IL-6 as a central driver of immune evasion in PDAC: from IDO-mediated tolerance to multi-pathway immunosuppression.
Pancreatic ductal adenocarcinoma (PDAC) is among the most lethal cancers and is characterised by an immunologically "cold" microenvironment that limits responses to immunotherapy. This review focuses on interleukin-6 (IL-6), produced by stromal and immune cells as well as PDAC cells, as a central driver of immune evasion via JAK-STAT3 signalling. We outline how SOCS3 silencing in tumour cells inverts the IL-6-IDO relationship seen in dendritic cells, generating an autocrine IDO-Kyn-AhR-IL-6-STAT3 feedforward loop. We further describe IL-6-mediated stabilisation of PD-L1, sustained PD-1 expression on CD8+ T cells, and ST6GAL1-driven hypersialylation that activates Siglec glyco-immune checkpoints. In addition, we examine the IL-6-Blimp-1-IL-10 axis and its reprogramming of dendritic cell and T cell compartments. Given the repeated failure of IL-6(R) blockade in clinical trials, we contrast these outcomes with the more encouraging signals from RAS-targeted strategies. We propose rational IL-6-integrated combinations with upstream oncogenic targeting may represent an unrealised frontier for this disease.