Fig. 3

Rationale for the combination of OV with immuno-and targeted therapies in the TME for cancer. The TME is composed of diverse cell types, secreted factors, and extracellular matrix that provide targets for combination of OV therapies. We could arbitrarily divide these targets and mechanisms of action into steps A-G. A. OV replicate selectively in tumor and have the capacity for direct oncolysis. B. OV-mediated increases in the release of DAMPs, PAMPs and cytokines promote the accumulation of CTLs at tumor beds and retention of their killing capability. C. OV induce IFN pathways followed by elicitation of immune responses, thus mediating a broader range of long-lasting antitumor effects. D. OV infection leads to increased expression of immune checkpoint molecules such as PD-L1 and CTLA-4 from cancer and stromal cells, that sensitizes infected tumors to ICI. E. Cytotoxic chemotherapy destroys tumor cells by induction of cell death, often via ICD, or targeted therapies interrupt aberrant signaling pathways and potentially death of cancer cells. This may induce weak or moderate immune responses against tumor. F. Relevant cells such as TAMs, DCs, CAFs, and MDSCs secrete ECM components, growth factors, and cytokines, which can contribute to the regulation of tumor progression and therapeutic response in unique ways, such as CAFs suppress T and NK cells via cytokines and growth factors including PGE2 and TGF-β. Some OVs are designed to target not only cancer cells, but also stromal cells (e.g., CAFs). G. OV shape the TME for immunotherapy by shifting the tumor status from ‘cold’ to ‘hot’, thus, improving immune cell recruitment and effector function