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Hamilton, Maxwell S.; Ellis, Samuel T.; Cao, Zheng; Tutanov, Oleg S.; Simmons, Alan J.; Aramandla, Radhika; Higginbotham, James N.; Ramirez, Marisol; Schnee, Katherine W.; Bechard, Matthew E.; Kaur, Harsimran; Franklin, Jeffrey L.; Mandal, Swastika; Lau, Ken S.; Liu, Qi; Goettel, Jeremy A.; Pozzi, Ambra; Coffey, Robert J. (2026).Ìý.ÌýCancer Research Communications, 6(9), 2149–2163.Ìý

Immune checkpoint blockade (ICB), a treatment that helps the immune system attack cancer, works well in some colorectal cancers but is largely ineffective in microsatellite-stable (MSS) tumors because they contain few cancer-killing CD8+ T cells. This study investigated DDR1, a protein linked to the exclusion of these immune cells. The researchers found that DDR1 promotes the alignment of collagen fibers around tumors, creating conditions that limit CD8+ T-cell access. A cleaved form of DDR1 was also found in tiny secreted particles called supermeres, which caused fibroblasts—cells that help form tumor-supporting tissue—to contract and reorganize collagen. These findings suggest that DDR1 helps create a physical barrier that keeps immune cells out of MSS colorectal tumors and could be a promising therapeutic target.

Figure 1. High DDR1 immunoreactivity is associated with decreased CD8⁺ T-cell infiltration in MSS colorectal cancer.ÌýA, Representative DDR1, CD8, PanCK, and DAPI immunofluorescence images of three 1-mm tumor cores from an MSS colorectal cancer TMA binned into DDR1 low and high based on epithelial DDR1 fluorescence intensity. Epithelial area outlined with dashed white line. Intraepithelial CD8⁺ T cells are marked by white arrowheads. Scale bars, 200 μm.ÌýBÌý²¹²Ô»åÌýC, Pirate plots of the relative number of CD8⁺Ìý(B) and CD4⁺Ìý(C) T cells per epithelial area in each DDR1 low and high MSS tumor sample. Each point represents the average of 1 tumor.ÌýN = 58 DDR1-low and 13 DDR1-high patients. ns, not statistically significant; *, P < 0.05.