Pancreatic cancer cell-intrinsic transglutaminase-2 promotes T cell suppression through microtubule-dependent secretion of immunosuppressive cytokines

Pancreatic ductal adenocarcinoma (PDAC) remains resistant to immunotherapy due to a highly immunosuppressive tumor microenvironment. Lahusen <i>et al</i> identify transglutaminase 2 (TGM2) as a critical tumor cell-intrinsic regulator of immune suppression in PDAC. TGM2 enhances the secretion of suppressive cytokines such as granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage-CSF (GM-CSF) via a microtubule-dependent pathway that secondarily impairs T-cell activation and cytotoxicity. Targeting TGM2, either genetically or with microtubule-disrupting agents, restores T cell function and promotes tumor control in preclinical PDAC models. These findings are discussed in the context of our recent work on vasoactive intestinal peptide (VIP) signaling in PDAC, which independently drives immune evasion through VIP receptor (VPAC)-mediated induction of TGF-β1 secretion from tumor cells, upregulation of programmed death-ligand 1 on myeloid cells, and inhibition of effector T cells. Here, we have explored the mechanistic intersections between TGM2 and VIP signaling-including cytokine secretion, vesicle trafficking, and immune checkpoint regulation-and propose combination strategies that integrate TGM2 or VIP inhibition with checkpoint blockade. Together, these insights suggest a new framework for overcoming immune resistance in PDAC by targeting cancer cell-intrinsic secretory programs and offer a rationale for biomarker-guided, multimodal immunotherapeutic approaches.