Wu-wei-zi decoction reshapes the tumor immune microenvironment by targeting the IL-6/CD73 axis in myeloid-derived suppressor cells to inhibit non-small cell lung cancer.

[ETHNOPHARMACOLOGICAL RELEVANCE] Wu-wei-zi decoction (WWZ) is a clinically utilized classical herbal formula for non-small cell lung cancer (NSCLC). Nevertheless, the underlying mechanism of WWZ-treated lung cancer that is still unknown requires further investigation.

[AIM OF THE STUDY] This study investigates how WWZ reprograms tumor immune micro-environment (TIME) by regulating myeloid-derived suppressor cells (MDSCs).

[METHODS] Orthotopic NSCLC models were established in immunocompetent and immunodeficient mice to evaluate WWZ efficacy. MDSCs dynamics (frequency, apoptosis, immunosuppressive function) and CD8 T cells infiltration were assessed by flow cytometry. Target specificity was validated by depleting MDSCs with anti-Gr-1 antibodies. The key pathways were identified via network pharmacology, molecular docking and RNA-sequencing, validated through immunofluorescence co-localization in human NSCLC tissues, bioinformatic analysis, and CD73-knockdown in the immortalized MDSCs (MSC-2).

[RESULTS] WWZ significantly prolonged survival by decreasing MDSCs infiltration and immunosuppressive function to restore the CD8 T cells cytotoxicity. MDSCs depletion abrogated WWZ's therapeutic effects, confirming their pivotal role. Mechanistically, we reveal for the first time that IL-6 modulates MDSCs immunosuppression via CD73 activation in NSCLC. WWZ suppressed the IL-6/CD73 axis in MDSCs, decreasing CD73 MDSCs and downregulating immunosuppressive markers iNOS/Arg1, thereby reversing TIME suppression.

[CONCLUSIONS] WWZ modulates immunosuppressive activity by inhibiting the IL-6/CD73 axis in MDSCs in the TIME, thereby delaying tumor progression in NSCLC. This study provides the first mechanistic evidence supporting WWZ's clinical utility as a TCM immunomodulatory agent for NSCLC.