What question did this study set out to answer?

To investigate how radiotherapy-induced metabolic changes in the tumor microenvironment promote immunosuppression via neutrophil PD-L1 expression.

April 5, 2026

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

Key Points

To investigate how radiotherapy-induced metabolic changes in the tumor microenvironment promote immunosuppression via neutrophil PD-L1 expression.
Analyzed serum and tumor interstitial fluid from lung cancer patients after radiotherapy.
Conducted 13C6-glucose-based metabolic flux analysis to assess glycolytic activity.
Measured lactate dynamics using extracellular acidification rate (ECAR) assessments.
Performed spatial scRNA sequencing on tumor samples from Lewis models.
Utilized Cut&Tag assay to identify histone lactylation sites in neutrophils.
Lactate levels significantly elevated in both serum and irradiated tumors.
Radiation increased glycolytic flux and lactate secretion in non-small cell lung cancer (NSCLC) cells.
MCT4 emerged as a key regulator of glycolytic adaptations post-irradiation.
Inhibition of MCT4 reversed lactate accumulation and immunosuppressive neutrophil phenotypes.
Histone lactylation in neutrophils was linked to increased PD-L1 expression, impairing CD8+ T cell functions.

Abstract

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 Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 6603.

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