A new study has found that people born with inherited cancer-risk syndromes may carry distinctive signs of immune-system activation years before cancer becomes clinically apparent. The research, published in BMC Medicine, examined the systemic immune environment of 391 individuals, including 227 people living with hereditary cancer predisposition syndromes (HCPSs). The findings suggest that inherited cancer risk is associated not only with changes in DNA repair and tumor biology, but also with measurable differences in circulating immune cells and inflammatory signaling. Researchers say these immune patterns could eventually help guide personalized cancer-prevention strategies, although the current work is cross-sectional and does not establish whether the observed immune changes directly cause, prevent, or predict cancer development.
The investigation focused principally on two important hereditary syndromes: hereditary breast and ovarian cancer associated with germline pathogenic variants in BRCA1, and Lynch syndrome, which arises from inherited defects in DNA mismatch-repair genes. Germline variants are present in virtually every cell of the body, meaning that their biological effects can extend beyond the tissues in which tumors eventually develop. In BRCA1-associated disease, impaired repair of DNA double-strand breaks can increase genomic instability. Lynch syndrome, by contrast, is linked to faulty correction of replication errors, producing mismatch-repair deficiency and a high burden of mutations. Both settings can generate abnormal cells that immune surveillance mechanisms may recognize and eliminate before they progress into invasive cancer.
To investigate how these inherited risks intersect with immunity, the researchers combined three complementary technologies. Single-cell transcriptomics measured gene-expression programs in individual immune cells, allowing the team to distinguish subtle functional states that can be hidden when millions of cells are analyzed together. Multiparametric mass cytometry used metal-tagged antibodies and time-of-flight mass spectrometry to identify numerous proteins on and inside immune cells simultaneously, enabling detailed classification of lymphocyte and myeloid-cell populations. Cytokine profiling provided a biochemical readout of soluble immune signals circulating in blood. Together, these methods offered a multidimensional picture of immune-cell abundance, activation, differentiation, and communication in people with and without hereditary cancer risk.
One of the clearest observations was a reduction in the abundance of peripheral B cells in both women with BRCA1 germline pathogenic variants who had breast cancer and individuals with Lynch syndrome. The B-cell compartment also displayed a more differentiated phenotype. B cells are best known for producing antibodies, but they also present antigens to T cells, organize immune memory, and release regulatory molecules that influence inflammation. Their maturation proceeds through several stages, from naïve cells that have not yet encountered their target antigen to memory and antibody-secreting populations. A shift toward more differentiated states, together with lower overall abundance, may therefore reflect altered immune experience or regulation rather than a simple loss of immune function. The study does not show whether these changes are harmful, protective, or consequences of other biological processes.
The immune profile was especially notable among cancer-free women carrying BRCA1 pathogenic variants. Although these participants had no manifest cancer at the time of assessment, multiple immune-cell lineages showed an activated phenotype resembling that observed in patients with established disease. Activation can involve increased expression of antigen-presentation molecules, co-stimulatory proteins, inflammatory receptors, or cytotoxicity-associated markers. In practical terms, the result suggests that the immune system may be responding to persistent cellular stress, altered tissue signals, or the continual emergence and removal of abnormal cells in individuals with inherited susceptibility. This interpretation remains provisional: an activated peripheral immune profile is not equivalent to a tumor-specific response, and it should not be treated as evidence that cancer is present or imminent.
Lynch syndrome revealed a different pattern. In this group, B-cell phenotypes showed the largest changes associated with cancer eradication, indicating that the immune system’s circulating B-cell landscape may be particularly sensitive to the presence or removal of Lynch-associated tumors. The researchers also detected increased levels of interleukin-6, or IL-6, in presymptomatic individuals with Lynch syndrome. IL-6 is a multifunctional cytokine involved in acute and chronic inflammation, B-cell maturation, hematopoiesis, and communication between immune and nonimmune tissues. Persistently elevated IL-6 has been reported in several inflammatory and malignant conditions, but its presence in people without diagnosed cancer should be interpreted cautiously. The finding may reflect a syndrome-associated immune state, yet it requires validation in larger longitudinal cohorts before it can be considered a risk marker.
The contrast between the two syndromes is scientifically important because it argues against a single, universal immune signature of hereditary cancer predisposition. BRCA1 carriers appeared to show broad activation across several immune lineages even before disease became clinically evident, whereas Lynch syndrome was characterized more strongly by changes in B-cell states and systemic IL-6 elevation. These differences may arise from the distinct molecular defects underlying the syndromes, the tissues most vulnerable to transformation, the types of abnormal antigens generated, or the immune consequences of previous cancers and treatments. The study’s use of single-cell and high-dimensional protein measurements allowed the researchers to detect this biological complexity rather than reducing immunity to a single white-blood-cell count or inflammatory marker.
The findings also have potential implications for cancer interception, an emerging field focused on preventing malignancy or detecting it at its earliest stages. If immune alterations can be confirmed as stable, syndrome-specific, and predictive, they might eventually be used alongside genetic testing, imaging, endoscopic surveillance, and clinical history to refine individual risk assessments. They could also help identify biological pathways that are susceptible to intervention. The study points toward possible relevance for immune-checkpoint inhibitors, drugs that release inhibitory signals on T cells and are already important in mismatch-repair-deficient cancers. However, the researchers do not present evidence that immune therapy should be given to cancer-free carriers, and preventive treatment would require rigorous trials because immune activation can produce serious toxicity without providing benefit.
Several limitations place the results in context. The research captures immune features at one point in time, so it cannot determine how these profiles evolve before cancer, during tumor formation, after treatment, or over long-term surveillance. The participants also represent specific hereditary syndromes and clinical groups, meaning that the findings should not automatically be generalized to every inherited cancer-risk gene. Immune measurements can be influenced by age, sex, infection, medication, previous cancer, surgery, hormonal status, and other environmental factors. Even highly detailed molecular signatures may be difficult to translate into routine clinical testing unless they demonstrate reproducibility and clear predictive value. Future prospective studies following unaffected carriers over time will be essential to determine whether the observed immune states identify individuals at greater risk or instead reflect protective surveillance.
For now, the study provides evidence that hereditary cancer predisposition is accompanied by systemic immunological changes that can be detected in the bloodstream, including in people who appear clinically healthy. Its central message is not that an activated immune profile diagnoses cancer, but that inherited susceptibility and immune biology are closely connected. By mapping these connections across B cells, T cells, myeloid populations, and circulating cytokines, the researchers have created a foundation for investigating how the body recognizes and controls precancerous cells. The long-term goal is a more individualized approach to prevention—one that combines inherited genetic information with dynamic measurements of immune function to identify the most appropriate surveillance and risk-reduction strategies for each person.
Subject of Research: Systemic immune activation and peripheral immune alterations in hereditary cancer predisposition syndromes, particularly BRCA1-associated hereditary breast and ovarian cancer syndrome and Lynch syndrome.
Article Title: Systemic immune activation in hereditary cancer predisposition syndromes: a cross-sectional study
Article References: Kelemen, I., Horti-Oravecz, K., Bozsik, A. et al. “Systemic immune activation in hereditary cancer predisposition syndromes: a cross-sectional study.” BMC Medicine (2026).
Image Credits: AI Generated
DOI: 10.1186/s12916-026-05188-x
Keywords: Hereditary breast and ovarian cancer syndrome, BRCA1, Lynch syndrome, precancer immunity, peripheral immune phenotype, cancer immunosurveillance, immune-checkpoint inhibitors, mass cytometry, single-cell transcriptomics, cytokine profiling
