CTDSPL (CTD small phosphatase like) is a serine/threonine phosphatase that negatively regulates RNA polymerase II transcription by preferentially dephosphorylating Ser-5 residues in the C-terminal domain (CTD) of POLR2A, controlling the transition from initiation to elongation 1. The enzyme also dephosphorylates and activates the retinoblastoma protein (Rb), promoting cell cycle arrest at the G1/S boundary 2. CTDSPL exhibits tumor suppressor properties across multiple cancer types. In clear cell renal cell carcinoma (ccRCC), CTDSPL shows reduced expression associated with poor patient survival, and its overexpression inhibits ccRCC cell growth in vitro 3. In lung adenocarcinoma, microRNA hsa-miR-503-5p suppresses CTDSPL expression to promote cisplatin resistance and angiogenesis; blocking this miRNA resensitizes resistant cells to therapy 4. CTDSPL is frequently inactivated in human cancers through somatic mutations and methylation 56, and functions alongside related phosphatases CTDSP1 and CTDSP2 in regulating mTORC1 and autophagy 7. Its loss of function contributes to malignant progression, making CTDSPL a potential therapeutic target for cancer treatment.