Retinoic acid receptor gamma (RARγ) drives M2-like macrophage polarisation via CFI to promote thyroid cancer progression.

Thyroid carcinoma (TC), the most prevalent endocrine malignancy, accounts for 3-4% of global cancer cases and continues to increase in incidence worldwide. Despite advances in diagnosis and treatment, a subset of thyroid cancers remains clinically incurable, underscoring the urgent need to elucidate molecular pathogenesis and identify novel therapeutic targets. Here, we identify complement factor I (CFI) as a key downstream effector of Retinoic acid receptor gamma (RARγ). Mechanistically, RARγ transcriptionally upregulates CFI expression, and analyses of clinical TC specimens demonstrated a strong correlation between RARγ and CFI expression. Conditioned media from RARγ-overexpressing TC cells induced M2-like polarisation of THP-1-derived macrophage-like cells, as evidenced by increased CD206 expression and elevated IL-10 levels-effects that were abolished by CFI neutralisation. In xenograft models, RARγ/CFI-mediated TAM reprogramming drove tumour progression, with RARγ-knockdown tumours exhibiting reduced volumes via macrophage-dependent mechanisms. Importantly, CFI did not affect TC cell-autonomous proliferation, suggesting that its pro-tumoural effects are mediated by the TME rather than directly on tumour cells. Collectively, Our findings establish RARγ/CFI signalling as a microenvironmental rheostat controlling TAM polarisation and provide new insights into the immunobiology of thyroid cancers.