Thyroid hormones as systemic regulators of melanoma progression and dissemination

Melanoma (ME) is the most lethal form of skin cancer, and resistance to immune checkpoint inhibitors remains a major clinical challenge. Thyroid hormones (THs) are master regulators of metabolism, proliferation, and differentiation, yet their role in melanoma biology remains poorly defined. This study aimed to elucidate both the direct and systemic effects of THs on melanoma progression. We first assessed the expression of nuclear (TR) and membrane (integrin alphaVbeta3) TH receptors in human (A375, WM35) and murine (B16F10, B16F1) melanoma cell lines. Both receptor types were detected at mRNA and protein levels in all cell lines analyzed. Functional assays demonstrated that physiological and supraphysiological TH concentrations increased ME cell proliferation by 20-40% (p<0.01), an effect prevented by the alphaVbeta3 inhibitor cilengitide (p<0.05), indicating that THs promote melanoma growth predominantly through alphaVbeta3-mediated signaling. Consistently, TCGA-SKCM data showed co-expression of alphaV and beta3 integrins in patient melanoma samples, supporting alphaVbeta3 as a potential therapeutic target. To evaluate systemic effects of THs, syngeneic B16F1 and B16F10 melanoma models were established in euthyroid, hypothyroid, and hyperthyroid mice. In both models, hyperthyroid mice exhibited significantly increased tumor growth rates compared with euthyroid controls (p<0.05), whereas hypothyroidism did not markedly affect primary tumor expansion. In contrast, in experimental metastasis assays using B16F10 cells, hypothyroid mice developed a significantly higher number and larger size of lung metastatic foci (p<0.01), indicating that TH deficiency facilitates metastatic dissemination. Immune profiling of tumor-infiltrating cells did not reveal significant differences among experimental groups. However, tumor-draining lymph nodes from hyperthyroid mice showed reduced cytotoxic CD8⁺ T lymphocytes (p<0.05), while spleens from hypothyroid mice exhibited increased B lymphocytes (p<0.01) and myeloid-derived suppressor cells (p<0.05), suggesting that TH status modulates systemic immune cell distribution. Overall, these findings demonstrate that thyroid hormones exert dual and context-dependent effects on melanoma: TH excess enhances primary tumor growth through integrin alphaVbeta3 signaling, whereas TH deficiency promotes metastatic dissemination, likely through modulation of systemic antitumor immunity. The thyroid axis emerges as a novel systemic regulator and potential therapeutic target in melanoma.