Xue Jiahao, Zhang Jingchang, Chen Gang, Chen Liucui, Lu Xinjun
Department of Biliary-Pancreatic Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China.
Tianjin Key Laboratory of Acute Abdomen Disease Associated Organ Injury and ITCWM Repair, Institute of Integrative Medicine for Acute Abdominal Diseases, Tianjin Nankai Hospital, Tianjin Medical University, Tianjin, 300100, China.
Oncol Res. 2025 Aug 28;33(9):2309-2329. doi: 10.32604/or.2025.063719. eCollection 2025.
Hepatocellular carcinoma (HCC) is a highly aggressive malignancy, largely driven by an immunosuppressive tumor microenvironment (TME) that facilitates tumor growth, immune escape, and resistance to therapy. Although immunotherapy-particularly immune checkpoint inhibitors (ICIs)-has transformed the therapeutic landscape by restoring T cell-mediated anti-tumor responses, their clinical benefit as monotherapy remains suboptimal. This limitation is primarily attributed to immunosuppressive components within the TME, including tumor-associated macrophages, regulatory T cells (Tregs), and myeloid-derived suppressor cells (MDSCs). To address these challenges, combination strategies have been explored, such as dual checkpoint blockade targeting programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), as well as synergistic use of ICIs with anti-angiogenic agents or TME-targeted interventions. These approaches have shown encouraging potential in enhancing immune efficacy. This review outlines the complex crosstalk between the TME and immunotherapeutic responses in HCC, emphasizing how combination regimens may overcome immune resistance. Furthermore, we discuss the remaining hurdles, including therapeutic resistance and immune-related adverse events, and propose future directions involving TME-associated biomarkers and individualized treatment strategies to improve patient outcomes.
肝细胞癌（HCC）是一种高度侵袭性的恶性肿瘤，主要由免疫抑制性肿瘤微环境（TME）驱动，这种微环境促进肿瘤生长、免疫逃逸和对治疗的抵抗。尽管免疫疗法——尤其是免疫检查点抑制剂（ICIs）——通过恢复T细胞介导的抗肿瘤反应改变了治疗格局，但其作为单一疗法的临床益处仍然不尽人意。这一局限性主要归因于TME中的免疫抑制成分，包括肿瘤相关巨噬细胞、调节性T细胞（Tregs）和髓源性抑制细胞（MDSCs）。为应对这些挑战，人们探索了联合策略，如针对程序性细胞死亡蛋白1（PD-1）、程序性死亡配体1（PD-L1）和细胞毒性T淋巴细胞相关抗原4（CTLA-4）的双重检查点阻断，以及ICIs与抗血管生成药物或TME靶向干预的协同使用。这些方法在增强免疫疗效方面显示出令人鼓舞的潜力。本综述概述了HCC中TME与免疫治疗反应之间复杂的相互作用，强调联合方案如何克服免疫抵抗。此外，我们讨论了剩余的障碍，包括治疗抵抗和免疫相关不良事件，并提出了涉及TME相关生物标志物和个体化治疗策略以改善患者预后的未来方向。
