Astragalus polysaccharide antagonized anti PD-1 efficacy in melanoma through inhibiting JAK-STAT1/CIITA and TLR/NF-κB signaling.

OBJECTIVE

Advanced melanoma remains a major clinical challenge due to resistance to immune checkpoint inhibitors (ICIs, e.g., anti PD-1). Astragalus Polysaccharide (APS) is a clinically approved immunomodulator for cancer treatment. However, its interaction with anti PD-1 remains largely unknown. This study aims to explore the efficacy and underlying mechanism of APS combined with anti PD-1 in melanoma.

METHODS

For in vivo studies, the anti-tumor effect of APS combined with anti PD-1 was evaluated in a B16-OVA melanoma mouse model. For mechanism exploration, immunohistochemistry, flow cytometry, ELISA, PCR array, qRT-PCR, Western blotting and confocal microscopy were employed to detect tumor immune microenvironment changes and related signaling pathway activation.

RESULTS

Unexpectedly, APS significantly antagonized the anti-tumor efficacy of anti PD-1 in melanoma mice. APS reversed anti PD-1-induced infiltration of CD4+ T cells, CD8+ T cells and dendritic cells (DCs) in the tumor microenvironment, and impaired DC maturation and CD4+ T cell activation. Mechanistically, APS significantly inhibited JAK-STAT1 signaling, downregulated MHCII master regulator CIITA, and subsequently reduced MHCII expression. Meanwhile, APS markedly suppressed TLR signaling and attenuated NF-κB mediated inflammatory responses in B16-OVA melanoma cells and DCs.

CONCLUSION

APS antagonized anti PD-1 efficacy by inducing an immunosuppressive microenvironment via dual inhibition of JAK-STAT1/CIITA signaling and TLR/NF-κB signaling. This study suggests that the combination of natural polysaccharides and ICIs may warrant caution, although further studies are needed to validate these findings and determine their clinical relevance.