Pancreatic ductal adenocarcinoma (PDA) patients have not yet benefitted from the revolution in cancer immunotherapy due in large part to a dominantly immunosuppressive tumor microenvironment (TME). MEK inhibition combined with autophagy inhibition leads to transient tumor responses in some PDA patients. We examined the functional effects of combined MEK and autophagy inhibition on the PDA immune microenvironment and the efficacy of synergizing the combined inhibition of MEK and autophagy with CD40 agonism against PDA using immunocompetent model systems.