Cancer Genetics and Epigenetics 2024, Vol.12, No.6, 306-316 http://medscipublisher.com/index.php/cge 307 (Cyprian et al., 2019; Varma et al., 2022; Wu et al., 2022). However, the efficacy of ICIs varies among patients, and their use is often accompanied by immune-related adverse events, necessitating further research to optimize their application (Semba et al., 2020; Wu et al., 2022; Zhao et al., 2023). This review will comprehensively summarize the current status, efficacy, limitations, and future directions of immune checkpoint inhibitors (ICIs) in the treatment of triple-negative breast cancer (TNBC). By analyzing the latest clinical evidence and exploring the potential mechanisms of ICIs, this review highlights the potential of these therapies to improve TNBC management and identifies research areas needed to further enhance their effectiveness and safety. 2 Biological Basis of ICIs in TNBC 2.1 Tumor immunogenicity in TNBC Triple-negative breast cancer (TNBC) is characterized by a high mutational burden, which leads to the generation of numerous neoantigens. These neoantigens can be recognized by the immune system, making TNBC more immunogenic compared to other breast cancer subtypes (Thomas et al., 2021; Yi et al., 2021). The presence of these neoantigens is crucial for the effectiveness of immune checkpoint inhibitors (ICIs), as they provide targets for the immune system to attack the cancer cells (Farshbafnadi et al., 2021). The tumor microenvironment (TME) of TNBC is highly immunosuppressive, which poses a significant challenge for effective immune responses. TNBC tumors often exhibit high levels of tumor-infiltrating lymphocytes (TILs), including both cytotoxic T cells and regulatory T cells (Tregs) (Semba et al., 2022; Zhao et al., 2023). The presence of TILs is associated with better responses to ICIs, as these immune cells can be reactivated to attack the tumor. However, the TME also contains myeloid-derived suppressor cells (MDSCs) and other immunosuppressive factors that inhibit anti-tumor immunity (Semba et al., 2022). 2.2 Immune evasion mechanisms in TNBC TNBC employs several mechanisms to evade immune detection and destruction. One of the primary strategies is the upregulation of immune checkpoint molecules such as PD-L1, which binds to PD-1 on T cells and inhibits their activity (Singh et al., 2021). Additionally, TNBC tumors can secrete immunosuppressive cytokines and chemokines, such as CCL2, which attract Tregs and MDSCs to the TME, further dampening the immune response (Semba et al., 2022). These mechanisms collectively create an environment that is hostile to immune cell activity, allowing the tumor to grow and metastasize. 2.3 Role of immune checkpoint molecules (PD-1, PD-L1, CTLA-4) in TNBC progression Immune checkpoint molecules play a critical role in the progression of TNBC by inhibiting the activity of cytotoxic T cells. PD-1 and its ligand PD-L1 are the most studied checkpoint molecules in TNBC. The interaction between PD-1 on T cells and PD-L1 on tumor cells leads to the suppression of T cell activity, allowing the tumor to evade immune surveillance (Cyprian et al., 2019; Farshbafnadi et al., 2021). PD1/PDL1 antibodies have demonstrated significant efficacy across various solid tumors. However, their effectiveness varies depending on the tumor microenvironment and PDL1 expression levels in patients. CTLA4 blockade provides a complementary effect by modulating the initial activation of T cells, CTLA-4 is another checkpoint molecule that inhibits T cell activation by competing with CD28 for binding to B7 molecules on antigen-presenting cells (Figure 1) (Yi et al., 2021). The expression of these molecules in TNBC is associated with poor prognosis and resistance to conventional therapies. 2.4 Scientific rationale for the use of ICIs in TNBC The use of ICIs in TNBC is based on the premise that blocking these checkpoint molecules can restore the activity of cytotoxic T cells and enhance anti-tumor immunity. Clinical trials have shown that ICIs, particularly when combined with chemotherapy, can improve progression-free survival and overall response rates in both early-stage and metastatic TNBC (Simmons et al., 2020; Wu et al., 2022). The combination of ICIs with chemotherapy is thought to be particularly effective because chemotherapy can increase the release of tumor antigens and enhance the immunogenicity of the tumor, making it more susceptible to immune attack (Varma et al., 2022; Zhao et aL.,
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