Pan-cancer multi-omics analysis reveals dysregulation and prognostic significance of exercise-responsive factors

Exerkines are exercise-responsive factors that contribute to systemic homeostasis and have emerging roles in tumor regulation. However, their molecular characteristics and clinical implications at the pan-cancer level remain limited. We performed a comprehensive pan-cancer analysis of 30 well-characterized exerkines in tumor tissues across 33 cancer types using The Cancer Genome Atlas (TCGA) datasets. Multi-omics data, including transcriptomics, mutations, copy number variations (CNVs), and DNA methylation, were integrated with clinical outcomes and pharmacogenomic profiles. Most exerkines showed significant differential expression in multiple cancers, with ANGPT1, APLN, and CTSB being the most frequently dysregulated. The mRNA expression levels of several exerkines, such as IL6 and LIF, were strongly associated with poor prognosis. Although mutations in exerkines were observed in 66.5% of tumor samples, most did not exhibit significant prognostic relevance. CNVs were positively correlated with mRNA expression and prognostically relevant in cancers like KIRP and UCEC. Epigenetic regulation via DNA methylation, notably in BDNF and METRNL, also influenced gene expression and survival. Gene set variation analysis (GSVA) revealed global exerkine-associated perturbations in oncogenic signaling and immune cell infiltration. Additionally, exerkine expression was significantly correlated with drug sensitivity or resistance in cell-line pharmacogenomic datasets. Exerkines are widely dysregulated in cancer and influence patient prognosis, genomic stability, immune microenvironment, and therapeutic response. These findings highlight their potential as prognostic biomarkers and therapeutic targets in precision oncology.