Cancer Genetics and Epigenetics, 2025, Vol.13, No.5, 236-244 http://medscipublisher.com/index.php/cge 239 Although immunity may be activated in the early postoperative period, the immunosuppressive environment often reappears before recurrence. The ways of immune escape include attracting regulatory T cells and myeloid-derived suppressor cells, increasing the expression of immune checkpoint molecules, and secreting inhibitory factors. These changes cause residual or nascent tumor cells to evade immune surveillance, eventually leading to disease recurrence or metastasis (Yeo et al., 2022; Chen et al., 2023). 4 Mechanism of Association between TIME and Recurrence 4.1 The Role of immunosuppressive cells in recurrence Immunosuppressive cells, such as regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), and M2-type macrophages, play a crucial role in the formation of the tumor microenvironment. They help tumors grow and promote the recurrence of hepatocellular carcinoma (HCC). Tregs can inhibit the functions of effector T cells and natural killer (NK) cells, thereby weakening anti-tumor immunity and making it easier for residual tumor cells after surgery to evade the surveillance of the immune system (Mundhara and Sadhukhan, 2024). MDSCs further weaken the function of T cells and promote tumor development by releasing inhibitory molecules and altering the metabolic patterns of the tumor microenvironment (Cheng et al., 2022; Kim and Cho, 2022; Chen et al., 2023). M2 macrophages with anti-inflammatory and tissue repair properties often increase in the microenvironment of recurrent tumors. Such cells secrete factors that promote angiogenesis, extracellular matrix alteration and tumor invasion, thereby jointly facilitating recurrence and metastasis (Mundhara and Sadhukhan, 2024). The expansion and aggregation of such immunosuppressive cells after surgery are closely related to the poorer prognosis and higher recurrence risk of HCC patients (Agosti et al., 2023). 4.2 Functional impairment of effector cells and its relationship with recurrence Immune checkpoint pathways such as PD-1/PD-L1 and CTLA-4 are important mechanisms for regulating immune tolerance in the tumor microenvironment. Tumor cells and peripheral immune cells increase the expression of these molecules, thereby inhibiting the activation and proliferation of T cells, enabling tumors to evade immune attacks and leading to recurrence (Kim and Cho, 2022). In recurrent tumors, high levels of PD-L1 are commonly found on tumor and immune cells. Binding to PD-1 on the surface of T cells can cause T cell failure (Cheng et al., 2022; Chen et al., 2023). In addition, immunosuppressive factors such as IL-10 and TGF-β can weaken the function of effector cells, while promoting the expansion of Tregs and M2-type macrophages, further aggravating the immunosuppressive environment (Goenka et al., 2023). These factors not only reduce anti-tumor immunity but also promote tumor growth, angiogenesis and metastasis, and are important factors for the recurrence of HCC. 4.3 Immune checkpoint pathways and immunosuppressants in recurrence Immune checkpoint pathways, such as PD-1/PD-L1 and CTLA-4, are important mechanisms for regulating immune tolerance in the tumor microenvironment. The upregulation of such checkpoint molecules by tumor cells and peripheral immune cells inhibits the activation and proliferation of T cells, thereby enabling tumors to evade immune attack and leading to recurrence (Kim and Cho, 2022). In recurrent tumors, the expression of PD-L1 on tumor and immune cells is usually high, and its binding to PD-1 on T cells can cause T cell exhaustion (Cheng et al., 2022; Chen et al., 2023). Immunosuppressive factors such as IL-10 and TGF-β can weaken the function of effector cells and promote the increase of Tregs and M2-type macrophages, thereby further strengthening the immunosuppressive microenvironment (Goenka et al., 2023). These factors not only reduce anti-tumor immunity but also promote tumor growth, angiogenesis and metastasis, becoming an important factor for HCC recurrence. 5 Case Analysis 5.1 Immune microenvironment characteristics of patients with early recurrence Patients whose tumors recur shortly after resection usually exhibit a significant immunosuppressive state in their
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