Intercellular nanotube-mediated mitochondrial transfer enhances Tcell metabolic fitness and antitumor efficacy.

Abstract

Mitochondrial loss and dysfunction drive Tcell exhaustion, representing major barriers to successful Tcell-based immunotherapies. Here, we describe an innovative platform to supply exogenous mitochondria to Tcells, overcoming these limitations. We found that bone marrow stromal cells establish nanotubular connections with Tcells and leverage these intercellular highways to transplant stromal cell mitochondria into CD8+ Tcells. Optimal mitochondrial transfer required Talin 2 on both donor and recipient cells. CD8+ Tcells with donated mitochondria displayed enhanced mitochondrial respiration and spare respiratory capacity. When transferred into tumor-bearing hosts, these supercharged Tcells expanded more robustly, infiltrated the tumor more efficiently, and exhibited fewer signs of exhaustion compared with Tcells that did not take up mitochondria. As a result, mitochondria-boosted CD8+ Tcells mediated superior antitumor responses, prolonging animal survival. These findings establish intercellular mitochondrial transfer as a prototype of organelle medicine, opening avenues to next-generation cell therapies.