One of the top causes of cancer-related mortality globally is hepatocellular carcinoma (HCC). Despite the approval of new treatments, the prognosis and treatment response of patients with advanced HCC remain dismal. A membrane protein known as claudin-1 (CLDN1) is expressed both in tight junctions and non-junctional locations, such as the basolateral membrane of human hepatocytes. Although the function of CLDN1 at tight junctions was well understood, little was known about the function of non-junctional CLDN1 and its potential as a therapeutic target in HCC.

For a study, researchers sought to examine the function of CLDN1 as a therapeutic target for HCC using humanized monoclonal antibodies (mAbs) targeting precisely the extracellular loop of human non-junctional CLDN1 and a vast array of patient-derived cell-based and animal model systems.

In cell line-based models of HCC and patient-derived 3D ex vivo models, targeting non-junctional CLDN1 significantly reduced tumor growth and invasion. A vast number of animal models established from patient-derived and cell line-derived xenografts (CDX) revealed the substantial influence on tumor development in vivo. It was determined through mechanistic investigations, such as single-cell RNA sequencing of multicellular patient HCC tumorspheres, that CLDN1 controlled tumor stemness, metabolism, and oncogenic signaling, and disturbed the tumor immune microenvironment.

The findings supported the need for CLDN1 targeting in HCC and opened the door to creative therapeutic approaches using CLDN1 mAbs to boost the meager effectiveness of existing treatments.