Why are some tumors “invisible” to the immune system?

The study, published in the journal Molecular Systems Biology, analyzed the genetic characteristics of more than 9,300 tumor samples and demonstrated that the effects of mutations affecting proteins are not infinitely diverse. “Genetic changes can be classified into just five characteristic amino acid substitution patterns” – says Dr. Szilvia Juhász, head of the HCEMM Cancer Microbiome Research Group and one of the study’s lead authors. “This means that it is not only the number of mutations in a tumor that matters, but also the types of protein changes they cause and how recognizable they become to the immune system.”

The immune system recognizes tumor cells based on the altered protein fragments they produce—so-called neopeptides—which are presented to T cells by HLA molecules on the cell surface. One of the most important findings of the research is that the five identified patterns lead to the formation of neopeptides recognized by the immune system to significantly different degrees. “One pattern proved particularly problematic: the protein changes caused by such mutations bind poorly to certain HLA molecules. Since this binding is essential for immune recognition, the tumor can become ‘invisible’ to the immune system. In these cases, an ‘immunologically cold’ microenvironment often develops, resulting in a weaker immunotherapeutic response—even when the tumor’s mutational burden is high,” explains Dr. Benjamin Papp, a researcher in the Systems Immunology Research Group at the HUN-REN Szeged Biological Research Center and the study’s other first author.

The research also highlighted that an individual’s genetic background significantly influences the tumor’s “visibility.” Certain HLA variants, such as HLA-B*07:02, which is common in Europe, are capable of partially counteracting the effects of patterns poorly recognized by the immune system. “This finding reinforces the view that true personalization of immunotherapies can only be achieved by examining the genetic characteristics of the tumor and the patient’s genetic background together,” emphasized Dr. Máté Manczinger, head of the HUN-REN SZBK Systems Immunology Research Group.

The study is an outstanding example of inter-institutional collaboration: the integrated work of the HUN-REN SZBK Systems Immunology Research Group, the HCEMM Cancer Microbiome Research Group, and the Evolutionary Systems Biology Research Group led by Csaba Pál combined large-scale bioinformatics analysis, immunological interpretation, and an evolutionary perspective. This interdisciplinary approach allowed researchers to consider not only the mutational burden of tumors but also qualitative patterns and the patient’s genetic characteristics.

“The research could provide a new framework for predicting the immunotherapeutic response and, in the long term, contribute to the development of personalized, effective cancer treatments,” summarized Dr. Szilvia Juhász. The study’s findings could serve as a basis for the development of biomarkers used in clinical practice, which would allow for faster and more accurate identification of which patients will respond well to various immunotherapy treatments.

The full study is available here: https://doi.org/10.1038/s44320-026-00193-x.