Abstract Most current cancer therapies are largely developed based on the genetic characterization of primary tumors and show limited efficacy against metastatic disease. Immune checkpoint blockade (ICB) has emerged as a promising therapeutic strategy for breast cancer and many other cancer types. However, its clinical benefit in metastatic disease is frequently constrained by therapeutic resistance and relapse. Here, we report that collagen triple helix repeat containing 1 (CTHRC1) is a key regulator of immune evasion and is epigenetically inactivated at metastatic sites. Using genetic, epigenomic, and proteomic approaches, we demonstrate that loss of CTHRC1 diminishes CTHRC1-mediated inhibition of LAG3+ T cell immunosuppression. Mechanistically, CTHRC1 directly interacts with the LAG3 ligand, galectin-3 (GAL3), in a N-glycosylation-dependent manner. Epigenetic downregulation of CTHRC1 facilitates the activation of the GAL3-LAG3 axis, leading to the expansion of LAG3+ T cells and immunosuppressive microenvironment. Importantly, therapeutic targeting of LAG3 in preclinical mouse models of triple-negative breast cancer significantly enhanced the efficacy of ICB and suppresses metastatic relapse. Together, these finding uncover an epigenetically regulated immune evasion mechanism in metastatic progression and suggest targeting the CTHRC1-GAL3-LAG3 axis likely represents a strategy to improve immunotherapy outcomes in metastatic breast cancer. Citation Format: Jae Young So, Tiffany Andohkow, Wooyong Park, Cui Kairong, Qingsong Tang, Gangqing Hu, Alexei Lovanov, Jing Bian, Maggie Cam, Keji Zhao, Li Yang. Epigenetic inactivation of CTHRC1 promotes immune suppressive microenvironment and cancer metastatic relapse abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts) ; 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86 (8Suppl): Abstract nr LB478.
So et al. (Fri,) studied this question.
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: