Pharmacological inhibition of LIF signaling reverses PD-L1-mediated immune suppression in gastric cancer.

introductionGastric cancer (GC) is a major clinical challenge, characterized by limited response rates to immune checkpoint inhibitors (ICIs) and persistent immune evasion. Leukemia Inhibitory Factor (LIF), an IL-6 family cytokine, reshapes the tumor microenvironment, yet its contribution to PD-L1-mediated immune suppression in GC has not been investigated. MATERIAL AND

methodsLIF and PD-L1 expression were quantified in resected GC specimens and matched mucosa by immunohistochemistry and gene expression (Log2), and their associations with clinicopathological variables and survival were evaluated. GC cell lines were exposed to recombinant LIF and to anovel LIF antagonist, LRI-305. Activation of the JAK1/STAT3 pathway, PD-L1 transcription and protein and epithelial-mesenchymal transition (EMT) markers were analyzed. By t-SNE analysis we profiled LIF⁺/PD-L1⁺ cell subsets across myeloid and non-haematopoietic compartments, and by functional assays we have assessed whether LIF blockade modulates T cell activation.

resultsLIF expression was significantly elevated in GC tissues and correlates with poor prognosis and increased PD-L1 levels. LIF promotes immune escape by activating the JAK1/STAT3 pathway, leading to transcriptional upregulation of PD-L1 and enhancement of EMT. The t-SNE analysis revealed that LIF⁺/PD-L1⁺ myeloid and non-hematopoietic cells were enriched in the neoplastic mucosa. Pharmacological blockade of LIF signaling effectively suppressed STAT3 phosphorylation and downregulated PD-L1 expression. LRI-305 treatment partially restored immune activation signatures, supporting its potential as a therapeutic adjuvant to ICIs. DISCUSSION: LIF/STAT3 enhances PD-L1 expression and participate to GC immune evasion. Targeting LIF signaling could be a strategy to overcome resistance to immunotherapy.