hypoxia, and Metabolism · Immune cells in cancer · Ferroptosis and cancer prognosis

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

Department of Thoracic Surgery Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences) Southern Medical University Guangzhou China

State Key Laboratory of Oncology in South China Guangdong Provincial Clinical Research Center for Cancer Sun Yat‐sen University Cancer Center Guangzhou China

Medical Research Institute Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences) Southern Medical University Guangzhou China

Department of Radiology Sun Yat‐sen University Cancer Center Guangzhou Guangdong China

Department of Urology The First Affiliated Hospital of Guangzhou Medical University Guangzhou China

Department of Thoracic Surgery Zhujiang Hospital Southern Medical University Guangzhou China

State Key Laboratory of Respiratory Diseases National Clinical Research Center for Respiratory Disease National Center for Respiratory Medicine Department of Pulmonary and Critical Care Medicine Guangzhou Institute of Respiratory Health The First Affiliated Hospital of Guangzhou Medical University Guangzhou China

Department of Pathology Sun Yat‐sen University Cancer Center Guangzhou China

Department of Thoracic Surgery Sun Yat‐sen University Cancer Center Guangzhou China

Funding

National Natural Science Foundation of China · Natural Science Foundation of Guangdong Province

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