Biomarker-based profiling of fatigue in childhood cancer survivors: evidence for distinct inflammatory and glial-associated profiles

Background: Fatigue is a prevalent and burdensome late effect in childhood cancer survivors (CCS), yet its biological underpinnings remain poorly understood. This study examined associations between fatigue and blood-based biomarkers in CCS compared to healthy controls (HCs) and explored whether biologically distinct CCS profiles with respect to fatigue could be identified. Procedure: Eighty CCS (aged 14-28) and 35 age- and sex-matched HCs provided blood samples and completed the Pediatric Quality of Life Inventory Multidimensional Fatigue Scale (PedsQL-MFS). Plasma concentrations of 12 biomarkers (e.g., IL-2, TNF-α, BDNF, Total Tau, NfL, MCP-1, GFAP) were quantified using Meso Scale Discovery immunoassays. Analyses included group comparisons, Spearman correlations, and unsupervised clustering (hierarchical and k-means). Results: CCS reported significantly higher fatigue than HCs and showed significantly elevated levels of GFAP (d = 0.43), MCP-1 (d = 0.74), and Total Tau (d = 0.54). No individual biomarkers differentiated fatigued from non-fatigued CCS. Clustering revealed two biomarker-based CCS subgroups: one with high levels of inflammatory and neurodegenerative markers, and one with lower levels, yet fatigue severity was comparable. Within-cluster analyses showed distinct patterns: in the low-biomarker group, fatigue was associated with GFAP (ρ = -0.26 and ρ = -0.27, p < 0.05), whereas in the high-biomarker group, fatigue was more consistently linked to IL-8, IL-1α, and TNF-α (ρ = -0.38 to -0.49, p < 0.05). Conclusion: Findings suggest that fatigue in CCS may be associated with distinct biological pathways, including astrocyte-linked processes in one subgroup and systemic inflammation in another. This suggests the need for more personalized, biomarker-informed strategies to understand and manage fatigue in pediatric cancer survivorship.