Thyroid hormones modulate the lung immune microenvironment to regulate breast cancer metastasis

Thyroid disorders and breast cancer (BC) are both more prevalent in women, yet the influence of thyroid hormones (THs) on BC progression and metastasis remains poorly understood. We previously showed that hyperthyroid mice bearing 4T1 BC tumors display accelerated primary tumor growth, whereas hypothyroid mice develop slower-growing tumors but a higher number of lung metastases. To elucidate the mechanisms underlying these effects, we first evaluated the direct influence of THs on 4T1 cell migration using wound-healing assays. We then examined the impact of thyroid status on the immune subpopulations and cytokine milieu in the lungs. For this, female Balb/c mice were induced to a hyperthyroid state by daily thyroxine (T4) administration for 4 weeks, to a hypothyroid state by propylthiouracil (PTU) for 2 weeks, or to a reverted euthyroid condition by supplementing triiodothyronine (T3) after PTU treatment. Mice were subsequently inoculated with 4T1 cells orthotopically or intravenously. In vitro, T3 and T4 did not modify 4T1 cell migration, indicating that THs regulate metastasis indirectly through host mechanisms. In vivo, thyroid status profoundly altered the pulmonary immune landscape. Lungs from hyperthyroid mice exhibited increased proportions of cytotoxic T lymphocytes, natural killer (NK) cells, and B cells, accompanied by higher IFN-gamma and IL-2 levels (p < 0.05), consistent with a more cytotoxic microenvironment. In contrast, lungs from hypothyroid mice displayed increased myeloid-derived suppressor cells (MDSCs) and elevated CCL5, CCL17, and CCL22 levels (p < 0.05), which are associated with heightened immunosuppression, cell recruitment, and metastasis formation. These alterations were reverted by short-term T3 treatment. Moreover, hyperthyroid mice intravenously inoculated with 4T1 cells also showed increased NK cell levels, whereas hypothyroid mice exhibited higher MDSCs, suggesting that this effect is independent of the primary tumor. Collectively, our findings demonstrate that thyroid hormones do not directly affect BC cell migration but critically modulate the immune microenvironment in metastatic target organs. Hyperthyroidism promotes cytotoxic and humoral immune responses that may restrain metastasis, while hypothyroidism drives an immunosuppressive cytokine network that favors lung colonization. Understanding how thyroid hormones influence immune responses is key to developing more effective therapeutic strategies for breast cancer.