D-serine identified as driver of gastric cancer immune evasion

A team of researchers at Keio University has identified an unexpected culprit in gastric cancer's ability to hide from the immune system: a molecule called D-serine that appears to act as a chemical shield, allowing tumors to grow unchecked even when patients receive immunotherapy drugs designed to strip away that protection.

The discovery emerged from a simple question. Assistant Professor Shohei Suzuki and his colleagues knew that cancer cells deploy various signaling molecules to evade immune attack, and they knew that immune checkpoint inhibitor therapy works by disrupting some of these evasion tactics. But they wondered whether a class of molecules called D-amino acids—mirror-image versions of the amino acids that build proteins—might play a role in this immunological arms race. D-amino acids exist naturally in the body, arriving through diet, gut bacteria, and metabolic processes. Earlier work by Suzuki's group had shown these molecules could reduce inflammation in mice with colitis. Could they also affect how tumors escape immune surveillance?

To find out, the team induced gastric cancer in healthy mice and injected their tumors with various amino acid solutions. Only the mice receiving D-serine showed dramatically accelerated tumor growth. When the researchers examined the tumors under the microscope, the mechanism became clear: D-serine was flooding the tumor microenvironment with anti-inflammatory immune cells, particularly a type of macrophage called M2-like. At the same time, it was suppressing CD8+ cytotoxic T cells—the immune system's primary assassins, the cells that would normally kill cancer cells. The tumor had essentially created a chemical environment hostile to its own destruction. Further investigation revealed that the macrophages in D-serine-treated tumors were pumping out two immunosuppressive molecules, fibronectin 1 and secreted phosphoprotein 1, both known to silence CD8+ T cells. When researchers injected antibodies against one of these molecules into the tumors, growth rates dropped back toward normal.

The findings took on clinical weight when Suzuki's team examined patient records. They discovered that people with gastric cancer had significantly higher levels of D-serine circulating in their blood compared to healthy controls. More striking still: the higher the D-serine concentration, the more likely the patient's tumor would resist immune checkpoint inhibitor therapy. Patients with advanced, treatment-resistant gastric cancer had the highest D-serine levels of all. The molecule appeared to be a reliable marker of immunotherapy failure.

This matters because immune checkpoint inhibitors have become a standard first-line treatment for gastric cancer, yet many patients don't respond to them, and the drugs can trigger serious immune-related side effects. Doctors currently have limited ways to predict who will benefit and who will suffer through ineffective treatment. A simple blood test measuring D-serine could change that calculus. Suzuki's group is now investigating whether D-serine levels in blood and stool samples can forecast treatment response before therapy begins. The longer-term goal is more ambitious: developing drugs that lower D-serine concentrations or target the gut bacteria that produce it. If successful, such treatments could restore the immune system's ability to attack gastric cancer, transforming a molecule of evasion into a point of vulnerability.