Abstract: Tumor cells systematically reshape the ecological niche of tumor microenvironment (TME) through mitochondrial metabolic reprogramming while sustaining their own malignant proliferation, serving as a crucial mechanism driving resistance to immunotherapy. Different from the conventional research perspective focusing merely on energy metabolism, this review systematically analyzes how mitochondria act as an immunoregulatory hub to drive the evolution of the TME toward an immunosuppressive phenotype. On this basis, it mainly illustrates the intercellular signaling cascades induced by nutrient competition, abnormal metabolite accumulation and mitochondrial homeostasis imbalance in the TME, and elucidates the cross-regulatory mechanisms of key signaling pathways including AMP-activated protein kinase and mammalian target of rapamycin. Furthermore, this review systematically summarizes the clinical translational progress of targeted mitochondrial metabolism combined with immunotherapy, clarifying the holistic regulatory relationship among mitochondrial metabolic remodeling, immune microenvironment disorder and tumor immune resistance, aiming to provide theoretical support and innovative insights for reshaping anti-tumor immune responses via metabolic intervention and developing novel combined metabolic and immunotherapeutic strategies.