Abstract 6603: MCT4-driven lactate shuttle in the irradiated tumor microenvironment upregulates neutrophils PD-L1 expression for immunosuppression in lung cancer.

作者：Wenqian Yuan, Yijun Wang, Lingyi Kong, Minqi Zhou, Yuhan Sheng, Yajie Sun, K. Yang · 发表于：Cancer Research · 年份：2026 · DOI：10.1158/1538-7445.am2026-6603 · 研究领域：Cancer, Hypoxia, and Metabolism、Immune cells in cancer、Ferroptosis and cancer prognosis

Abstract Purposes: Although tumor metabolic heterogeneity is known to shape tumor microenvironments (TME), the metabolic consequences of radiotherapy remain poorly defined. Thus, this study aims to elucidate the radiation-induced metabolic alterations in the TME, delineate their functional roles in radioresistance, and identify targetable metabolic vulnerabilities. Methods: Metabolic perturbations were investigated through metabolomic profiling of lung cancer patients serum 5 days after radiotherapy and tumor interstitial fluid collected at 48h post-irradiation. Glycolytic flux was assessed via 13C6-glucose-based metabolic flux analysis. Lactate dynamics were assessed through extracellular acidocation rate (ECAR) measurements. Spatial scRNA sequencing was conducted on tumors from Lewis models. All the histone modification antibodies available were used to identify the lactylation site of neutrophils. Cut&Tag assay was performed to elucidate the downstream genes. Results: Metabolomic profiling of patients serums and irradiated tumors revealed a significantly elevation of lactate. Subsequent functional analyses demonstrated that radiation induces metabolic reprogramming in NSCLC cells, characterized by amplified glycolytic flux, elevated ECAR, and enhanced lactate secretion. Proteomic screening identified MCT4 as the most prominently upregulated glycolytic regulators post-irradiation. MCT4 blockade attenuated radiation-induced glycolytic potentiation and suppressed lactate ...