Thymocyte selection-associated high mobility group box protein (TOX)

Thymocyte selection-associated high mobility group box protein (TOX) is a nuclear transcription factor encoded by the TOX gene in humans. It belongs to the HMG-box family of chromatin-associated proteins and binds DNA in a sequence-independent but structure-dependent manner. TOX is required for the development of several lymphoid lineages including CD4⁺ and CD8⁺ T cells, regulatory T cells, natural killer T cells, and various innate lymphoid cells[1][2][3]. It is a crucial regulator of T cell exhaustion: upregulated in chronically stimulated T cells (such as those in cancer or chronic infection), TOX promotes persistent, but functionally dampened, T cells by inducing an exhaustion transcriptional program and upregulation of inhibitory receptors such as PD-1[1]. As a key checkpoint in immune development, TOX is also required for positive selection during thymocyte maturation and supports lymphoid tissue organogenesis. Its dysregulation is implicated in several diseases, including cancer, where high TOX expression marks exhausted T cells in the tumor microenvironment, as well as in certain immune and neurodevelopmental conditions[1][3]. The broad functional roles, disease associations, and emerging interest in modulating T cell exhaustion make it a potential, though as yet untargeted, therapeutic target.

Other names

KIAA0808TOX1Thymocyte selection-associated high mobility group boxThymus high mobility group box protein TOX

Drugs targeting TOX would likely aim to modulate its transcriptional or chromatin remodeling activity, especially impacting T cell exhaustion (no approved drugs to date)