Eomesodermin in renal cell carcinoma: Epigenetic and immune crosstalk driving tumor progression (Review)

Renal cell carcinoma (RCC) is the main pathological type of kidney cancer, which accounts for approximately 85‑95% of all cases of kidney cancer. Despite the emergence of targeted therapies and immunotherapies, however, the development of resistance remains common. Eomesodermin (Eomes) is a member of the T‑box transcription factor family that links both developmental biology and immune regulation with tumor‑associated programs. In RCC, its function appears to be context‑dependent. In tumor‑infiltrating leukocytes, Eomes has been shown to support mature natural killer cell and memory CD8⁺ T‑cell function, whereas persistent or dysregulated Eomes is associated with exhausted CD8⁺ T cells and Eomes‑positive type 1 regulatory T‑like immunosuppressive cells. In both intrinsic RCC tumor cells and stromal/endothelial compartments, current knowledge remains relatively limited, and what evidence there is has often been derived from indirect RCC pathway research, other tumor types or developmental models. The present review summarizes Eomes‑associated mechanisms in RCC through distinguishing among infiltrating leukocytes, tumor cells and stromal/endothelial compartments, and also through separating direct RCC evidence from indirectly derived mechanistic inferences. Epigenetic regulation, PI3K/Akt/mTOR signaling, Wnt/β‑catenin signaling, angiogenesis and therapeutic resistance are also discussed according to the strength of the available evidence. Current data support that Eomes stands as an exploratory biomarker and hypothesis‑generating therapeutic node, rather than as an established clinical target. Further research should be performed, however, to validate the cell‑type‑specific functions of Eomes in RCC tissues, single‑cell and spatial datasets, in addition to experimental RCC models.