EPB41L2 encodes a 113-kDa cytoskeletal adaptor protein that is widely expressed across human tissues 1. The protein contains conserved domains for membrane binding, spectrin-actin interaction, and a C-terminal domain shared with its paralog EPB41 1. EPB41L2 is essential for recruiting the dynein-dynactin complex and NUMA1 to the mitotic cell cortex during anaphase, supporting proper cell division. Alternative polyadenylation and splicing generate diverse EPB41L2 isoforms with tissue-specific subcellular localizations 2. In cancer contexts, EPB41L2 expression in cancer-associated fibroblasts (CAFs) correlates with poor prognosis in bladder cancer and promotes tumor microenvironment remodeling 3. Conversely, circRNA EPB41L2 functions as a tumor suppressor in lung adenocarcinoma by acting as a competing endogenous RNA that sequesters miR-211-5p, indirectly upregulating the tumor-suppressive gene CDH4 4. EPB41L2 appears in ubiquitin-related prognostic signatures for epithelial ovarian carcinoma, associated with altered immune landscape composition 5. Notably, BRAF::EPB41L2 gene fusions have been identified in pilocytic astrocytomas 6. These findings indicate EPB41L2 has dual roles: structural functions in cytoskeletal organization and context-dependent roles in cancer biology and immunotherapy response.