The interplay between p21-activated kinases and tumour-infiltrating dendritic cells and T cells and its implication in pancreatic cancer immunotherapy.

Pancreatic Ductal Adenocarcinoma (PDA) remains one of the deadliest malignancies, characterized by the paucity of effective therapies and an inferior prognosis, driven by an immunosuppressive tumour microenvironment (TME), marked by defective dendritic cells (DCs) function, exclusion or dysfunction of effector T cells, and dominance of suppressive stromal and myeloid cells. p21-activated kinases (PAKs) play crucial roles in PDA tumorigenesis. Emerging evidence highlights PAKs as pivotal regulators of PDA immune evasion by inhibiting the recruitment and function of DCs and T cells, integrating oncogenic, metabolic, and cytoskeletal signaling to shape the tumour immune microenvironment. Although immune checkpoint inhibitors (ICIs), DC cancer vaccines, and T cell-based immunotherapies have demonstrated safety and immunogenicity, the clinical efficacy remains uncertain in PDA. It has been shown in preclinical models that inhibition of PAKs reduces tumour growth, enhances DCs and T cells infiltration, restores DC and cytotoxic T cell function, and improves the efficacy of chemotherapy and ICIs. In this review, we summarized current evidence on the roles of PAKs in DC and T cell dysfunction in PDA and discussed their impact on PDA immunotherapy. The combination of PAK inhibition with immunotherapies may present promising regimens to enhance immune responsiveness and clinical outcomes of PDA patients.