Chimeric antigen receptor therapy for hepatocellular carcinoma

Adapting the success of chimeric antigen receptor T cell therapy from hematologic malignancies to solid tumors has become a major focus of ongoing research activities. However, the unique challenges posed by solid tumors, such as limited immune cell infiltration, reduced T cell persistence, and antigen loss, have led to only limited success in early clinical trials. Recently, combinatorial strategies incorporating next-generation armored CAR T cells along with various alternative immune cell types have rekindled optimism in the field. Hepatocellular carcinoma represents a distinct entity due to the unique characteristics of the liver microenvironment, including the influence of lipid metabolism, bile acids, and microbial compounds from the gut-liver axis. Furthermore, HCC is characterized by a variety of tumor-specific and tumor-associated antigens, enabling targeted approaches with minimal risk of on-target/off-tumor effects. The unique complexity of HCC, along with the underlying liver diseases that give rise to these tumors, presents both challenges and opportunities for cellular therapies. In this review, we examine the current landscape of CAR T cell therapy for HCC, highlighting recent clinical and preclinical developments. Furthermore, we discuss why HCC may be especially well-suited for tailored CAR-based strategies, given the liver's specific anatomical and immunological properties.