Abstract 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 αVβ3) 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% (p0.01), an effect prevented by the αVβ3 inhibitor cilengitide (p0.05), indicating that THs promote melanoma growth predominantly through αVβ3-mediated signaling. Consistently, TCGA-SKCM data showed co-expression of αV and β3 integrins in patient melanoma samples, supporting αVβ3 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 (p0.05), 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 (p0.01), 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 (p0.05), while spleens from hypothyroid mice exhibited increased B lymphocytes (p0.01) and myeloid-derived suppressor cells (p0.05), 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 αVβ3 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. Citation Format: Helena Andrea Sterle, María M. Debernardi, Gonzalo Gonzalez, Lucero Alvarado, Florencia Menay, María A. Paulazo, Graciela A. Cremaschi, Florencia Cayrol. Thyroid hormones as systemic regulators of melanoma progression and dissemination abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 186.
Sterle et al. (Fri,) studied this question.