Fig. 2

Mechanism of oncolytic viruses (OVs) targeting the TME. (i) Direct oncolysis: immunogenic cell death (ICD) induced by OVs leads to the release of numerous molecules, including pathogen-associated molecular pattern molecules (PAMPs), damage-associated molecular pattern molecules (DAMPs), and tumor-associated antigens (TAAs), which enhance activation of antigen presenting cells (APCs) such as dendritic cells (DCs). Simultaneously, infected tumor cells also produce various inflammatory cytokines such as type I interferon (IFN) and chemokines. (ii) Anti-tumor immunity: Inflammatory cytokines and chemokines are produced under OV infection, leading to the recruitment of innate immune cells such as neutrophils and natural killer (NK) cells. Antigen-loaded DCs after OV infection trigger T cell priming and degraded extracellular matrix (ECM) by OVs enhances intratumoral infiltration of T cells. The proinflammatory microenvironment created by OVs includes M2-to-M1 transition of tumor-associated macrophages (TAMs), decreased level of regulatory-T cells (Tregs) and myeloid-derived suppressor cells (MDSCs), and upregulated major histocompatibility complex-I (MHC-I) on tumor cells, which facilitate T cells to overcome immune suppression and complete the final recognition and killing step. Further immunostimulatory effect of OVs was achieved by synergizing with immune checkpoint blockade (ICB) therapy. (iii) Vascular pruning: OVs exert anti-angiogenic effects through direct lysis of tumor-associated endothelial cells (ECs) and reducing the level of vascular endothelial growth factor (VEGF), preventing the immunosuppressive effect from those angiogenic components. (iv) Stroma degradation: various ECM-degrading agents expressed by engineered OVs induce stroma degradation. Concurrently, OV-induced CAF lysis also inhibits excessive ECM production. Alleviated stroma fibrosis subsequently promotes the infiltration of T cells