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

Abstract 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.