DYRK1A coordinates tumor–stroma secretory programs that promote an immunosuppressive microenvironment in pancreatic cancer

Abstract Pancreatic ductal adenocarcinoma (PDAC) is characterized by a desmoplastic, immunosuppressive stroma dominated by cancer-associated fibroblasts (CAFs). Paracrine signals from cancer cells and CAFs shape the tumor microenvironment (TME), facilitating interactions that drive tumor growth and immune evasion, yet the molecular regulators of this crosstalk remain incompletely understood. Here, we show that Dual-specificity Tyrosine-Regulated Kinase 1A (DYRK1A), previously shown to promote PDAC growth by stabilizing c-MET in cancer cells, is also expressed in CAFs at levels comparable to those in cancer cells. Secretome profiling of DYRK1A-depleted cancer cells and CAFs by quantitative mass spectrometry revealed DYRK1A-dependent factors in each cell type associated with terms related to cell migration, while combining the DYRK1A-regulated proteins from both compartments highlighted additional categories associated with immune infiltration and cell-cell interactions in the TME. Genetic or pharmacological inhibition of DYRK1A reduced CCL2, CCL5 and CSF-1 secretion in cancer cells, and CXCL12 in CAFs, linking DYRK1A activity to immunosuppressive paracrine signaling. Conditioned media from DYRK1A-depleted cancer cells or CAFs impaired the migration of monocytes and myeloid-derived suppressor cells, indicating that DYRK1A remodels the PDAC secretome to recruit immunosuppressive myeloid populations. These findings extend the established role of DYRK1A beyond cancer cell-intrinsic signaling, highlighting its role as a regulator of secreted factors that shape the PDAC TME, and position this kinase as a potential target to reduce immunosuppressive signaling. Significance DYRK1A regulates chemokine and cytokine secretion in PDAC cancer cells and CAFs, promoting recruitment of immunosuppressive myeloid populations, and revealing a previously unrecognized role for this kinase in shaping the TME.