Systematic investigation of mitochondrial transfer between cancer cells and T cells at single-cell resolution

Mitochondria (MT) participate in most metabolic activities of mammalian cells. A near-unidirectional mito-chondrial transfer from T cells to cancer cells was recently observed to "metabolically empower"cancer cells while "depleting immune cells,"providing new insights into tumor-T cell interaction and immune evasion. Here, we leverage single-cell RNA-seq technology and introduce MERCI, a statistical deconvolution method for tracing and quantifying mitochondrial trafficking between cancer and T cells. Through rigorous bench -marking and validation, MERCI accurately predicts the recipient cells and their relative mitochondrial com-positions. Application of MERCI to human cancer samples identifies a reproducible MT transfer phenotype, with its signature genes involved in cytoskeleton remodeling, energy production, and TNF-a signaling path-ways. Moreover, MT transfer is associated with increased cell cycle activity and poor clinical outcome across different cancer types. In summary, MERCI enables systematic investigation of an understudied aspect of tumor-T cell interactions that may lead to the development of therapeutic opportunities.