Primary or acquired resistance to immunotherapies, including immune checkpoint inhibitors (ICIs) and CAR-T cells, remains a major clinical challenge. This resistance is particularly prevalent in "immune-cold" tumors like acute myeloid leukemia (AML), which are characterized by low immunogenicity, an immunosuppressive microenvironment, and immune escape by leukemia stem cells (LSCs). Activating the tumor-intrinsic cGAS-STING pathway to induce Type I interferon (IFN-I) responses is a promising strategy to convert "cold" tumors to "hot". However, achieving this selectively in cancer cells while sparing normal tissues remains a critical, unsolved barrier. We sought to identify novel mechanisms controlling innate immune signaling in OXPHOS-heightened cancers like AML to develop a strategy for overcoming immunotherapy resistance.We employed an inducible CRISPR-KO screen to identify regulators of mitochondrial homeostasis and cGAS-induced innate immunity. The screen identified a subset of minor mitochondrial dehydrogenases (including DHODH, SDHs) as critical regulators of mitochondrial redox balance and mtDNA integrity. We demonstrate that genetic or pharmacologic inhibition of these enzymes reroutes metabolic flux toward the Electron Transport Chain (ETC) Complex I (C-I). This paradoxically hyperactivates C-I, amplifying mtROS, inducing mtDNA instability, and causing mtDNA leakage into the cytosol. The cytosolic mtDNA is sensed by cGAS, leading to robust STING activation and systemic IFN-I responses in vivo. Crucially, this immune-stimulatory mechanism is independent of the canonical metabolic roles of these enzymes; for instance, this response after DHODH inhibition was not rescued by uridine supplement. In immunocompetent murine AML models, we found that while tumor-selective DHODH ablation was curative, systemically pharmacologic inhibition of DHODH was profoundly immunosuppressive, as it blunted T-cell proliferation essential for an anti-leukemia response. To overcome this toxicity-efficacy barrier, we developed "DHODHi-ADC", a first-in-class, immune-boosting ADC that achieves leukemia-selective delivery of a potent DHODH inhibitor (DHODH-IN16). The ADC preserves systemic immune function while inducing potent, tumor-intrinsic innate immune activation, a clear distinction from purely cytotoxic ADCs. In humanized AML models, our ADC synergized remarkably with both ICIs and CAR-T cell therapy, resulting in highly effective, durable leukemia clearance, including the eradication of LSCs.Our findings define a novel, therapeutically exploitable immune-metabolic axis where ETC homeostasis controls innate immunity via mtDNA dynamics. Disrupting this homeostasis through C-I hyperactivation provides a powerful and highly translational strategy to sensitize OXPHOS-dependent cancers to immunotherapy.