ITM2B Truncation Promotes Migrasome Formation to Accelerate Renal Cell Carcinoma Growth

Abstract Integral membrane protein 2B (ITM2B), a transmembrane protein, frequently undergoes cleavage. The physiological functions of ITM2B are primarily studied in the context of neurological disorders, but their roles in cancers are largely overlooked. Here, it is demonstrated that in renal cell carcinoma (RCC) cells, N‐terminal truncation of ITM2B facilitates migrasome swelling through the recruitment of TSPAN4 and promotes migrasome formation. Moreover, ITM2B truncation acts as a carrier, sorting active caspase‐7 into migrasomes for migracytosis. The active caspase‐7‐enriched migrasomes are then taken up by macrophages, leading to caspase‐7‐induced IL‐6 secretion from macrophages, which eventually aggravates RCC growth through a feedback mechanism. Physiologically, hyperuricemia enhances ITM2B cleavage to aggravate RCC growth. Clinically, RCC tissues tend to produce ITM2B truncations compared with corresponding para‐carcinoma tissues. Moreover, compared with the urine from normal volunteers, that from RCC patients contains higher levels of ITM2B truncation‐enriched migrasomes. This study not only highlights novel functions of ITM2B truncation in migrasome formation and active caspase‐7 migracytosis but also elucidates the role of hyperuricemia in RCC progression via regulation of the ITM2B truncation–migrasome axis.