Spatial dynamics links PD-L1 and Tumor-Associated Macrophage–Enriched Niches to Immune and Mesenchymal States in microsatellite stable colorectal cancer

Bulk RNA expression analysis showed that PD-L1–negative tumors exhibited an expression profile consistent with abundant cancer-associated fibroblast infiltration, increased matrix stiffness, and impaired immune activation—features aligned with tumor progression and poorer clinical outcomes. In contrast, PD-L1–positive tumors displayed stromal programs enriched in immune activation and controlled remodeling, consistent with an immunologically active microenvironment.

Spatial transcriptomics added an additional layer of evidence, revealing that epithelial-to-mesenchymal transition–related programs can dominate stromal niches in PD-L1–negative tumors, particularly within macrophage-enriched stromal regions. In conclusion, our observations suggest a crosstalk link between PD-L1 expression on immune cells and immune-activated vs mesenchymal-dominant states driven within tumor-associated macrophage-enriched stromal niches.

These results provide insight into the biological mechanisms underlying disease progression and highlight tumor-associated macrophages as a potential therapeutic target to overcome immune resistance particularly in PD-L1–negative MSS-CRC tumors.