T cells in AML: are they functionally impaired? a call for comprehensive characterization

Abstract Background Acute myeloid leukemia (AML) is an aggressive cancer marked by uncontrolled proliferation of myeloid blasts in the bone marrow (BM). Management of newly diagnosed AML is guided by patient fitness and molecular risk stratification, incorporating intensive chemotherapy (IC), venetoclax-based regimens, targeted therapies, and allogeneic hematopoietic stem cell transplantation in selected patients (allo-HSCT). Despite initial responses, frequent relapses lead to a five-year survival rate below 30%. A factor linked to AML relapse is T cell exhaustion/dysfunction, especially after stem cell transplantation. Main body T cell exhaustion is often assessed solely based on the expression of inhibitory receptors which provides an incomplete picture of T cell impairment. We propose a more comprehensive and standardized definition of T cell functionality that extends beyond inhibitory receptor expression. This should encompass cytokine secretion and cytotoxic capacity, activation and proliferative potential, metabolic profile, T cell subset composition, telomere length, and epigenetic state. Additionally, we examine how the AML tumor microenvironment can lead to T cell impairment and based on emerging data we argue that T cells in AML are not uniformly dysfunctional. Conclusion A deeper and more comprehensive understanding of T cell functional heterogeneity in AML—based on standardized, multidimensional assessments rather than inhibitory receptor expression alone—is essential for advancing immunotherapy in this disease. Recognizing that T cells in AML are not uniformly dysfunctional but instead exhibit context-dependent impairment shaped by the tumor microenvironment, challenges prevailing assumptions and opens new therapeutic opportunities. Integrating functional, metabolic, and epigenetic insights into T cell profiling will be critical for the rational design, timing, and optimization of T cell–based therapies, with the potential to overcome immune failure and improve durable disease control in AML.