Scientists at UT Southwestern Medical Center have uncovered a sophisticated molecular mechanism that explains how cancer cells disable the body’s natural defenses. The research, published in Nature Immunology, reveals that tumors exploit a hormone called secretogranin 2 (SCG2) to essentially flip a switch that converts immune system defenders into tumor protectors.

The discovery centers on an intricate biological conversation between cancer cells and immune cells. When tumors produce SCG2, this hormone binds to a receptor called LILRB4 found on myeloid cells, which are among the first immune responders to reach tumors. This binding triggers a cascade of molecular events that fundamentally reprograms these cells from tumor fighters into tumor supporters.

Dr. Cheng Cheng Zhang and his team identified this pathway through systematic investigation of how myeloid cells lose their cancer-fighting abilities. Several years ago, they discovered the LILRB4 receptor and found that stimulating it blocked myeloid cells from attacking tumors. Using genome-wide screening, they searched for proteins that interact with LILRB4 and identified SCG2 as the key binding partner.

The mechanism operates through precise molecular choreography. When SCG2 latches onto LILRB4, it activates internal signaling pathways that recruit SHP proteins and independently activate STAT3, a master switch that controls gene expression in immune cells. This cascade transforms myeloid cells into immunosuppressive agents that not only stop fighting tumors themselves but also prevent T cells from reaching and attacking cancer.

Laboratory experiments demonstrated the pathway’s significance using mice genetically modified to express human LILRB4. Cancer cells engineered to produce SCG2 grew rapidly as tumors in these animals. However, when researchers blocked LILRB4 with antibodies or artificially removed SCG2, tumor growth slowed significantly. The tumor-promoting effects of SCG2 disappeared entirely when T cells were removed from the equation, confirming that the hormone works by suppressing the broader immune response rather than directly feeding cancer growth.

This discovery addresses a critical limitation in cancer treatment. Current immunotherapies like checkpoint inhibitors benefit only 20 to 30 percent of cancer patients, suggesting that tumors use multiple strategies to evade immune attack. The SCG2-LILRB4 pathway represents an entirely different mechanism from known checkpoint pathways, potentially explaining why many patients fail to respond to existing treatments.

The therapeutic implications extend in two directions. Disrupting the SCG2-LILRB4 interaction could restore immune function against tumors, offering a new immunotherapy approach that could complement existing treatments. Early evidence from multiple myeloma research suggests that blocking LILRB4 can slow disease progression in laboratory studies. Conversely, because this pathway naturally suppresses immune activity, carefully administering SCG2 might help treat autoimmune or inflammatory disorders where excessive immune responses cause damage.

Source.