Matrix stiffness shapes immunometabolic states and response to PD-1 blockade in gastric cancer

Higher extracellular matrix stiffness in gastric cancer is linked to collagen accumulation, immune exclusion, and poorer response to PD-1 blockade, while matrix softening reshapes immunity and enhances PD-1 efficacy.

• Why it matters: Spatially heterogeneous tumor stiffness may constrain antitumor immunity, but its immunometabolic consequences and impact on PD-1 blockade in gastric cancer remain unclear.
• What they did: The study integrated anti-PD-1 clinical cohorts, gastric cancer specimens, single-cell and spatial transcriptomics, a syngeneic mouse model, and tunable-stiffness hydrogels to test how stiffness alters immune microenvironments and PD-1 response.
• The result: Stiff matrices promoted F-actin remodeling and YAP nuclear enrichment, driving LDHA-dependent glycolytic reprogramming that impaired CD8 T-cell effector function; softening enhanced PD-1 blockade efficacy and increased IFN-{gamma}-responsive PD-L1 expression.