Study Identifies Mechanism of Early Colorectal Cancer Metastasis, With Specific Immune Cells Promoting Growth and Spread

Researchers in South Korea have identified the mechanism by which colorectal cancer metastasizes at an early stage. The findings show that a specific type of immune cell simultaneously promotes tumor growth and metastasis.

A research team led by professors Zhao Xiaodi, Lu Yuanyuan, Wang Xin and Wang Liang of Air Force Military Medical University published the findings Aug. 26, 2026, in the international journal Science Translational Medicine.

The researchers confirmed that a deficiency of latent transforming growth factor-beta (TGFβ) binding protein 4 (LTBP4) is a key factor in colorectal cancer progression. When LTBP4 is deficient, tumor-associated macrophages are reprogrammed, generating a specific subpopulation that drives tumor progression through immune evasion and extracellular matrix remodeling.

Clinically, LTBP4 deficiency was associated with colorectal cancer progression and lower patient survival. Removing the Ltbp4 gene in immunocompetent mice substantially increased tumor growth and metastasis, but this effect was attenuated in immunodeficient mice. This indicates that host immunity plays a key role in mediating the effects of LTBP4 deficiency.

Single-cell RNA sequencing showed that LTBP4 deficiency induced a mannose receptor C-type 1-positive (MRC1⁺)/CD44⁺ macrophage subpopulation, which was associated with reduced CD8⁺ T-cell infiltration.

Mechanistically, LTBP4 deficiency increases levels of active TGFβ1. TGFβ1 acts on surrounding cells to increase MRC1 expression in macrophages and, through its own signaling, induces hyaluronan synthase 2 (HAS2) expression and hyaluronan production, thereby increasing CD44.

During this process, CD44 signaling in macrophages activates collagen-degrading enzymes, while MRC1 draws collagen into the cells and remodels the extracellular matrix, helping tumor infiltration. In addition, this macrophage population induced by TGFβ1 suppressed CD8⁺ T-cell function by weakening the CXCL16-CXCR6 axis.

From a therapeutic perspective, targeted elimination of MRC1⁺/CD44⁺ macrophages improved the efficacy of PD-1 immune checkpoint inhibitors in LTBP4-deficient tumors. The research team said, "LTBP4 is a key regulator of tumor progression" and that the findings "present a new therapeutic strategy for LTBP4-deficient colorectal cancer."

Colorectal cancer is the third most common cancer worldwide and the second-leading cause of cancer-related death. Metastasis is the primary cause of death from colorectal cancer, but its molecular basis has not been fully elucidated. Approximately 22% of patients with colorectal cancer already have metastases at the time of initial diagnosis, and 7% to 23% of patients who receive treatment with curative intent subsequently develop metastases.

The researchers focused on the fact that factors enabling metastasis are acquired during the early stages of cancer evolution. However, they explained that previous studies have focused on intrinsic mechanisms within cancer cells and have not sufficiently clarified how the tumor microenvironment changes during the early stages, before metastasis becomes clinically apparent.

LTBP4 is a secreted protein that maintains TGFβ in its latent state and regulates extracellular matrix homeostasis. Its expression is known to be reduced in several cancers, including breast, esophageal, liver and skin cancers.

This study demonstrated that LTBP4 deficiency drives colorectal cancer progression by creating a tumor microenvironment that promotes metastasis. The researchers identified LTBP4 as a key regulator of a macrophage-driven metastatic program and suggested the therapeutic potential of targeting MRC1⁺/CD44⁺ macrophages in LTBP4-deficient colorectal cancer.