Inflammatory Correlates and Prospective Associations of Cancer-Related Fatigue: A Systematic Review and Meta-Analysis.

BACKGROUND

Cancer-related fatigue (CRF) is a prevalent and disabling symptom across the cancer continuum and is increasingly conceptualized as a biobehavioral symptom with inflammatory underpinnings. However, evidence linking specific circulating inflammatory biomarkers to CRF remains fragmented and inconsistent.

AIMS: To compare biomarker-CRF associations across cross-sectional and prospective observational studies.

METHODS

PubMed, Web of Science, Cochrane Library, Embase, Scopus, and PsycINFO were searched from inception to 17 November 2025. Random-effects meta-analyses were stratified by study design and effect-size metric; non-comparable estimates were synthesized narratively. Certainty was assessed using GRADE.

RESULTS

Forty-two studies (11,629 participants) were included. Cross-sectional CRF was positively associated with C-reactive protein (CRP; r = 0.30, 95% CI 0.21-0.38). Positive associations were also observed for interleukin-6 (IL-6; r = 0.17, 95% CI 0.06-0.29) and tumor necrosis factor (TNF; r = 0.13, 95% CI 0.01-0.24). Interleukin-1 receptor antagonist was likewise associated with CRF (IL-1ra; r = 0.23, 95% CI 0.09-0.36). Prospectively, CRP was associated with subsequent CRF in odds ratio (OR = 1.20, 95% CI 1.05-1.37) and standardized regression syntheses (β = 0.26, 95% CI 0.09-0.43). Evidence for IL-6, TNF, IL-1β, and IL-8 was less stable or inconclusive. Certainty was high for four evidence bodies, moderate for four, low for one, and very low for one.

CONCLUSION

Current evidence supports systemic inflammation as a clinically relevant biological correlate of CRF, with CRP/hsCRP showing a comparatively more replicable signal across study designs. However, observational evidence does not establish causality or clinical utility. Standardized longitudinal and intervention studies are needed to evaluate temporal relationships, predictive performance, and clinical applicability.