Targeting TCF21-TCF3 heterodimer in tumor-associated pericytes attenuates hematogenous metastasis by restoring pericyte gatekeeper function.

Hematogenous metastasis is the leading cause of cancer mortality, with dysfunction of pericytes, key components of tumor vessels, playing a central role in facilitating metastatic spread. Although anti-pericyte therapies are gaining recognition for treating metastasis, current strategies that directly eliminate tumor pericytes (TPCs) may increase vascular leakiness, which paradoxically promotes further metastasis. Here, we identify a TPC-specific transcription factor heterodimer, TCF21-TCF3, which drives metastasis by enhancing collagen hydroxylation and extracellular matrix deposition. Based on the TCF21 residues that interact with TCF3, we rationally design a peptide to disrupt their dimerization and downregulate TCF21-TCF3-dependent collagen deposition. Notably, in murine models of colorectal cancer and osteosarcoma, the TCF21-derived peptide significantly inhibits metastasis by restoring the physiological gatekeeper function of pericytes on vessels, offering a potential therapeutic strategy to target TPCs and suppress metastasis. Our findings reveal a TPC-specific transcription factor heterodimer and provide a promising pericyte-targeting strategy for preventing hematogenous metastasis.