Molecular regulatory network of PD-L1 expression under Helicobacter pylori infection and its clinical translational value: a review of multi-pathway crosstalk mechanisms

Helicobacter pylori ( H. pylori ) infection is a well-established risk factor for gastric cancer (GC), acting in part through modulation of the immune checkpoint molecule programmed death-ligand 1 (PD-L1) within the tumor microenvironment (TME). Previous reviews have described H. pylori -induced PD-L1 upregulation, but a synthesis of the underlying molecular regulatory networks—particularly the crosstalk among nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), mitogen-activated protein kinase (MAPK), signal transducer and activator of transcription 1 (STAT1), and Sonic Hedgehog (Shh) pathways—is lacking. This review integrates recent basic and clinical findings to elucidate how H. pylori virulence factors, including cytotoxin-associated gene A (CagA) and vacuolating cytotoxin A (VacA), orchestrate PD-L1 expression through multiple signaling cascades. We compare the differential effects of distinct virulent strains on PD-L1 upregulation and examine the dual-edged nature of H. pylori -induced PD-L1 overexpression—serving both as a marker of immune suppression and a potential predictor of immune checkpoint inhibitors (ICIs) sensitivity—with emphasis on how Epstein-Barr virus (EBV) infection and microsatellite instability (MSI) modify and amplify this duality. By providing a comprehensive overview of these multi-pathway regulatory mechanisms and their clinical implications, this review aims to offer theoretical foundations and translational guidance for optimizing immunotherapeutic strategies, particularly ICIs, in GC management.