STYK1 as a targetable vulnerability enhances the efficacy of anti-PD-L1 therapy in pancreatic cancer.

Background: Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy with limited treatment options. Immunotherapy, though effective in various tumors, has limited efficacy in PDAC due to immune tolerance. Thus, identifying new targets to enhance immunotherapy response is crucial.

Methods: This study used bioinformatics analysis and public database data to identify STYK1 as a potential PDAC biomarker. We analyzed STYK1 expression in PDAC tissues, its link to patient prognosis and immune cell infiltration. In vitro experiments assessed the impact of STYK1 knockdown on PDAC cell proliferation, migration, and invasion. Immunohistochemical analysis was performed on 79 PDAC tissue samples to evaluate CD8⁺ T cell infiltration. In vivo studies examined the effects of STYK1 knockdown on tumor growth, T cell infiltration and activation, especially with anti-PD-L1 antibodies. We also investigated the molecular mechanisms of STYK1's regulation of T cell infiltration, focusing on its association with CCL20 and its role beyond the PD-1/PD-L1 pathway.

Results: Elevated STYK1 expression in PDAC tissue is associated with poor prognosis and reduced CD8⁺ T cell infiltration. STYK1 knockdown inhibits PDAC cell proliferation, migration, and invasion in vitro. In vivo, it decreases tumor growth and, when combined with anti-PD-L1 antibody treatment, significantly enhances T cell infiltration and activation without affecting PD-L1 expression. STYK1 regulates T cell infiltration via CCL20, independently of the PD-1/PD-L1 signaling pathway.

Conclusions: STYK1 is a potential predictive biomarker for immunotherapy response in PDAC, as its regulation of T cell infiltration via CCL20, independent of the PD-1/PD-L1 pathway, may provide a strategy to potentially augment immunotherapy efficacy, pending mechanistic confirmation.