Abstract
Tumor cells adapt their metabolism to meet the demands for energy and biosynthesis. Mitochondria, pivotal organelles in the metabolic reprogramming of tumor cells, contribute to tumorigenesis and cancer progression significantly through various dysfunctions in both tumor and immune cells. Alterations in mitochondrial dynamics and metabolic signaling pathways exert crucial regulatory influence on the activation, proliferation, and differentiation of immune cells. The tumor microenvironment orchestrates the activation and functionality of tumor-infiltrating immune cells by reprogramming mitochondrial metabolism and inducing shifts in mitochondrial dynamics, thereby facilitating the establishment of a tumor immunosuppressive microenvironment. Stress-induced leakage of mitochondrial DNA contributes multifaceted regulatory effects on anti-tumor immune responses and the immunosuppressive microenvironment by activating multiple natural immune signals, including cGAS-STING, TLR9, and NLRP3. Moreover, mitochondrial DNA-mediated immunogenic cell death emerges as a promising avenue for anti-tumor immunotherapy. Additionally, mitochondrial reactive oxygen species, a crucial factor in tumorigenesis, drives the formation of tumor immunosuppressive microenvironment by changing the composition of immune cells within the tumor microenvironment. This review focuses on the intrinsic relationship between mitochondrial biology and anti-tumor immune responses from multiple angles. We explore the core role of mitochondria in the dynamic interplay between the tumor and the host to facilitate the development of targeted mitochondrial strategies for anti-tumor immunotherapy.