肝癌微环境重塑与免疫治疗策略

Microenvironment Remodeling and Immunotherapy of Hepatocellular Carcinoma

肝细胞癌是消化系统常见的恶性肿瘤之一,局部免疫微环境与肿瘤疾病的发生发展及治疗效果密切相关。肿瘤细胞可诱导免疫细胞表型和功能改变塑造免疫抑制微环境,减弱免疫系统杀伤功能。同时,免疫细胞代谢调节对机体抗肿瘤免疫应答至关重要。肝癌微环境中的代谢产物及肠道菌群代谢物失衡可通过调控免疫细胞表型和功能重塑影响肝癌进展。目前,肝癌细胞与微环境免疫细胞之间相互作用导致肿瘤免疫逃逸已成为当前研究的热点。本文总结了肝癌免疫抑制微环境的构成及其代谢调控,并探讨了靶向微环境重塑治疗肝癌的潜在策略,为肿瘤免疫治疗提供新思路。

Hepatocellular carcinoma(HCC)is one of the most common malignant tumors in the digestive tract system,which is induced by multiple factors,involving multiple genes and complicated mechanism.Its incidence and mortality rank fourth and second respectively in China,and accounting for more than 85%of primary liver cancers.Tumor immune microenvironment(TIME),plays a critical role in determining the tumor progression and treatment outcomes,making it become a hotspot in current studies.Summarising the previous studies,it is found that the progression of HCC is significantly influenced by the TIME and its complex interactions.TIME consists of various cellular and non-cellular components,such as myeloid-derived suppressor cells(MDSCs),tumor associated macrophages(TAMs),tumor-associated neutrophils(TANs),regulatory T cells(Tregs),innate lymphoid cells(ILCs),as well as growth factors,proteolytic enzymes,and extracellular matrix proteins.Due to long-term exposure to bacterial components carried by the portal vein,food-derived antigens,and a large amount of foreign antigenic substances,the microenvironment of liver exhibits a certain degree of immune suppression to resist excessive inflammation caused by the non-pathogenic intestinal environment.Besides,the inhibitory immune microenvironment shaped by tumor cells which induces changes in the phenotype and function of immune cells,and attenuates the cytotoxic capabilities of immune system.Meanwhile,the regulation of immune cell metabolism is crucial for anti-tumor immune response.Abnormal metabolites of liver cancer microenvironment and intestinal flora metabolites regulate the remodeling of immune microenvironment and the progression in liver cancer.Normally,the cancer immune cycle functions effectively to remove tumor cells,while the immunosuppressive,exhausted T cells and metabolic disorders of the TIME leads to defects in the cancer immunity cycle and promotes to tumor progression.Furthermore,during the processes of rapid proliferation and differentiation,tumor cells alter their metabolic status through“metabolic reprogramming”,allowing them to compete with anti-tumor immune cells for vital nutrients including glucose,lipids,and nucleotides.At the same time,the abnormal consumption of metabolites leads to local hypoxia,lower pH levels,and the accumulation of metabolic products,which in turn suppress the proliferation and effector functions of immune cells,ultimately facilitating immune evasion and tumor progression.According to the above,local immune imbalance and metabolic disorders in the liver collectively shape the unique microenvironment of HCC,resulting in the accumulation of immunosuppressive cytokines,extracellular matrix and abnormal metabolites.These factors induce abnormal tumor angiogenesis,recruitment of immunosuppressive cells,reduce T-cell infiltration,and diminish anti-tumor function,which accelerates the progression of HCC and immune escape.Currently,there are still remarkable limitations in the clinical treatment methods and outcomes for HCC,while immunotherapy offers a new strategy.The advantages of immunotherapy demonstrate relatively higher specificity and fewer side effects compared to traditional treatment methods such as surgery,radiotherapy,and chemotherapy.Up to now,more and more evidence has been uncovered that liver cancer immunotherapy is closely related to TIME.Targeting the TIME of HCC provides a new perspective into a deeper understanding of the mechanisms of immunotherapy resistance and the development of new immunotherapy approaches.However,single immunotherapy has not shown satisfactory results in improving the prognosis of HCC patients.At present,dual immune checkpoint inhibitors or their combination with existing therapies are being widely explored in clinical studies,hoping to overcome the limitations of HCC therapy.Therefore,this review summarizes the composition of immunosuppressive microenvironment in liver cancer and metabolic regulation,and further discusses clinical therapeutic strategies by targeting microenvironment remodeling for the treatment of liver cancer,which provides new avenues for tumor immunotherapy.