Leukemia inhibitory factor (LIF)

Class

Anti-LIF humanized monoclonal antibody

Pathway

Blocks LIF-LIFR-gp130-STAT3 signaling, reprogramming the immunosuppressive tumor microenvironment

Leukemia inhibitory factor (LIF) is a small signaling protein belonging to the interleukin-6 (IL-6) family of cytokines. It binds a two-part receptor made of LIF receptor (LIFR) and the shared subunit gp130, triggering an intracellular relay called the JAK-STAT3 pathway that changes gene expression inside the cell. In cancer, tumor cells and surrounding stromal cells often secrete excess LIF, which acts on immune cells within the tumor to make them less able to attack the cancer and more supportive of tumor growth, invasion, and treatment resistance. Blocking LIF with a monoclonal antibody prevents it from engaging LIFR and gp130, dampening STAT3 activity and, in principle, shifting the tumor microenvironment from an immunosuppressive to a more immune-permissive state. This mechanism is of interest across a range of solid tumors where LIF and STAT3 signaling have been linked to poor immune infiltration and resistance to other therapies, including immunotherapies. Because LIF also participates in normal processes such as embryo implantation, stem cell maintenance, and tissue repair, therapeutic blockade must be considered alongside these broader physiological roles. The approach reflects a general strategy in oncology: neutralizing a soluble signaling protein upstream of an intracellular pathway rather than targeting the pathway's intracellular components directly.