Bingnan Chen, Xuyang Chen, Jian‐Xin Li, Ruohan Hu, Lijun Yang, Hongli Li, Xinmi Liu, Richard D. Cannon, Richard Saffery, Boris Novakovic, Hongbo Qi, Hua Zhang, Xiaobo Zhou
Adipose-derived stem cells (ADSCs) represent a promising therapeutic resource, yet their immunometabolic regulation remains poorly defined. Here, we reveal a tunneling nanotube (TNT)-mediated communication mechanism between ADSCs and adipose tissue macrophages (ATMs) that maintains metabolic homeostasis during pregnancy. Using gestational diabetes mellitus (GDM) mouse models combined with live-cell imaging, scanning electron microscope, and multi-omics approaches, we demonstrate that mitochondrial transfer from ADSCs to ATMs via TNTs sustains ATM metabolic fitness. This process is governed by the WNT5A-RhoA-ROCK1 axis and becomes impaired under metabolic stress, driving ATMs inflammatory polarization and insulin resistance. Importantly, in situ ADSC administration restores mitochondrial transfer and improves metabolic parameters in GDM mice. Collectively, our work establishes TNT-mediated organelle sharing as a fundamental mechanism of stem cell-immune interaction and demonstrates that ADSC-based therapy represents a promising strategy for GDM by reprogramming the metabolism of immune cells.