Gut microbiota affects PD-L1 therapy and its mechanism in melanoma

Abstract

Immune checkpoint inhibitors (ICIs), particularly PD-1/PD-L1 blockade, have shown great success in treating melanoma. PD-L1 (B7-H1, CD274), a ligand of PD-1, binds to PD-1 on T cells, inhibiting their activation and proliferation through multiple pathways, thus dampening tumor-reactive T cell activity. Studies have linked PD-L1 expression in melanoma with tumor growth, invasion, and metastasis, making the PD-1/PD-L1 pathway a critical target in melanoma therapy. However, immune-related adverse events are common, reducing the effectiveness of anti-PD-L1 treatments. Recent evidence suggests that the gut microbiome significantly influences anti-tumor immunity, with the microbiome potentially reprogramming the tumor microenvironment and overcoming resistance to anti-PD-1 therapies in melanoma patients. This review explores the mechanisms of PD-1/PD-L1 in melanoma and examines how gut microbiota and its metabolites may help address resistance to anti-PD-1 therapy, offering new insights for improving melanoma treatment strategies.

Keywords: Checkpoint blockade; Intestinal flora; Melanoma; PD-L1 therapy; Tumor immunotherapy mechanisms; Tumor microenvironment.

Fig. 1

Mechanism of action of PD-1 and PD-L1 in melanoma, a Schematic diagram of the process of melanoma proliferation, infiltration and migration from the primary site. This process is closely related to the tumor microenvironment. b Schematic diagram of the mechanism of action of the PD-1: PD-L1 signaling pathway in melanoma. The binding of PD-1 and PD-L1 can block the proliferation and activation of T cells, and the interaction between PD-L1 expressed by melanoma and PD-1 receptors in neighboring melanoma can promote their proliferation and migration

Fig. 2

Six signaling pathways associated with the PD-L1 and PD-1 pathways in melanoma. The expression and regulation of the PD-1:PD-L1 pathway in melanoma are associated with multiple signaling pathways, including the PI3K/AKT/mTOR signaling pathway, MAPK pathway, JAK/STAT pathway, WNT pathway, NF-κB pathway, and Hedgehog signaling pathway, all of which can directly or indirectly promote the expression of PD-L1 or the proliferation of melanoma. The green dotted line indicates a promoting effect on the PD-1:PD-L1 pathway or on the proliferation of melanoma; the red dotted line indicates an inhibitory effect on the PI3K signaling pathway or on the proliferation of T cells