Therapeutic potential of Traditional Chinese Medicine Yisui Shengxue pills to inhibit hypoxia-inducible factor-1alpha and general control nonderepressible 2 to regulate the post-chemotherapy immune response: integrating network pharmacology and experimental validation.

Objective: To investigate the efficacy and mechanism of Traditional Chinese Medicine Yishui Shengxue pills (, YSSX) in mouse models of immunosuppression induced by three chemotherapy drugs.

Methods: We determined an optimal intervention dose of YSSX to investigate efficacy. Changes in immune cell subpopulations were detected by flow cytometry, while immunofluorescence, immunohistochemistry, and other molecular biology methods, were used to verify pathway targets. We used PX-478, an inhibitor of hypoxia-inducible factor-1α (HIF-1α), to validate the mechanism of action.

Results: Analysis showed that YSSX enhanced the immunity of mouse models of immunosuppression. At the cellular level, YSSX reduced the numbers of myeloid-derived suppressor cells (MDSCs) and enhanced CD8+ T cell infiltration. At the molecular level, YSSX reduced the expression levels of hypoxia-inducible factor-1α (HIF-1α), inducible nitric oxide synthase (iNOS), general control nonderepressible 2 (GCN2), and eukaryotic initiation factor 2α (eIF2α) in mouse MDSCs, thereby reducing the transcription of HIF-1α, GCN2, and eIF2α mRNA. Collectively, these changes led to the increased secretion of interferon-γ and interleukin 12, concomitant with a reduction in tumor necrosis factor-α level.

Conclusions: YSSX improved MDSC-mediated immunosuppression in a mouse model after chemotherapy by inhibiting the HIF-1α/iNOS-GCN2/eIF2α signaling axis.