Ncoa2, also known as Nuclear receptor coactivator 2, is a member of the Ncoa family of coactivators. It serves as a transcription coactivator, regulating the activation and inhibition of transcription factors and proteins like those in the basic helix-loop-helix Per-ARNT-SIM family. It is involved in multiple biological processes and signaling pathways, with its dysregulation linked to various diseases [2,3]. Genetic models, such as KO/CKO mouse models, are valuable tools for studying its functions.

In T cells, Ncoa2-deficient mice (Ncoa2fl/fl/CD4Cre) had defective immune responses against implanted MC38 tumors, with reduced tumor-infiltrating CD8+ T cells and IFNγ production. CD8+ T cells from these mice also failed to reject tumors after adoptive transfer. Mechanically, TCR-stimulated Ncoa2-deficient CD8+ T cells had impaired mitochondrial function due to lower PGC-1α expression, as T-cell activation-induced phosphorylation of CREB recruits Ncoa2 to enhance PGC-1α expression [2]. In HEY1-NCOA2-induced mesenchymal chondrosarcoma mouse models, the fusion gene modulated chondrogenic differentiation. Treatment with the HDAC inhibitor panobinostat suppressed tumor growth, affecting genes downstream of HEY1-NCOA2 and Runx2 [1].

In conclusion, Ncoa2 is crucial in regulating T-cell-mediated antitumor immunity by enhancing mitochondrial function in CD8+ T cells and in modulating chondrogenic differentiation. Mouse models, especially KO/CKO models, have been instrumental in revealing its role in tumor-related immune responses and mesenchymal chondrosarcoma development, providing potential therapeutic insights for these disease areas.