Tumor necrosis factor alpha (TNFα)–Janus kinase 1 (JAK1)–Intercellular adhesion molecule 1 (ICAM-1)–Lymphocyte function-associated antigen 1 (LFA-1) axis (TNFα–JAK1–ICAM-1–LFA-1 axis)

The Tumor necrosis factor alpha (TNFα)–Janus kinase 1 (JAK1)–Intercellular adhesion molecule 1 (ICAM-1)–Lymphocyte function-associated antigen 1 (LFA-1) axis is a specialized signaling and adhesion pathway that regulates the susceptibility of acute myeloid leukemia (AML) blasts to immune-mediated killing. This axis is initiated when effector immune cells, such as double-negative T cells (DNTs), recognize AML cells and secrete TNFα. The cytokine then triggers a noncanonical JAK1-dependent signaling cascade within the AML blasts, leading to the rapid upregulation of the surface adhesion molecule ICAM-1. The increased density of ICAM-1 facilitates high-affinity binding to LFA-1 receptors on the T cells, stabilizing the immunological synapse and enabling efficient granzyme- and perforin-mediated lysis of the leukemia cells. This pathway is a critical mechanism for overcoming intrinsic immune resistance in AML, but it can be negatively regulated by SOCS1 or disrupted by the clinical use of JAK inhibitors, potentially leading to tumor immune evasion.

Other names

TNFα–JAK1–ICAM-1 cytotoxic axisDNT-AML cytotoxic axisTNFα-JAK1-ICAM-1 pathwayTNFα-JAK1-ICAM-1-LFA-1 signaling axis

Activation of the TNFα-JAK1 signaling pathway to induce ICAM-1 expression on target cells, thereby enhancing LFA-1-mediated adhesion and cytotoxic effector function of immune cells.