In a groundbreaking development that could reshape our understanding of cancer progression and treatment, researchers from leading institutions including the Francis Crick Institute, University College London (UCL), Gustave Roussy, and Memorial Sloan Kettering Cancer Center (MSK) have unveiled pivotal findings linking age-associated blood cell mutations to poorer cancer outcomes. This extensive study reveals that the expansion of mutated blood cells— a condition commonly associated with aging—does not merely reside within the bloodstream but can infiltrate solid tumors, thereby influencing disease progression and patient survival.
The phenomenon at the center of this discovery is clonal haematopoiesis of indeterminate potential (CHIP). CHIP emerges when hematopoietic stem cells in the bone marrow acquire somatic mutations as individuals age and are exposed to environmental stresses. Although CHIP has been previously associated with increased risks for cardiovascular diseases and blood cancers, its role in the evolution of solid tumors remained unclear until now. By leveraging large-scale genomic and clinical data sets, the researchers were able to establish that CHIP mutations are present in the circulating blood of cancer patients and critically, in a substantial proportion of tumor-infiltrating immune cells.
This comprehensive study incorporated data from over 400 lung cancer patients enrolled in the Cancer Research UK-funded TRACERx and PEACE trials, as well as an expansive cohort of nearly 49,000 patients with various cancer types treated at Memorial Sloan Kettering Cancer Center. Blood samples from these cohorts underwent deep sequencing to identify the presence of CHIP mutations. Matching the genomic data with clinical outcomes uncovered a stark correlation: patients harboring CHIP mutations exhibited markedly reduced overall survival, independent of their age or tumor stage at diagnosis. This observation introduced a previously unappreciated dimension of how age-related clonal blood mutations can influence cancer prognosis.
Digging deeper, the team identified a subset of patients in whom these mutated blood cells had physically infiltrated the tumor microenvironment, a situation they termed tumor-infiltrating clonal haematopoiesis (TI-CH). Remarkably, about 42% of patients with CHIP demonstrated TI-CH, highlighting the significant cross-talk between the hematopoietic system and tumor biology. It was TI-CH, rather than CHIP alone, that emerged as a powerful predictor of cancer relapse and mortality, thus emphasizing the biological relevance of these infiltrating mutant cells.
Further investigation into metastatic sites, studied through postmortem analyses under the PEACE protocol, reinforced the notion that TI-CH is not confined to primary tumors but is prevalent in secondary lesions where cancer dissemination occurs. The presence of TI-CH mutations in metastatic foci implicates these mutant myeloid cells as active players in the terminal phases of cancer progression, possibly facilitating the establishment and persistence of aggressive disease phenotypes.
Crucially, the study dissected the cellular composition and genotypic profiles of these tumor-infiltrating cells. Myeloid cells—a diverse group of immune cells involved in inflammation and tissue remodeling—were found to be the predominant cell type housing CHIP mutations within the tumor microenvironment. Unlike cytotoxic lymphocytes that target and eliminate cancer cells, myeloid cells often adopt immunosuppressive or tumor-supportive roles. This shift in immune landscape could enable tumor cells to evade immune surveillance and accelerate their growth and spread.
Among the mutated genes identified within TI-CH cells, TET2 stood out due to its critical regulatory functions in hematopoiesis and epigenetic control. TET2 mutations were disproportionately represented in tumor-infiltrating myeloid populations compared to other immune subsets. By analyzing hundreds of single cells from tumors of patients with TI-CH, the researchers confirmed that these alterations were predominantly restricted to myeloid cells, indicating a selective advantage or tropism for TET2 mutant cells to colonize the tumor microenvironment.
To translate these observations into functional insights, the research team collaborated with experts on blood cancers and CHIP at the Crick Institute, including the laboratory led by Dominique Bonnet. Together, they engineered three-dimensional lung tumor organoids co-cultured with TET2 mutant myeloid cells, effectively mimicking the complex interactions within human tumors. The presence of mutant myeloid cells induced pronounced remodeling of the tumor microenvironment and accelerated organoid growth, providing experimental evidence that TET2 mutations in infiltrating immune cells actively foster tumor progression rather than serving as passive bystanders.
Expanding the scope of their findings, the investigators examined a diverse array of cancers beyond lung cancer, validating TI-CH as an independent prognostic factor for reduced survival across multiple tumor types. Notably, TI-CH prevalence was elevated in malignancies historically linked with poor therapeutic responses, including pancreatic cancer and head and neck squamous cell carcinomas. This suggests that age-related clonal hematopoiesis may contribute to the treatment resistance observed in these cancer subsets, potentially through modulation of the tumor immune milieu.
This research marks a pivotal milestone in clarifying the interface between aging, clonal hematopoiesis, and cancer biology. While prior studies have focused on intrinsic tumor mutations and microenvironmental factors, the recognition that mutated blood-derived immune cells infiltrate and reprogram tumors introduces a paradigm shift. Understanding the precise molecular mechanisms by which CHIP-driven TI-CH influences cancer cell behavior and immune evasion could unlock new avenues for targeted therapies and intervention strategies.
Future research directions, as outlined by the team, will focus on establishing the causal relationships linking CHIP and aggressive cancer phenotypes, alongside elucidating the signaling pathways governing myeloid cell expansion and tumor infiltration. Such knowledge may pave the way for novel clinical approaches to modulate the impact of clonal hematopoiesis—either by targeting mutant myeloid populations or by reversing their tumor-promoting activities.
Oriol Pich, a postdoctoral scientist at the Crick’s Cancer Evolution and Genome Instability Laboratory and lead author of the study, stressed the clinical significance of these findings: “Our results reveal that blood cells carrying age-related mutations are not mere passive passengers but can actively infiltrate tumors, shaping cancer evolution and ultimately influencing patient outcomes.” The study highlights CHIP as a widespread, age-associated phenomenon common in cancer patients, underscoring the need to consider patient age and hematopoietic mutation status in personalized oncology.
Charlie Swanton, Deputy Clinical Director at the Francis Crick Institute and Chief Investigator for the TRACERx project, emphasized the transformative potential of linking two clonal proliferations—CHIP and solid tumor evolution. “This is a first-of-its-kind demonstration at scale that integrates age-related mosaicism in the hematopoietic system with cancer development. As we decode the mutations emerging during aging in bone marrow cells and their systemic effects, we open a new frontier in cancer prevention and treatment.”
Supported by Cancer Research UK and the National Institute of Health and Care Research UCLH Biomedical Research Centre, this landmark study published in the New England Journal of Medicine on April 23, 2025, charts unexplored territory in the intertwined pathologies of aging and cancer. It calls for the oncology community to incorporate the dynamics of clonal hematopoiesis into future clinical trials, risk assessment models, and therapeutic design, heralding a new era of precision medicine informed by the biology of aging.
Subject of Research: Animals
Article Title: Tumor-Infiltrating Clonal Hematopoiesis
News Publication Date: 23-Apr-2025
References: Pich, O. et al. (2025). Tumor-Infiltrating Clonal Hematopoiesis. New England Journal of Medicine.
Keywords: Lung cancer, Myeloid cells
Tags: age-related genetic alterationsaging and cancer treatment implicationsblood cell mutations and cancercancer outcomes and agecancer survival and blood healthCHIP and solid tumorsclonal haematopoiesis of indeterminate potentialenvironmental stress and cancer progressiongenomic data in cancer researchhematopoietic stem cells mutationslung cancer patient studytumor-infiltrating immune cells
