D-Serine May Predict Immune Checkpoint Therapy Resistance in Gastric Cancer

Gastric cancer remains difficult to control when tumors evade cytotoxic T cells, limiting the effectiveness of immune checkpoint inhibitor (ICI) therapy. Tumors can release signaling molecules that reshape the tumor microenvironment and suppress antitumor immunity, contributing to treatment resistance. Identifying tumor-derived factors that drive or predict this immune escape is therefore an important clinical priority. New findings suggest that the D-amino acid D-serine can accelerate gastric tumor growth by suppressing cancer-fighting T-cell activity.

Keio University researchers investigated how D-serine (D-ser) influences tumor immunity using mouse models of gastric cancer (GC) together with analyses of human patient cohorts. In the animal experiments, tumors were injected with solutions containing various D- and L-amino acids. Among those tested, only D-ser significantly accelerated tumor growth compared with controls. Further analyses showed that D-ser increased anti-inflammatory, M2-like macrophages within the tumor microenvironment while reducing both the number and function of CD8+ cytotoxic T cells.

Image: D-serine is a metabolic byproduct that aids immune evasion by gastric cancer tumors. It increases immunosuppressive macrophage activity and reduces the numbers and function of cytotoxic T cells. This aids tumor growth and provides resistance against immune checkpoint inhibitor therapy. (Image Credit: Keio University Global Research Institute [KGRI])

The researchers identified tumor-associated macrophages as key mediators of this immune suppression. In tumors exposed to D-ser, these macrophages produced elevated levels of fibronectin 1 (FN1) and secreted phosphoprotein 1 (SPP1), molecules associated with inhibition of CD8+ T-cell activity. Blocking SPP1 with antibodies reduced the D-ser-associated acceleration of tumor growth, bringing progression closer to that observed in tumors with low D-ser levels.

The team also examined clinical data from multiple human cohorts. Serum D-ser concentrations were higher in patients with gastric cancer than in healthy controls, and elevated levels were associated with resistance to ICI therapy, supporting a potential role for D-ser as both a mediator and biomarker of immune resistance.

The study, published in eBioMedicine on July 31, 2026, characterizes D-serine as a metabolic immune checkpoint in the tumor microenvironment. The authors indicate that serum D-ser merits evaluation as a biomarker and outline next steps to determine whether blood and fecal D-ser levels can help forecast ICI response, while exploring strategies that target D-ser or the gut bacteria that produce it.

“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,” said Shohei Suzuki, assistant professor at Keio University School of Medicine.

“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,” said Suzuki.

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