Cai Yifan, Li Xinyue, Zhu Shuang, Wu Hao, Nie Jun, Huang Fang
Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Institute of Radiation Oncology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Hubei Key Laboratory of Precision Radiation Oncology, Wuhan 430022, China.
State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430022, China; Hubei Hongshan Laboratory, Wuhan 430022, China; Interdisciplinary Sciences Research Institute, Huazhong Agricultural University, Wuhan 430022, China.
Int Immunopharmacol. 2026 Feb 1;170:116125. doi: 10.1016/j.intimp.2025.116125. Epub 2025 Dec 29.
Small cell lung cancer (SCLC) responds poorly to immunotherapy. This study investigates how glycolytic reprogramming drives immune evasion in SCLC by epigenetically suppressing MHC-I mediated antigen presentation.
Bioinformatic and murine model studies confirmed SCLC with high ASCL1 expression (SCLC-A) as an immunologically "cold" subtype, exhibiting elevated glycolytic activity that was inversely correlated with profoundly suppressed MHC-I pathway activity. High LDHA expression was associated with advanced disease stage and shorter overall survival in patients. In vitro and in vivo studies demonstrated that LDHA knockdown or its pharmacological inhibition restored the expression of MHC-I (H2Db/H2Kb; HLA-ABC) and β2-microglobulin (B2M). This promoted antitumor immunity, increasing CD4 and CD8 T cell infiltration and inhibiting tumor growth. These effects were reversed by sodium lactate, confirming lactate as the key metabolite. Mechanistically, LDHA-derived lactate promoted histone H4K5 lactylation (H4K5la) via the acyltransferase P300. This modification enriched at the promoters of the PRC2 core subunits EZH2 and EED, enhancing their transcription and thus PRC2-mediated silencing of MHC-I. The restoration of MHC-I following LDHA loss was mediated by a parallel H4K5la-PRC2 regulatory axis independent of the canonical NLRC5 pathway. Combination therapy with LDHA inhibitor FX11 and anti-PD-1 antibody synergistically inhibited tumor growth and enhanced immune activation with a favorable safety profile.
Our work uncovers the LDHA-H4K5la-PRC2 axis as a novel metabolic-epigenetic pathway that suppresses antigen presentation in SCLC-A. Targeting this axis with an LDHA inhibitor effectively sensitizes SCLC to anti-PD-1 therapy, representing a promising strategy to overcome immunotherapy resistance.
