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Simple Summary: Cancer immunotherapy has evolved rapidly in the last decade. A newly emerging immunotherapeutic approach utilizes oncolytic viruses to enhance the ability of the body's own immune system to recognize and clear tumor cells. We have recently developed a novel chimeric oncolytic virus and demonstrated its anti-tumoral effects in various preclinical mouse models. To gain mechanistic insights into the immune response to this form of therapy at the cellular level and to identify targets to potentially further improve the therapy, we analyzed the immune cell signature in the tumors, blood, and lymphoid tissue in a syngeneic melanoma mouse model by flow cytometry. Both local and systemic immune responses were observed. Furthermore, selective depletion of cytotoxic T cells indicated that these cells are the main players in mediating the therapeutic response to this novel virotherapy. Background/Objectives: Oncolytic virotherapy is a promising approach in cancer immunotherapy. We have previously described a recombinant hybrid oncolytic virus (OV), VSV-NDV, which has a favorable safety profile and therapeutic immunogenicity, leading to direct oncolysis, abscopal effects, and prolonged survival in syngeneic in vivo tumor models. While OVs are known to mediate systemic anti-tumor immune responses, the detailed characterization of local and systemic immune responses to fusogenic oncolytic virotherapy remains unexplored. Methods and Results: We analyzed immune cell compartments in the spleen, blood, tumor-draining lymph nodes (TDLNs), and tumors over the course of VSV-NDV therapy in a bilateral syngeneic melanoma mouse model. Our results revealed significant local infiltration and activation of T lymphocytes in tumors and globally in the blood and spleen. Notably, in vivo CD8+ T cell depletion led to complete abrogation of the tumor response, highlighting the crucial role of T cells in promoting the therapeutic effects of oncolytic VSV-NDV. In vitro co-culture experiments enabled the interrogation of human immune cell responses to VSV-NDV-mediated oncolysis. Human peripheral blood mononuclear cells (PBMCs) were efficiently stimulated by exposure to VSV-NDV-infected cancer cells, which recapitulates the in vivo murine findings. Conclusions: Taken together, these data characterize a broad anti-tumor immune cell response to oncolytic VSV-NDV therapy and suggest that CD8+ T cells play a decisive role in therapeutic outcome, which supports the further development of this chimeric vector as a multimechanistic immunotherapy for solid cancers. [ABSTRACT FROM AUTHOR]