Researchers at the HUN-REN Szeged Biological Research Centre and HCEMM have identified five distinctive mutation patterns, or “fingerprints,” that could significantly enhance the prediction of tumor visibility to the immune system. Their study indicates that the nature of these mutations is more critical than the sheer number of mutations when it comes to immunotherapy efficacy. Published in the journal Molecular Systems Biology, the findings highlight a new dimension in understanding how tumors interact with immune responses.
The research team discovered that tumors often exhibit one of five dominant patterns of protein-altering mutations, known as amino acid substitution signatures. By analyzing nearly 9,300 cancer genomes across various cancer types, the researchers found that these patterns arise from DNA damage caused by environmental factors, such as tobacco smoke and UV light, as well as errors during DNA replication and repair.
Understanding Tumor Visibility to the Immune System
Not all mutations are equivalent in their impact on tumor visibility. Some mutations produce highly immunogenic protein fragments, known as neoantigens, which are easily recognized by immune cells. In contrast, other patterns yield less recognizable neoantigens, resulting in “cold” tumors that can evade detection by the immune system.
Dr. Szilvia Juhász, Head of the Cancer Microbiome Research Group at HCEMM and one of the study’s lead authors, emphasized the significance of these findings: “Despite the diversity of mutational processes, their protein-level consequences converge into just five recurring fingerprints, which can strongly influence immune recognition.”
One particularly concerning aspect identified in the study involves a mutation pattern associated with DNA repair deficiencies and exposure to harmful chemicals. Tumors exhibiting this pattern frequently demonstrate poor responses to immune checkpoint inhibitor therapies, even if they possess a high overall mutational burden. This suggests that a tumor can contain numerous mutations yet still lack adequate targets for an effective immune attack.
Dr. Benjamin Papp, co-first author of the study and researcher at the HUN-REN Szeged Biological Research Centre, remarked on this crucial finding: “Mutational burden alone is insufficient. Qualitative, protein-level consequences of mutations are critical for understanding why immunotherapy fails in many patients.”
Implications for Personalized Immunotherapy
The researchers also discovered that specific genetic variants in the human immune system, particularly certain HLA class I types common among Europeans, can enhance the presentation of mutated peptides to T cells. This finding indicates that the same tumor may be perceived differently by the immune system in different patients, enhancing the potential for personalized treatment strategies.
Dr. Máté Manczinger, Head of the Systems Immunology Research Group at the HUN-REN Szeged Biological Research Centre and senior author of the study, discussed the implications for future immunotherapy approaches: “Tumor visibility to the immune system is not determined by mutation numbers alone, but also by the protein-level patterns those mutations create.” This supports a framework for personalized immunotherapy that integrates tumor genomics with a patient’s immunogenetic background.
The significance of this research extends beyond academic interest. Improved prediction of therapy responses could lead to reduced unnecessary treatments, decreased side effects, and quicker identification of effective therapies tailored to individual patients.
This study represents a collaborative effort between the Systems Immunology Research Group at the HUN-REN Szeged Biological Research Centre, the HCEMM Cancer Microbiome Research Group, and the Evolutionary Systems Biology Research Group led by Csaba Pál. The comprehensive findings have been published in the March 2026 edition of Molecular Systems Biology.