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Protective immune mechanism induced by live-attenuated double-deleted L. monocytogenes ∆actA/∆inlB vaccine strain delivering tumor antigens keeps hepatobiliary malignancies under control. Live-attenuated, double-deleted L. monocytogenes ∆actA/∆inlB strain expressing model tumor antigen was used in both, prophylactic and therapeutic vaccination settings. Vaccination was safe and led to: (i) induction of protective tumor-specific Th1 immune responses in premalignant and malignant stages and strong increase of tumor-specific IFN-ɣ+ CD4 and CD8 T cells; (ii) decrease of T regulatory cells; (iii) downregulation of several tumor-promoting ICI molecules (PD-1, CD160, LAG3, 4-1BBL) on CD4/CD8 T lymphocytes; (iv) decrease of tumor-specific IgG in serum, and (v) decrease of B lymphocytes, DC and MΦ locally in livers. iCCA, intrahepatic cholangiocarcinoma.