Inflammatory reprogramming of the solid tumor microenvironment by infiltrating clonal hematopoiesis is associated...

Clonal hematopoiesis (CH)-the expansion of somatically mutated hematopoietic cells-is common in solid cancers. CH is associated with systemic inflammation, but its impact on tumor biology is underexplored. Here, we report the effects of CH on the tumor microenvironment (TME) using 1,550 treatment-naive patient samples from the Clinical Proteomics Tumor Analysis Consortium (CPTAC) cohort. CH is present in 18.3% of patients, with one-third of CH mutations also detectable in tumor-derived DNA from the same individual (CH-Tum), reflecting CH-mutant leukocyte infiltration. Across cancers, the presence of CH-Tum is associated with worse survival outcomes. Molecular analyses reveal an association between CH-Tum and an immune-rich, inflammatory TME that is notably distinct from age-related gene expression changes. These effects are most prominent in glioblastoma, where CH correlates with pronounced macrophage infiltration, inflammation, and an aggressive, mesenchymal phenotype. Our findings demonstrate that CH shapes the TME, with potential applications as a biomarker in precision oncology.