AIMS: To determine whether using a pH-sensitive peptide (CBX-15) for antigen-independent targeting of MMAE to tumors induced anti-tumor efficacy via direct and immunological mechanisms in the rat tumor model. METHODS: CBX-15 was assessed for its ability to kill tumor cells and induce immunogenic cell death (ICD) in female Fischer rats bearing syngeneic 13762 mammary adenocarcinoma tumors via and functional assays. RESULTS: CBX-15 demonstrated efficacy, safety and anti-tumor immunologic memory, demonstrated by the ability of both CBX-15-cured and vaccinated rats to reject further tumor challenge. Responding rats exhibited the induction of ICD-induced immunomodulatory activity, including recognition of tumor cells , recruitment of TILs and increases in memory CD4 T lymphocytes in the bone marrow. CONCLUSION: CBX-15 eradicates tumors by a combination of both direct cytotoxic action of MMAE as well as through the induction of ICD, the latter of which results in long term anti-tumor immunological memory. To our knowledge, this is the first work demonstrating both anti-tumor efficacy and induction of long-term anti-tumor immune memory by a tumor-selective drug in the rat, the species used for preclinical toxicological evaluation. This study provides a strong justification for exploring combination therapies with CBX-15 and other immunomodulators.