Hydrogen suppressed tumor growth during chronic intermittent hypoxia via modulating macrophage polarization

Lung cancer remains a major challenge in clinical treatment, as current therapeutic strategies often fail to effectively halt disease progression. Chronic intermittent hypoxia (CIH), a hallmark pathological feature of obstructive sleep apnea (OSA), has been implicated in promoting tumor invasion and metastasis. This study aimed to investigate the potential of hydrogen as an innovative adjunctive therapy for lung cancer. To evaluate the therapeutic effects of hydrogen, both in vitro and in vivo models were established. In vitro, an intermittent hypoxia (IH) tumor cell-macrophage co-culture system was used to assess cell proliferation, migration, and macrophage polarization. In vivo, tumor growth was monitored in a CIH mouse model, and tissue samples were subsequently analyzed via immunohistochemistry and western blot. Our results demonstrated that hydrogen exerted significant antitumor effects in vivo. Mechanistically, this effect was associated with a shift in macrophage polarization toward the pro-inflammatory M1 phenotype and suppression of the CCL2-CCR2 signaling axis. In addition, in vitro studies revealed that hydrogen directly inhibited lung cancer cell survival and migration, and downregulated key components of the CCL2-CCR2 pathway, mirroring the effects observed with a CCR2 inhibitor. These findings highlighted that hydrogen treatment suppressed tumor growth by modulating the tumor immune microenvironment and inhibiting angiogenesis. Collectively, our results suggested that hydrogen may represented a novel and promising therapeutic strategy for lung cancer.