Unveiling the Role of Tumor-Infiltrating T Cells and Immunotherapy in Hepatocellular Carcinoma: A Comprehensive Review

SIMPLE SUMMARY: Hepatocellular carcinoma (HCC) is a pressing global health concern, ranking third in cancer-related deaths. Current treatments have limited success, with low survival rates and high recurrence. Immunotherapies show promise in improving outcomes, such as combining atezolizumab and bevacizumab. However, more effective treatments are needed. This review explores the immune landscape of HCC, shedding light on the complex interactions among T cells within the tumor environment and strategies to reinvigorate these cells. It also summarizes ongoing trials of immune checkpoint inhibitors, combination therapies, and CAR-T or TCR-T cell therapies for HCC, which may transform its management. ABSTRACT: Hepatocellular carcinoma (HCC) is a rapidly rising global health concern, ranking as the third-leading cause of cancer-related mortality. Despite medical advancements, the five-year survival rate remains a dismal 18%, with a daunting 70% recurrence rate within a five-year period. Current systematic treatments, including first-line sorafenib, yield an overall response rate (ORR) below 10%. In contrast, immunotherapies have shown promise by improving ORR to approximately 30%. The IMbravel150 clinical trial demonstrates that combining atezolizumab and bevacizumab surpasses sorafenib in terms of median progression-free survival (PFS) and overall survival (OS). However, the therapeutic efficacy for HCC patients remains unsatisfactory, highlighting the urgent need for a comprehensive understanding of antitumor responses and immune evasion mechanisms in HCC. In this context, understanding the immune landscape of HCC is of paramount importance. Tumor-infiltrating T cells, including cytotoxic T cells, regulatory T cells, and natural killer T cells, are key components in the antitumor immune response. This review aims to shed light on their intricate interactions within the immunosuppressive tumor microenvironment and explores potential strategies for revitalizing dysfunctional T cells. Additionally, current immune checkpoint inhibitor (ICI)-based trials, ICI-based combination therapies, and CAR-T- or TCR-T-cell therapies for HCC are summarized, which might further improve OS and transform the management of HCC in the future.