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Colorectal cancer (CRC), the third-most prevalent and second deadliest cancer, requires new therapeutic strategies due to the significant side effects of current treatments. We investigated the anticancer properties of MakA, a cytotoxin from Vibrio cholerae, administered systemically in a mouse model, with a focus on its impact on the tumor microenvironment (TME) and immune cell infiltration. Our findings demonstrate that MakA administration is non-toxic and does not cause systemic tissue damage. It increases immune cell abundance in the TME, suppresses tumor growth, promotes cancer cell apoptosis, and enhances leukocyte recruitment and activation. Elevated neutrophil and macrophage densities were associated with increased production of pro-inflammatory mediators with anti-neoplastic properties. These findings highlight MakA’s potential as a targeted, less harmful CRC therapy by modulating the TME immune response.