An interdisciplinary team from the Medical University of Innsbruck and the University of Zurich has shown for the first time that KRAS-mutated colorectal tumors reprogram neutrophils in the bone marrow, thus turning them into tumor-promoting immune cells. The findings, published in the journal Cancer Cell, open up new approaches for immunotherapies for microsatellite-stable colorectal carcinomas.

Colorectal cancer remains one of the deadliest cancers. In particular, microsatellite-stable tumors, which account for 85 to 90 percent of cases, respond only to immunotherapies to a limited extent. In about 40 percent of these tumors, there is a mutation in the KRAS gene, which is associated with poorer treatment response.

The team, led by Zlatko Trajanoski and Stefan Salcher, first created a comprehensive single-cell atlas for colorectal cancer. To do this, the researchers integrated data from over 48 studies with samples from about 650 patients, more than 4.27 million cells and seven billion expression values. Neutrophils, the most abundant white blood cells, were severely underrepresented in these datasets because they are fragile, short-lived, and low in mRNA.

To close this gap, the scientists analyzed new samples from blood, tumor tissue and adjacent tissue from patients of the Comprehensive Cancer Center Innsbruck (CCCI). Deep single-cell sequencing established in Innsbruck enabled precise mapping of neutrophils. The analyses showed a high degree of heterogeneity: neutrophils can switch between anti-inflammatory and tumor-promoting states.

Functional experiments in organoid models and mice confirmed the findings. Especially in KRAS-mutated tumors, the cancer sends signals to the bone marrow that condition neutrophils to tumor-favoring subtypes during their maturation. This early reprogramming explains, at least in part, the resistance to existing therapies.

The study derives a new therapeutic approach from this: Instead of fighting the tumor directly, drugs could be used specifically in the bone marrow to modify the neutrophils before their tumor-induced modification. Such substances already exist, but are not yet established in oncology. The work provides an important basis for the development of tailor-made strategies, especially for patients with KRAS-mutated colorectal cancer.

Further investigations are planned to translate the findings into clinical applications. The participation of researchers such as Dominik Wolf, Andreas Pircher and the first authors Valentin Marteau, Niloofar Nemati and Kristina Handler underlines the interdisciplinary strength of the project.

The publication was published in Cancer Cell (DOI: 10.1016/j.ccell.2025.12.003).

Original Paper:

Single-cell integration and multi-modal profiling reveals phenotypes and spatial organization of neutrophils in colorectal cancer: Cancer Cell

Editor: X-Press Journalistenbüro GbR

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