A new study found that a protein called Secreted Phosphoprotein 1 (SPP1) plays an important role in helping colorectal cancer spread to the liver and resist immunotherapy. Researchers discovered that SPP1 levels are much higher in liver metastases than in primary colorectal tumors. Patients with high levels of SPP1 in their blood tend to have more advanced disease, poorer survival, and weaker responses to PD-1/PD-L1 immunotherapy.
The study showed that tumor cells release SPP1, which binds to the CD44 receptor on cancer-associated fibroblasts. This activates signaling pathways that cause the fibroblasts to produce a molecule called CXCL12. CXCL12 then creates a barrier around the tumor that keeps cancer-killing CD8+ T cells from entering. At the same time, CXCL12 encourages tumor cells to release more SPP1 and TGF-β, forming a cycle that strengthens tumor growth and spread in the liver.
Researchers also tested possible treatment strategies in preclinical models. Drugs that block fibroblasts, inhibit SPP1, or block the CXCL12 signal—such as Talabostat mesylate and Plerixafor—may help break this cycle and allow immune cells to attack the tumor. Combining these approaches with immunotherapy could improve treatment for patients with colorectal cancer liver metastases that do not respond well to current therapies.