The role of mitochondria in tumor metastasis and advances in mitochondria-targeted cancer therapy

Abstract

Mitochondria are central actors in diverse physiological phenomena ranging from energy metabolism to stress signaling and immune modulation. Accumulating scientific evidence points to the critical involvement of specific mitochondrial-associated events, including mitochondrial quality control, intercellular mitochondrial transfer, and mitochondrial genetics, in potentiating the metastatic cascade of neoplastic cells. Furthermore, numerous recent studies have consistently emphasized the highly significant role mitochondria play in coordinating the regulation of tumor-infiltrating immune cells and immunotherapeutic interventions. This review provides a comprehensive and rigorous scholarly investigation of this subject matter, exploring the intricate mechanisms by which mitochondria contribute to tumor metastasis and examining the progress of mitochondria-targeted cancer therapies.

Keywords: Immunotherapy; Metabolism; Mitochondria transfer; Mitochondrial genetics; Mitophagy; Tumor metastasis.

Fig. 1

The timeline of several important discoveries in mitochondria-related research

Fig. 2

TNT-dependent mitochondrial transfer between stromal cells and tumor cells influences tumor metastasis and invasion. a Lactate released by CAFs enhances the ability of cancer cells to hijack CAF-derived functional mitochondria by forming TNTs. b TNTs between macrophages and breast tumor cells were dependent on EGF–EGFR signaling to induce invasive tumor cell morphology. c Mitochondria transferred from osteocytes to cancer cells would trigger cGAS/STING-mediated antitumor responses, thereby inhibiting tumor metastasis

Fig. 3

The interaction of CAFs, TAMs, and T cells in the TME. In the TME, cancer cells undergo aerobic glycolysis, consume large amounts of glucose, produce lactate and H⁺ in the TME, and release elevated CSF1, promoting the polarization of M1 macrophages to immunosuppressive M2 macrophages. M2 macrophages can directly and negatively affect effector T cell infiltration and activation within tumors through the expression of ARG1. Glycolytic CAFs secrete lactate and pyruvate to fuel the TCA cycle of malignant cells and support mitochondrial metabolism. Lactate from cancer cells also serves as a fuel source for CAFs, further enhancing its tumor-promoting activity. Glycolytic CAF-secreted lactate directly overcomes immunosurveillance by reducing CD4⁺ Th1 populations and promoting FoxP3-mediated conversion of Naïve T cells to Tregs