The current status and future of targeted-immune combination for hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) is one of the most common cancers and the third leading cause of death worldwide. surgery, transarterial chemoembolization (TACE), systemic therapy, local ablation therapy, radiotherapy, and targeted drug therapy with agents such as sorafenib. However, the tumor microenvironment of liver cancer has a strong immunosuppressive effect. Therefore, new treatments for liver cancer are still necessary. Immune checkpoint molecules, such as programmed death-1 (PD-1), programmed death-ligand 1 (PD-L1), and cytotoxic T lymphocyte antigen-4 (CTLA-4), along with high levels of immunosuppressive cytokines, induce T cell inhibition and are key mechanisms of immune escape in HCC. Recently, immunotherapy based on immune checkpoint inhibitors (ICIs) as monotherapy or in combination with tyrosine kinase inhibitors, anti-angiogenesis drugs, chemotherapy agents, and topical therapies has offered great promise in the treatment of liver cancer. In this review, we discuss the latest advances in ICIs combined with targeted drugs (targeted-immune combination) and other targeted-immune combination regimens for the treatment of patients with advanced HCC (aHCC) or unresectable HCC (uHCC), and provide an outlook on future prospects. The literature reviewed spans the last five years and includes studies identified using keywords such as "hepatocellular carcinoma," "immune checkpoint inhibitors," "targeted therapy," "combination therapy," and "immunotherapy".

Keywords: CTLA-4; HCC; ICIS; anti-PD-1; anti-PD-L1; targeted-immune combination.

Figure 1

Overview of BCLC staging and treatment strategy in HCC.

Figure 2

Mechanisms of tumor immune evasion and suppression of immune checkpoints following restoration of anti-tumor immunity Tumor cells evade immune surveillance by promoting immune checkpoint activation. Tumor cells express the immune checkpoint activator PD-L1 and produce antigens, which are captured by antigen presenting cells. These cells present antigens to cytotoxic CD8⁺ T cells through the interaction of major histocompatibility complex (MHC) molecules and T cell receptor (TCR). T cell activation requires costimulatory signaling mediated by B7 and CD28 interactions. Inhibitory signals from CTLA-4 and PD-1 checkpoints inhibit T cell responses and promote tumor proliferation. ICIs, such as anti-PD-L1, anti-PD-1, and anti-CTLA-4, block immunosuppressive checkpoints (CTLA-4, PD-1, and PD-L1, respectively), thereby restoring anti-tumor immune responses. By Figdraw.