ICD of cancer cells induced by OVs leads to antitumor immunity. An OV, delivered either intratumorally or systemically, reaches to tumor tissue and selectively replicates in tumor or/and stromal cells. This leads to induction of death of these cells, presenting “eat me” signals on the cell surface and later release of danger signals from necrotic cells. Apoptotic bodies are engulfed by APC, and TAAs are processed and presented along with MHC complex and costimulatory molecules. The released DAMPs (and PAMPs) activate and mature DCs, and TAAs are cross-presented to naive T cells. This process can be further enhanced at different steps by other immunomodulatory agents (in a combination strategy). The resulting cytotoxic immune response against tumor and associated stromal cells, involving CD4+ and CD8+ T cells, may help in complete eradication of tumor mass. Additional immunotherapies targeting DCs, T cells, and the immunosuppressive TME can further enhance this antitumor immune response.