Researchers from the Sant Pau Research Institute (IR Sant Pau) have demonstrated, in a preclinical study, the effectiveness of a targeted nanotoxin in inhibiting colorectal cancer growth. The study, published in the journal International Journal of Nanomedicine, was conducted in an immunocompetent mouse model with microsatellite stable (MSS) colorectal cancer, a form known for its resistance to current immunotherapies.
MSS tumors represent the majority of colorectal cancer cases and are characterized by a lack of instability in DNA microsatellite sequences. This trait contributes to an immunosuppressive tumor microenvironment, which hampers the efficacy of conventional immunotherapies. Therefore, developing strategies to modify this environment is essential for improving available therapeutic options.
The developed nanotoxin, called T22-DITOX-H6, specifically targets tumor cells that overexpress the CXCR4 receptor, a protein associated with the progression and spread of advanced colorectal cancer. This nanotoxin is composed of nanoparticles that combine a CXCR4 receptor ligand with the active domain of diphtheria toxin, enabling a precise cytotoxic action on the tumor while sparing healthy tissues.
In the study, mice received three intravenous doses of T22-DITOX-H6 over the course of one week. The results showed a significant reduction in tumor growth compared to untreated animals. Notably, this decrease was observed consistently, and biochemical and histological analyses did not detect signs of systemic toxicity or damage to vital organs such as the liver or kidneys.
In addition to the direct effect on tumor cells, the treatment induced a specific type of cell death known as pyroptosis. Unlike other forms of programmed cell death, pyroptosis is highly inflammatory, as it causes the cell to rupture and release signals that activate the immune system. In the context of cancer, this process not only eliminates tumor cells but also helps reshape the immunosuppressive tumor microenvironment, making it more conducive to an effective immune response.
Significantly, the study demonstrates for the first time that inducing pyroptosis in an immunocompetent colorectal cancer model triggers local inflammation and activates host immune cells within the tumor tissue. This process is associated with eosinophil infiltration and degranulation, a mechanism by which eosinophils release cytotoxic compounds that contribute to halting tumor growth. This finding reveals a little-explored mechanism of action with a strong innate immune response component, especially relevant in MSS tumors.
“This study proves that targeted nanotoxins can become a powerful tool to fight aggressive and treatment-resistant tumors such as MSS colorectal cancer. They not only eliminate tumor cells but also activate immune mechanisms that are typically inactive in this type of tumor,” explains Dr. Lorena Alba-Castellón, lead researcher of the study at IR Sant Pau and member of CIBER-BBN.
These findings reinforce the potential of personalized nanomedicine as an innovative therapeutic strategy to tackle tumors that are unresponsive to conventional treatments and open the door to future clinical developments in patients with advanced colorectal cancer.
Carrasco-Díaz LM, Gallardo A, Voltà-Durán E, Virgili AC, Páez D, Villaverde A, Vazquez E, Álamo P, Unzueta U, Casanova I, Mangues R, Alba-Castellon L.
A Targeted Nanotoxin Inhibits Colorectal Cancer Growth Through Local Tumor Pyroptosis and Eosinophil Infiltration and Degranulation. Int J Nanomedicine. 2025;20:2445–2460
https://doi.org/10.2147/IJN.S499192
