**3. Overview of Common Experimental Models to Study OV Therapy in PDAC**

Oncolytic virus (OV) therapy is a relatively novel anticancer approach. Effective OV therapy is dependent on the oncoselectivity of OVs—their ability to preferentially infect, replicate in and kill infected cancer cells without damaging nonmalignant ("normal") cells. The ideal OV therapy not only requires the direct lysis of cancer cells by the virus but also activates innate and adaptive anticancer immune responses [49] (Figure 1).

**Figure 1.** General Overview of Oncolytic Virotherapy. This figure demonstrates the general method of action for the treatment of cancer by oncolytic virotherapy using VSV as an oncolytic virus. The images depict the infection and oncolysis of malignant cells over time, followed by immunostimulation of cells invading the cleared area. The figure was created by authors with BioRender software (BioRender.com).

Preclinical PDAC models are critical for understanding the biology of PDAC, are platforms for developing novel strategies against PDAC, and are a necessary part of the drug development pipeline. There are several features of an ideal PDAC model system to develop clinically relevant OV therapy against PDAC: (1) the ability to test OV against different PDACs, characterized by various responsiveness to different therapies, including OV therapy; (2) the model should recapitulate a complex TME of PDACs; (3) tractability of the model, including the ability to trace both tumor cells and OV; (4) the ability to deliver OV systemically, as the PDAC are difficult to access; (5) the ability to detect and evaluate innate and adaptive immune responses against both tumor cells and OV. Unfortunately, there is no single PDAC model that successfully recapitulates all these critical features and challenges of the disease. However, there are numerous models for PDAC, each with unique advantages and disadvantages. Here, we will briefly review the advantages and disadvantages of various in vitro and in vivo models of PDAC and how they can contribute to the development of OV therapeutics.
