A New Approach to Make Colorectal Tumors Resistant to Immunotherapy Sensitive
Metastatic microsatellite-stable colorectal cancers represent an aggressive form of the disease, often resistant to standard immunotherapy treatments. These tumors, which constitute the majority of metastatic cases, are characterized by low immune system activation and significant molecular diversity between different metastasis sites, limiting the effectiveness of current therapies.
A recent study conducted an in-depth analysis of the transcriptional profile of tumor biopsies taken from patients with this form of cancer and treated with a combination of two antibodies, botensilimab and balstilimab. Using advanced artificial intelligence techniques, researchers identified four distinct molecular types of tumors. The first, called liver-like, is distinguished by a metabolism similar to that of the liver and a suppressive immune environment. The other three types are proliferative, marked by rapid cell growth, inflammatory, rich in immune cells, and mesenchymal, associated with a strong presence of fibers and stromal cells.
Inflammatory and mesenchymal type tumors showed a better response to treatment as well as prolonged survival compared to proliferative and liver-like types. This is explained by a reprogramming of the tumor environment towards a state more conducive to immune activity, with an increase in antigen presentation, T lymphocyte recruitment, and cytotoxic activity.
The study also revealed that the expression of certain genes, such as those in the APOBEC3 family, is closely linked to an increased immune response. These genes, involved in mechanisms of localized mutation, could play a key role in generating neoantigens, molecules capable of triggering an immune response against the tumor. Their activation is associated with a high interferon signature, a marker of intense immune activity.
Another important aspect is cellular plasticity, that is, the ability of tumor cells to change shape and function to adapt to their environment. Researchers observed that tumors most sensitive to treatment exhibited a loss of their initial epithelial identity, accompanied by an increase in this plasticity. This suggests that tumor cells can evolve towards states more vulnerable to immune system attacks.
Treatment with botensilimab and balstilimab thus appears capable of modifying the tumor environment to make it more accessible to immune defenses. Patients whose tumors initially had an inflammatory or mesenchymal profile benefited from a significant reduction in tumor size and an improvement in their prognosis.
These results open promising perspectives for the development of targeted therapeutic strategies, capable of transforming traditionally resistant tumors into targets sensitive to immunotherapy. They also highlight the importance of fine molecular characterization of tumors to tailor treatments and improve the chances of success.
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Original Publication
DOI: https://doi.org/10.1038/s41388-026-03861-2
Title: Transcriptomic profiling identifies immunotherapy-responsive phenotypes in microsatellite-stable metastatic colorectal cancer
Journal: Oncogene
Publisher: Springer Science and Business Media LLC
Authors: Tomas Konecny; Nate Zadirako; Arpine Grigoryan; Melina Tamazyan; Sveta Mnatsakanyan; Luiza Stepanyan; Henry Loeffler-Wirth; Sean Bourdelais; Gabriel Mednick; Chloe Delepine; Dhan Chand; Hans Binder