Acute Myeloid Leukaemia (AML) is an aggressive cancer of the blood notoriously difficult to treat with dismal 5-year survival outcomes at <30%1. The curative potential of the allogeneic transplant to control AML progression through the graft-versus-leukaemia (GVL) effect is well-recognized and highlights the importance of immune-mediated control in AML2. However, the importance of natural immune surveillance against AML remains to be fully characterized. Cancer cells including leukaemia can adapt to oncogenic/environmental stress through a process called the integrated stress response (ISR). Using a murine model of a poor prognosis AML subset driven by the t(9;11)(p22;q23) translocation (MLL-AF9 hereafter referred to as MA9), we have identified GADD34 as a key component of the ISR protecting AML from anti-tumour immunity. MA9 AML represents a poorly immunogenic and an aggressive AML patient group. Strikingly, while both control and GADD34-/- MA9 AML progressively grew in immunodeficient hosts (Rag2-/-Il2r-/- mice), GADD34-/- MA9 AML, but not control MA9 was effectively controlled in immunocompetent wild type or natural killer (NK) cell-competent hosts (Rag2-/- mice). Similarly, antibody-mediated depletion of NK and CD8+ T cells exacerbated GADD34-/- AML development but mice with intact immunity remained tumour free. To gain further mechanistic insight, we performed RNA-sequencing on enriched leukemic hematopoietic stem and progenitor cells (HSPCs). Gene set enrichment analyses showed GADD34-/- AML is metabolically distinct, and this metabolic reprogramming was also evident in the proteome and metabolome profile. Our ex-vivo data suggest that GADD34-mediated modulation of the ISR drives metabolic regulation that critically contributes to cellular redox control where elevated intracellular reactive oxygen species were observed in both GADD34-deficient murine and human AML model systems. Indeed, ROS accumulation potentiates the apoptotic cascade and immune-derived cytokines are potent inducers of ROS. In this light, GADD34 deficient murine and human AML cells were susceptible to immune-mediated toxicity either by T-cell conditioned medium or by co-culture with NK cells. Our data establish a novel link between tumour ISR and anti-tumour immunity and suggest that targeting this pathway may sensitize immunotherapy resistant AML to cancer immunotherapy.