Circulating Cytokines in Melanoma Prognosis: Current Evidence and Future Perspectives

Cutaneous melanoma remains a highly lethal malignancy once metastatic. Current prognostic stratification relies primarily on staging and serum lactate dehydrogenase (LDH), which incompletely captures inter-patient biological heterogeneity. Increasing evidence highlights the importance of tumour-immune interactions in melanoma progression and response to therapy. This narrative review summarises and critically evaluates current evidence on circulating cytokines as prognostic and biologically informative biomarkers in melanoma, with particular emphasis on the immunotherapy era. Several circulating cytokines-most consistently interleukin-6 (IL-6) and interleukin-8 (IL-8)-are associated with adverse outcomes in advanced melanoma. However, baseline elevations predominantly reflect tumour burden and systemic inflammation, indicating prognostic rather than treatment-specific predictive value. In contrast, early on-treatment changes, particularly decreases in IL-8, may better capture evolving tumour-immune interactions during immune checkpoint inhibitor therapy. C-reactive protein (CRP), a downstream marker of IL-6 signalling, similarly reflects systemic inflammatory status and carries reproducible prognostic significance. Early circulating tumour DNA (ctDNA) dynamics demonstrate strong associations with response and survival and may provide complementary insight into tumour burden kinetics. Conversely, cytokines central to effective antitumour immunity, such as interferon-γ (IFN-γ), are more reliably characterised at the tumour transcriptional level than by circulating protein measurements. Circulating cytokines represent biologically meaningful but methodologically challenging biomarkers in melanoma. Their most realistic clinical role lies in complementing established prognostic factors within integrated biomarker frameworks rather than functioning as standalone tests. Standardisation of pre-analytical handling, assay platforms, and sampling time points, together with prospective validation, is essential before broader clinical implementation.