School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Sha Tin, Hong Kong, SAR, China.
Institute of Tissue Engineering and Regenerative Medicine, The Chinese University of Hong Kong, Sha Tin, Hong Kong, SAR, China.
Hepatol Commun. 2024 Oct 30;8(11). doi: 10.1097/HC9.0000000000000569. eCollection 2024 Nov 1.
HCC, the most common type of primary liver cancer, is a leading cause of cancer-related mortality worldwide. Although the advancement of immunotherapies by immune checkpoint inhibitors (ICIs) that target programmed cell death 1 or programmed cell death 1-ligand 1 has revolutionized the treatment for HCC, the majority is still not beneficial. Accumulating evidence has pointed out that the potent immunosuppressive tumor microenvironment in HCC poses a great challenge to ICI therapeutic efficacy. As a key component in tumor microenvironment, tumor-associated macrophages (TAMs) play vital roles in HCC development, progression, and ICI low responsiveness. Mechanistically, TAM can promote cancer invasion and metastasis, angiogenesis, epithelial-mesenchymal transition, maintenance of stemness, and most importantly, immunosuppression. Targeting TAMs, therefore, represents an opportunity to enhance the ICI therapeutic efficacy in patients with HCC. While previous research has primarily focused on biochemical cues influencing macrophages, emerging evidence highlights the critical role of biophysical signals, such as substrate stiffness, topography, and external forces. In this review, we summarize the influence of biophysical characteristics within the tumor microenvironment that regulate the phenotype and function of TAMs in HCC pathogenesis and progression. We also explore the possible mechanisms and discuss the potential of manipulating biophysical cues in regulating TAM for HCC therapy. By gaining a deeper understanding of how macrophages sense and respond to mechanical forces, we may potentially usher in a path toward a curative approach for combinatory cancer immunotherapies.
HCC 是最常见的原发性肝癌，是全球癌症相关死亡的主要原因。尽管免疫检查点抑制剂（ICIs）靶向程序性细胞死亡 1 或程序性细胞死亡配体 1 的免疫疗法的进步彻底改变了 HCC 的治疗方法，但大多数患者仍未受益。越来越多的证据指出，HCC 中强大的免疫抑制肿瘤微环境对 ICI 的治疗效果构成了巨大挑战。作为肿瘤微环境的关键组成部分，肿瘤相关巨噬细胞（TAMs）在 HCC 的发展、进展和 ICI 低反应性中发挥着重要作用。从机制上讲，TAM 可促进癌症侵袭和转移、血管生成、上皮间质转化、维持干细胞特性，最重要的是，抑制免疫。因此，针对 TAMs 代表了提高 HCC 患者 ICI 治疗效果的机会。虽然以前的研究主要集中在影响巨噬细胞的生化信号上，但新出现的证据强调了生物物理信号（如基质硬度、形貌和外力）的关键作用。在这篇综述中，我们总结了肿瘤微环境中的生物物理特性对 HCC 发病机制和进展中 TAMs 表型和功能的影响。我们还探讨了可能的机制，并讨论了操纵生物物理线索来调节 TAM 治疗 HCC 的潜力。通过更深入地了解巨噬细胞如何感知和响应机械力，我们可能会开创一种联合癌症免疫疗法的治疗方法。
