Despite the identification of numerous therapeutic targets in lung cancer, achieving significant efficacy has been challenging. TNFRSF21 plays an important role in various cancers. We investigated the function of TNFRSF21 in lung adenocarcinoma (LUAD).

The prognostic value of TNFRSF21 expression in lung cancer was evaluated by the GEPIA and Kaplan-Meier Plotter databases. Lung cancer cell viability was assessed by the CCK8 assay. TNFRSF21 expression patterns in lung cancer tissues and cells were examined using RT-PCR assay. Tumor sphere growth was evaluated through tumor sphere formation assays. MtROS contents in lung cancer cells were observed through MitoSOX fluorescent assays.

TNFRSF21 was up-regulated in LUAD patients. TNFRSF21 induction was particularly notable in LUAD, especially in cancerous cells (A549, H1299, H460, and SPC-A1), compared to BEAS-2B cells. Additionally, TNFRSF21 was increased in cisplatin (DDP)-resistant LUAD cells. Loss of TNFRSF21 significantly inhibited LUAD cell growth. It was observed that forced expression of TNFRSF21 contributed to tumor cell proliferation and DDP resistance. The production of ROS was found to participate in the inhibitory effects on lung cancer stem cells (CSCs), with decreased TNFRSF21 restraining ROS contents. Collectively, these findings reveal that the downregulation of TNFRSF21 promotes ROS contents to restrain the lung CSC-like characteristics via modulation of CD44 and CD133.

In conclusion, TNFRSF21 may act as a novel target for lung cancer chemotherapy, particularly for eradicating lung CSCs.