*2.3. Stimulation of Antitumor Immune Response*

Besides the release of DAMPs, cancer cell death also causes the release of viral PAMPs in the TME. These PAMPs mainly include DNA, ssRNA, dsRNA, proteins, and capsid contents that activate innate immune cells through stimulating PRRs such as retinoic acidinducible gene (RIG)-1, cyclic GMP-AMP synthase (cGAS), and stimulator of interferon genes (STING) [113]. DCs, as a bridge between the innate and adaptive immune systems, play a critical role in generating the antitumor response. DCs elicit a specific response against TAA-expressing tumor cells by engulfing OV-infected cells and cross-presentation of TAAs to CD8+ T and CD4+ T cells [117]. On the other hand, the OVs-derived PAMPs cause maturation of myeloid and plasmacytoid DCs, leading to the production of proinflammatory cytokines such as IFN-α, IFN-γ, IL-12, IL-1β, IL-6, IL-8, and tumor necrosis factor (TNF)-α [90,118,119]. These functional DCs, mainly CD103+ and BATF3+, prime CD8+ T cells against tumors [120]. Innate immune signaling, such as the cGAS-STING pathway, plays a pivotal role in the recruitment of lymphocytes to the TME through the expression of CXCL9 and CXCL10 [121]. Parallel to DCs, innate lymphoid cells (ILCs) also respond to the released PAMPs leading to higher inflammation and antitumor responses [18]. As an example, arenavirus-infected melanoma cells produce a high level of CCL5, leading to recruitment of NK cells and melanoma regression [122]. Interestingly, in situ antitumor responses following OVT are mainly mediated by IFN-I, whereas OVT-mediated systemic antitumor responses appear to be mediated by IFN-II excreted from TILs [123]. In general, the innate immune response to OVs increases lymphocyte infiltration, antigen presentation, and activation of the antitumor adaptive immune response through an IFN-mediated mechanism [18]. T cell activation requires at least three consecutive signals (peptide-MHC, CD28-B7, and stimulatory cytokines), all of which are defected in TME to escape adaptive immune responses. OVs, as potent immunogens, induce all three signals needed to activate T cells [18]. OVT increases the expression of B7-1/2 and CD40 on the surface of DCs and induces the expression of MHC-peptide on the surface of tumor cells leading to optimal activation of T cells [124]. Conversion of the TME phenotype from immunologically inert to immunologically active status can augment the effectiveness of the immunotherapeutic modalities.
