Abnormal metabolic activation of CD8⁺ T cells correlates with poor prognosis in acute myeloid leukemia

BACKGROUND: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a critical therapeutic strategy for acute myeloid leukemia (AML). However, relapse remains a major challenge, with limited effective options for managing post-transplant recurrence. Tumor cells escape immune surveillance by establishing a complex, immunosuppressive tumor microenvironment (TME), which plays a central role in immune evasion and disease relapse. Understanding the TME’s impact on immune cells and their functional alterations is therefore of significant clinical importance. METHODS: Utilizing a non-irradiated AML mouse model and bioinformatic analysis, we systematically analyzed T-cell dynamics during AML progression and identified abnormal metabolic activation in CD8+ T cells at early disease stages, which correlated with leukemia cell immune evasion. RESULT: We found that when major histocompatibility complex (MHC) molecules on AML cells were haplomatched with immune cells, CD8+ T cells exhibited robust cytokine and cytotoxic activation, retaining immune profiles similar to those of normal T cells. However, under the same tumor burden, T cells, particularly CD8+ T cells, showed dramatic metabolic gene activation in MHC-matched leukemic mice. This metabolic activation led to rapid exhaustion of CD8+ T cells, accelerating leukemia progression. Based on these activated metabolic genes, we established a metabolism-associated genes (MAGs) scoring system. Validation using public datasets revealed that a high MAG score is associated with poor prognosis in AML patients. CONCLUSIONS: Our findings provide molecular evidence supporting the stronger graft-versus-leukemia effects observed in HLA haploidentical HSCT. Moreover, they highlight that abnormal metabolic activation in CD8+ T cells during early AML progression contributes to rapid disease advancement and poor prognosis.