Mitochondrial Fitness as a Functional Immune Checkpoint in Cancer: Metabolic Plasticity, Tumor Evolution, and Immunotherapy

Mitochondria are increasingly recognized as dynamic regulators of cancer-cell adaptation, immune function, and therapeutic response. Beyond their canonical role in energy production, mitochondrial metabolism, dynamics, quality control, and stress signaling influence tumor-cell survival and the capacity of immune effector cells to sustain antitumor activity within the tumor microenvironment. In this narrative review, we examine mitochondrial fitness as a multidimensional functional property encompassing bioenergetic capacity, metabolic flexibility, redox homeostasis, mitochondrial quality control, and adaptation to cellular and therapeutic stress. We propose the mitochondrial functional immune checkpoint as a conceptual framework linking mitochondrial fitness in malignant and immune cells to tumor–immune interactions and immunotherapy response. We discuss how mitochondrial metabolic plasticity, mitochondrial stress and mtDNA signaling, reactive oxygen species, mitochondrial dynamics, and intercellular mitochondrial transfer contribute to immune escape and treatment resistance. We further examine the relevance of mitochondrial fitness to immune checkpoint blockade, CAR-T-cell therapy, and T-cell-redirecting bispecific antibodies, with particular attention to hematological malignancies, including acute myeloid leukemia and multiple myeloma, while incorporating selected evidence from solid tumors to highlight shared mitochondrial mechanisms and their broader oncologic relevance. Finally, we discuss emerging strategies for mitochondrial targeting and functional mitochondrial profiling and their potential integration with established molecular and measurable residual disease assessments. Current evidence supports mitochondrial biology as a complementary dimension of precision oncology, although important challenges remain regarding context dependence, biomarker standardization, therapeutic selectivity, and preservation of immune-cell fitness. Prospective studies are needed to determine whether functional mitochondrial profiling can improve patient stratification and guide rational therapeutic combinations that selectively exploit tumor mitochondrial vulnerabilities while preserving effective antitumor immunity.