Researchers from Keio University have found that D-serine increases the growth of gastric cancer by creating an immunosuppressive and anti-inflammatory tumor microenvironment. Higher levels of D-serine in serum correlated with greater immune checkpoint inhibitor therapy resistance in tumors. Suppressing D-serine in circulation could improve the efficacy of immunotherapies against gastric cancer. These findings position D-serine within the broader field of cancer amino acid metabolism and point to it as a possible target for tumor evasion.

One of the crucial steps in cancer proliferation is evading killer immune cells. Cancer cells use a variety of signaling molecules to evade the immune system. Immune checkpoint inhibitor (ICI) therapy interferes with some of these evasion tactics, improving the immune system's ability to suppress tumors. However, the success of ICI therapy depends on the specific signals being secreted by the tumor.

Recent research has identified D-amino acids (D-AAs) as a new class of signaling molecules. D-AAs are enantiomers, or "mirror images" of L-amino acids that make up proteins. D-AAs are normally present in human biological fluids and can be derived from the diet, microbiota, and metabolic byproducts. "Our previous research showed that oral administration of D-AAs improved colitis in a mouse model," says Assistant Professor Shohei Suzuki, from the Keio University School of Medicine.

Could D-AAs play a role in tumor immunity? That is the question Dr. Suzuki sought to answer. With support from Assistant Professor Kai Tsugaru and Associate Professor Tomohisa Sujino, also from the School of Medicine, the research team studied the effects of D-AAs, specifically D-serine (D-ser), in mouse models of GC and in human patients. Their findings were made available online in the journal eBioMedicine on July 31, 2026.

The team induced gastric cancer (GC) in healthy mice and injected the tumors with various solutions of D-AAs and L-AAs. Only mice that received D-ser showed significantly faster tumor growth compared to controls. Further analysis showed that D-ser had major immunosuppressive effects. D-ser administration increased both the numbers and activity of anti-inflammatory immune cells in the tumor microenvironment, particularly M2-like macrophages. As a result, CD8+ cytotoxic T cells, which would otherwise kill GC tumor cells, were in much smaller numbers and their activity was greatly reduced.

Further studies showed that tumor-associated macrophages (TAMs) in D-ser-injected tumors secreted excessive amounts of two immunosuppressive molecules, fibronectin 1 (FN1) and secreted phosphoprotein 1 (SPP1), both known to suppress CD8+ T cells. When anti-SPP1 antibodies were injected into the D-ser-enhanced tumors, tumor growth rate decreased, approaching that of the low-D-ser phenotype.

The researchers then examined clinical records across multiple human cohorts. "We discovered that the concentration of D-ser in the serum of patients with GC was higher than that of healthy control," says Dr. Suzuki. What's more, the concentration of D-ser in serum was correlated with resistance to ICI therapy; patients with stage IV, ICI-resistant GC tumors had the highest D-ser concentrations in their bloodstream.

"Although ICIs have become a first-line treatment option for GC, better predictors of treatment response are needed due to the risk of immune-related adverse events," says Dr. Suzuki. These findings show that serum D-ser could serve as a biomarker for both GC itself and the likelihood of ICI resistance in patients with the disease.

Encouraged by these results, Dr. Suzuki identified directions for future research in this field. "We are now investigating whether D-ser levels in blood and feces can help predict how patients respond to ICI therapy. Ultimately, we hope to develop new treatments that target D-ser and the gut bacteria that produce it," says Dr. Suzuki. Dr. Sujino adds, "A strategy to reduce the concentration of D-ser in the serum of patients with tumors might regulate immune activity against cancer," indicating that D-ser and its downstream signaling molecules may be potential new targets for anti-GC immunotherapies.

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