Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers, and current therapeutics provide limited benefits to patients. Desmoplasia and the highly immunosuppressive tumor microenvironment (TME) play a significant role in PDAC being elusive to current therapeutics. In this study, we strategically selected four transgenes to express from adenovirus (Ad) vectors to target desmoplasia and the highly immunosuppressive TME in PDAC: interferon γ (IFNγ), the extracellular (soluble) domain of transforming growth factor beta receptor 2 (sTGFβRII), interleukin 7 (IL7), and the extracellular (soluble) domain of T cell immunoglobulin and mucin domain–containing protein 3 (sTIM3). We used an immunocompetent syngeneic mouse model harboring tumors derived from KrasG12D/+;Trp53R172H/+; p48-Cre (KPC) cells, a common mouse pancreatic cancer cell line, to test the antitumor effects of our transgene-expressing Ad vectors. We showed that all four transgenes elicited significant antitumor effects and shifted the tumors to a more immunogenic profile by increasing intratumoral expression of immune activation proteins and infiltration of antitumor immune cells. Furthermore, inhibition of desmoplasia was observed in three of the four proteins. Of the four transgenes analyzed, IFNγ and sTGFβRII induced the greatest antitumor results and were combined in a single Ad vector. This dual-expressing Ad vector elicited the greatest antitumor effect, an increase in immunogenicity, and a decrease in fibrosis and showed abscopal effects. These results provide insight into how the analyzed transgenes can favorably alter the TME in patients with pancreatic cancer and show encouraging potential when combined with other therapeutic regimens.