Integrative Multi‐Omics Profiling Reveals Age‐Associated Genomic and Tumor Microenvironmental Heterogeneity in Colorectal Cancer

Abstract

Early‐onset colorectal cancer (EOCRC) is increasing worldwide, yet the molecular basis underlying its age‐related heterogeneity remains insufficiently defined. To address this gap, we performed whole‐exome sequencing in a Chinese EOCRC cohort diagnosed before 40 years of age ( n  = 111), bulk transcriptome sequencing in a subset of these tumors ( n  = 59), and whole‐exome sequencing in an independent Chinese colorectal cancer cohort spanning a broader age range ( n  = 210). We then integrated these data with publicly available somatic mutation, bulk RNA‐seq, and single‐cell transcriptomic datasets to characterize age‐associated tumor‐intrinsic and microenvironmental features. Genomic analyses revealed a distinct EOCRC landscape, including lower frequencies of APC and KRAS mutations, more frequent SMAD4 disruption through mutation or copy‐number loss, and enrichment of the PTPRK‐RSPO3 fusion. Single‐cell analyses further showed increased infiltration of CD4 + memory T cells and mast cells in EOCRC, whereas later‐onset colorectal cancer was characterized by SPP1 + macrophage predominance and a strengthened interaction axis between FAP + cancer‐associated fibroblasts and SPP1 + macrophages. Therapeutic evaluation in aged mouse models, together with single‐cell analysis of immunotherapy‐treated patients, indicated reduced PD‐1 blockade efficacy with increasing age. Together, these findings support age‐informed molecular classification and therapeutic stratification in colorectal cancer.