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Background Recent understandings of anti-tumoral immune mechanisms reveal that the strong and sustainable activation of specific CD8 + T cells in the tumor is the major key for successful immunotherapy. Checkpoint blockade, therapeutic vaccine, bi-specific T cell engager (TCE) and CAR-T cells have strongly contributed to such tumor-specific T cell activation, however especially for solid cancers complete remission is limited. Recently, we showed that the non-cytopathic lymphocytic choriomeningitis virus (LCMV) induces strong anti-tumor responses without directly killing tumor cells. LCMV triggers infiltration of CD8+ T cells into the tumor leading to a sustained T cell dependent tumor regression. Here, we aim to generate an optimized arenavirus based on LCMV for the application of this new anti-tumoral mechanism in cancer patients.Methods We aimed to adapt LCMV strain WE to tumor tissues. We performed multiple passaging of the wild-type strain LCMV-WE in several murine and human cancer cells. The occurring mutations were identified, their role in tumor cell tropism confirmed in vitro and in vivo, and the most effective ones were combined in an attenuated reassortant LCMV.Results We identified several mutations, which showed accelerated propagation in cancer cells. By combining the identified mutations in attenuated reassortant LCM viruses, we generated arenavirus strains with accelerated entry and replication in a broad spectrum of human cancer cells. One of these strains exhibited strong anti-tumoral efficacy in a variety of tumor models with minimal replication in healthy tissues and no severe disease symptoms in immune compromised murine model systems. Dissecting the anti-tumoral mechanism revealed that tumor-specific T cells were expanded, T cells recruited to tumors and differentiated into potent effector cells. Due to this specific mode of action, this virus strain amplified the anti-tumoral activity of a TCE (Trp1/CD3) to result in a strong synergistically acting tumor therapy. In non-human primates, treatment with this strain led to substantially increased virus-mediated cytokine and chemokine levels as well as T cells in the blood by maintaining a safe application.Conclusions In conclusion, by using the biological principle of mutation and selection, we developed an arenavirus-based immune therapy safely applied in preclinical model systems and GLP studies as well as harboring a unique mode of action and proprietary anti-tumoral efficacy. Combination with T cell-directed therapies including TCE results in strong synergistic anti-tumoral responses.Ethics Approval All experiments were carried out a with ethical approval.