Mitochondrial Stress Orchestrates Tumor Immune Evasion and Immunotherapy Resistance

Mitochondrial stress has emerged as a key regulator of tumor-immune interactions, extending beyond its classical bioenergetic role to coordinate metabolic adaptation and immune regulation. Rather than merely accompanying tumor progression, mitochondrial dysfunction contributes to immune evasion and resistance to immunotherapy. Here, we propose that mitochondrial stress functions as a unifying axis governing three key determinants of anti-tumor immunity: immune visibility, immune cell fitness, and the metabolic architecture of the tumor microenvironment. Mechanistically, mitochondrial reactive oxygen species, mitochondrial DNA release, and mitophagy modulate antigen presentation and T cell function. We further highlight emerging experimental platforms, including 3D spheroid and organoid systems, that enable physiologically relevant investigation of mitochondria-driven tumor-immune interactions. Together, this perspective provides a mechanistic framework for understanding and targeting resistance to immune checkpoint blockade.