WCLC 2025 - Posters & ePosters-PT1.02.01 Targeting NOX1/4-YAP/TEAD-CD47 Axis Promotes Macrophage Phagocytosis and Potentiates Radiotherapy Antitumor Efficacy in NSCLC

PT1.02.01 Targeting NOX1/4-YAP/TEAD-CD47 Axis Promotes Macrophage Phagocytosis and Potentiates Radiotherapy Antitumor Efficacy in NSCLC

Back to course

Pdf Summary

This study investigates a novel mechanism regulating the expression of CD47, an anti-phagocytosis immune checkpoint, in non-small cell lung cancer (NSCLC) cells, particularly its basal level and radiotherapy-induced upregulation. Radiotherapy, while a key NSCLC treatment, can increase CD47 expression on tumor cells, contributing to an immunosuppressive microenvironment and impairing macrophage-mediated phagocytosis. Anti-CD47 therapies hold promise but pose blood toxicity risks since normal blood cells also express CD47.<br /><br />The researchers identified that inhibiting NOX1 and NOX4 enzymes with the compound GKT137831 (GKT) suppresses both baseline and radiation-induced CD47 expression on NSCLC cells. Knockdown of NOX1 and NOX4 individually reduced CD47 levels, with combined knockdown producing the strongest effect. Co-culture experiments showed that GKT enhances macrophage phagocytosis of lung cancer cells, counteracting radiation-induced phagocytic impairment. RNA sequencing data revealed that GKT influences the YAP1/TEAD4 pathway within the Hippo signaling cascade, which is linked to reduced CD47 expression.<br /><br />In vivo studies using mouse tumor models demonstrated that GKT potentiates radiotherapy's antitumor efficacy through macrophage-dependent mechanisms without causing blood toxicity. This suggests that targeting the NOX1/NOX4-YAP1/TEAD4-CD47 axis can effectively promote macrophage phagocytosis and improve radiotherapy outcomes in NSCLC.<br /><br />Overall, this research provides a promising therapeutic strategy to enhance radiotherapy's effectiveness by selectively downregulating CD47 on tumor cells, thereby stimulating immune clearance while avoiding systemic toxicity. This approach may help overcome immune evasion mechanisms in NSCLC and improve patient responses to radiotherapy.

Asset Subtitle

Xiaorong Dong

Meta Tag

Speaker Xiaorong Dong

Topic Tumor Biology – Preclinical Biology

Keywords

CD47

non-small cell lung cancer

radiotherapy

NOX1

NOX4

GKT137831

macrophage phagocytosis

YAP1/TEAD4 pathway

Hippo signaling

immune checkpoint