Microenvironmental CTHRC1 has a pro-tumorigenic role in colorectal cancer

Collagen triple helix repeat containing 1 (CTHRC1) is a secreted protein that has previously been explored for its role in tissue remodeling and cancer. However, its function in the tumor microenvironment (TME) remains poorly understood, despite its known expression in tumor-associated stroma. Colorectal cancer (CRC), a malignancy characterized by extensive stromal involvement, poses an excellent opportunity to investigate this gap. Here, we provide the first evidence that host-derived CTHRC1 drives colon cancer progression, with this effect consistently observed across three independent cohorts. Specifically, when injected with CRC cells, Cthrc1 null (global knockout, KO) mice develop significantly smaller and less dense tumors compared to wild-type (WT) mice. Additionally, median survival increased approximately 2.5-fold in Cthrc1 KO mice, from 28 days post-inoculation in WT (n = 10) to 69 days in CTHRC1-deficient mice (n = 10), suggesting CTHRC1 promotes tumor growth within the TME. Immune cell profiling revealed differences in the composition of tumors and spleens of these mice; specifically, Cthrc1 KO mice exhibited an increased percentage of CD3+ T cells in both tumors and spleens and decreased Gr-1+ myeloid cells in the spleen, compared to WT, indicating an immunoregulatory role for CTHRC1 in CRC. These results identify CTHRC1 as a key driver of CRC that may suppress the immune system, allowing for easier immune evasion by tumor cells, highlighting CTHRC1 as a potential new target for therapy.