Hyperglycemia induces an immunosuppressive microenvironment in colorectal cancer liver metastases by recruiting peripheral blood monocytes through the CCL3-CCR1 axis.

Abstract

Background: The treatment of colorectal cancer liver metastasis (CRLM), a leading cause of mortality in patients with colorectal cancer, is complicated by type 2 diabetes (T2D). This study aimed to investigate the CRLM immune microenvironment in the context of T2D and identify potential therapeutic targets.

Methods: A hyperglycemic CRLM mouse model was established. Seven single-cell RNA sequencing datasets were analyzed, including three peripheral blood mononuclear cells (PBMCs) datasets (from healthy donors and T2D patients) and four datasets with 20 CRLM samples and matching PBMCs datasets, to explore the immune characteristics and remodeling of the tumor microenvironment in CRLM with concurrent T2D.

Results: CD8⁺T cells exhibited dysfunction and exhaustion in liver metastasis from patients with CRLM and T2D; the proportions of various CD4⁺T cell subpopulations were also altered, and the number of myeloid cells and their function was increased. Myeloid cells in CRLM from patients with T2D exhibited high expression levels of CCL3, which recruited peripheral blood monocytes expressing high levels of CCR1, leading to an accumulation of myeloid cells and an immunosuppressive tumor microenvironment. Recruited cells exhibited enhanced T cell communication abilities, indicating an augmented immunosuppressive capacity. In addition, CCR1 expression in peripheral blood monocytes from patients with CRLM was closely correlated with the immunosuppressive tumor microenvironment, suggesting that CCR1 expression levels may predict immune cell phenotype and prognosis in patients with CRLM and T2D.

Conclusions: Our study revealed complex changes in the tumor microenvironment of patients with CRLM and T2D. In particular, a novel mechanism was identified by which hyperglycemia regulates immunosuppression: the CCL3-CCR1 signaling axis. This finding offers a novel potential therapeutic target for patients with CRLM and T2D and provides an important theoretical basis for the future prediction of the prognosis of these patients.