Stem Cell-Derived Exosomes: Non-Coding RNA Cargos for Reprogramming the Tumor Immune Microenvironment

Stem cell-derived exosomes (SDEs) have emerged as revolutionary mediators in cancer immunotherapy, offering unprecedented potential to reprogram the immunosuppressive tumor immune microenvironment (TIME). These nano-sized extracellular vesicles, laden with non-coding RNAs (ncRNAs), serve as natural biocompatible carriers, capable of orchestrating immune cell dynamics, stromal remodeling, and tumor cell fate. Unlike their tumor-derived counterparts, which often propagate oncogenic signals, SDEs uniquely harbor immunomodulatory miRNAs (e.g., miR-155, miR-342-3p) and lncRNAs (e.g., MALAT1, XIST) that recalibrate TIME components, activating cytotoxic CD8+ T cells, polarizing macrophages toward anti-tumor M1 phenotypes, and suppressing regulatory T cells (Tregs). This review delineates how SDEs leverage ncRNA cargo to dismantle immunosuppressive barriers: by silencing checkpoint molecules (PD-L1), reversing chemoresistance, and rewiring cancer-associated fibroblasts (CAFs). We highlight the dual roles of exosomal ncRNAs, such as miR-126, which initially bolster cancer stemness but, upon sustained delivery, trigger tumor-selective necroptosis, underscoring their context-dependent therapeutic utility. Despite promising preclinical outcomes, challenges in scalable production, off-target effects, and tumor heterogeneity necessitate engineered solutions, CRISPR-edited exosomes, surface-targeted modifications, and combinatorial regimens with checkpoint inhibitors. By integrating mechanistic insights with translational advances, this review positions SDEs as a paradigm-shifting tool in precision oncology and advocates for multidisciplinary strategies to harness their full potential. As the field evolves, SDE-based therapies stand poised to redefine cancer treatment, transforming the TIME from a fortress of immune evasion into a battleground for tumor eradication.