Advances in improving the efficacy of anti-PD-1/PD-L1 therapy in intrahepatic cholangiocarcinoma

Abstract

Intrahepatic cholangiocarcinoma (ICC) is the second most common primary liver cancer following hepatocellular carcinoma (HCC), characterized by high malignancy and limited therapeutic options. For the majority of patients with advanced or recurrent ICC who are not candidates for surgical resection, non-surgical treatments have become the primary intervention. In recent years, immunotherapy, particularly immune checkpoint inhibitors (ICIs) either alone or in combination, has emerged as a promising systemic treatment for ICC. The programmed cell death protein 1 (PD-1) is a type I transmembrane glycoprotein primarily expressed in tumor-infiltrating lymphocytes, while its ligand PD-L1 is mainly expressed in tumor cells and antigen-presenting cells (APCs). As one of the best-known immune checkpoint molecules, PD-1 is a key mediator of immune tolerance in the human immune system and helps tumor cells evade immune surveillance by suppressing T cell function. Anti-PD-1/PD-L1 therapies are currently widely applied in the clinical care of ICC, however their low response rates limit the benefits for ICC patients. In this review, we focus on the latest research progress in enhancing the efficacy or reversing resistance to anti-PD-1/PD-L1 therapies in ICC, from three perspectives: characterizing relevant cellular components in the tumor immune microenvironment (TIME), identifying ICC subtypes with higher response rates, and investigating potential molecular targets for combination therapies. In summary, the core of the vast majority of therapeutic strategies focuses on how to reshape the TIME or modulate the expression levels of PD-1/PD-L1 in tumors.