Background: A clinical study in patients (pts) with metastatic breast cancer (mBC) treated with pelareorep resulted in significant improvements in overall survival. Clinical studies with checkpoint blockade inhibitors (CBIs) have also resulted in noteworthy clinical responses in a small subset of mBC pts. In pts who do not respond to CBIs, the absence of IFN-γ signalling in the tumor microenvironment has been proposed as a key mediator of innate resistance. IFN-γ signalling upregulates the expression of checkpoint ligands and promotes lymphocyte activation and infiltration to the tumor microenvironment. Thus, the expression of IFN-ɣ-related genes can be used to both facilitate and predict response to CBIs. Given pelareorep’s known capacity to promote an inflamed tumor phenotype, we hypothesised that pelareorep could also stimulate the expression of IFN-ɣ-related genes associated with response to CBIs. Methods: Cell lines derived from breast cancer (BC: MCF7, T47D, MD-231), colorectal cancer (CRC: HT-29, SW620), hepatocellular carcinoma, (HCC: SNU-387) and non-small cell lung cancer (NSCLC: H522) were infected with pelareorep at a multiplicity of infection equal to 50. We examined changes in gene expression and conducted cell viability assays at 6, 12, and 18 hours post-infection (including a non-infected control). To monitor changes in gene expression we employed a 780-gene panel (nanoString) to monitor for changes in the expression of key IFN-ɣ-related and other immunity-related genes. Results: All cell lines were susceptible to pelareorep induced cytopathic effect. Strikingly, BC and HCC cells lines significantly upregulated IFN-ɣ-related genes while CRC and NSCLC cell lines demonstrated only a modest and variable ability to promote IFN-ɣ pathway activation. Moreover, BC and HCC cells lines also upregulated key chemokines that are known to promote response to immunotherapy. Conclusions: These results suggest that various tumor types are amenable to immune priming for CBIs therapy with pelareorep. The role of pelareorep in the treatment of BC and HCC deserves further investigation, particularly in combination with other immunotherapies.