Immune checkpoint blockade (ICB) therapy has transformed cancer care. Yet in gastric cancer, many tumors still fail to respond, leaving patients with limited options and unpredictable outcomes. Increasingly, researchers recognize that treatment response is shaped not only by tumor cells themselves, but also by the surrounding immune ecosystem — a complex network that can either sustain or suppress anti-tumor immunity.
In a new study, scientists constructed a high-resolution single-cell atlas of this ecosystem, profiling more than 240,000 cells from gastric cancer patients. The analysis uncovered a defining feature of treatment response: a balance between two functionally distinct macrophage states.
Rather than the presence of a single cell type, it was the relative proportion of CXCL10 -high and OLR1 -high macrophages that tracked with clinical outcomes. Tumors with a higher Mac- CXCL10 /Mac- OLR1 ratio were more likely to respond to immunotherapy and showed longer progression-free survival, suggesting that this balance reflects a more permissive immune state.
Further investigation revealed that this balance is functionally linked to T cell immunity. Macrophages in the CXCL10 -high state were closely associated with interferon-responsive CD8⁺ T cells, together forming an “interferon-responsive immune hub” that supports T cell activation and anti-tumor function.
In contrast, OLR1 -high macrophages were associated with lipid metabolic programs and features of an immunosuppressive microenvironment. The study suggests that tumor-associated metabolic stress, including the accumulation of oxidized lipids, may contribute to the emergence of this state. Mechanistically, these macrophages produce prostaglandin E₂ (PGE₂), which suppresses T cell interferon signaling and effector function, potentially limiting anti-tumor immunity.
Taken together, the findings highlight the importance of macrophage balance in shaping immune responses within tumors. They also suggest that targeting lipid-associated macrophage programs or PGE₂ signaling could help improve responses to immunotherapy.
While further clinical validation is needed, the study offers new insight into how the tumor microenvironment may influence treatment outcomes — and where new intervention strategies might emerge.
Science Bulletin
Experimental study