The application of nanotechnology in regulating mitochondrial function in tumor microenvironment for cancer therapy.

Mitochondria are involved in energy production, signal conduction, and cellular differentiation in the human body, and they determine the direction of tumorigenesis and development. Mitochondria-targeted therapy in cancer cells has been reported since researchers discovered the relationship between mitochondria and cancer. However, the complexity of the tumor microenvironment (TME) can impair the therapeutic effect. Understanding the mechanisms of mitochondrial function in various cells of TME (e.g., tumor-associated macrophages (TAMs), cancer-associated fibroblasts (CAFs), cancer stem cells (CSCs), T cells, natural killer (NK) cells, tumor-associated neutrophils (TANs)), as well as mediated crosstalk with cancer cells, would be beneficial for accelerating these therapeutic strategies into clinical practice and leading to more effective disease treatment. Subsequently, we summarized representative small-molecule drugs targeting mitochondrial homeostasis, energy metabolism, and mitochondrial DNA (mtDNA) and evaluated their limitations. Building on this foundation, we reviewed the latest multifunctional nanomedicines. These agents leverage TME responsiveness, surface-targeting engineering, and multimodal synergy (combining chemotherapy, photodynamic therapy (PDT), sonodynamic therapy (SDT), radiodynamic therapy (RDT), and immunotherapy) to precisely deliver drugs, ions, genetic material, and even whole mitochondria to target organelles. This approach simultaneously remodels the immunosuppressive microenvironment and induces immunogenic cell death (ICD).