Cancer Genetics and Epigenetics 2024, Vol.12, No.6, 306-316 http://medscipublisher.com/index.php/cge 311 5.2 ICIs and targeted therapies The combination of ICIs with PARP inhibitors has shown potential in BRCA-mutated TNBC. PARP inhibitors exploit the DNA repair deficiencies in BRCA-mutated cells, and when combined with ICIs, they may enhance the anti-tumor immune response by increasing tumor mutational burden and neoantigen load, thereby making the tumor more recognizable to the immune system (Farshbafnadi et al., 2021). VEGF inhibitors can modulate the tumor microenvironment by normalizing tumor vasculature, reducing hypoxia, and enhancing immune cell infiltration. This creates a more favorable environment for ICIs to exert their effects. Combining VEGF inhibitors with ICIs has shown promise in preclinical models and early-phase clinical trials, suggesting that this strategy could improve outcomes in TNBC (Farshbafnadi et al., 2021; Thomas et al., 2021). 5.3 Integration of ICIs with radiotherapy and other treatment modalities Radiotherapy can induce immunogenic cell death and enhance the presentation of tumor antigens, potentially synergizing with ICIs to boost anti-tumor immunity. The combination of radiotherapy with ICIs is being explored in clinical trials, with early results indicating that this approach may improve response rates and survival outcomes in TNBC (Adams et al., 2016; Thomas et al., 2021). Thomas et al. (2021) found that TNBC has limited treatment options due to the absence of traditional targets for therapy. Immune checkpoint inhibitors (ICIs) show potential in cancer immunotherapy by restoring T cell activity. However, their efficacy is constrained by the complexity of the tumor microenvironment and immune evasion mechanisms. Studies indicate that combining ICIs with chemotherapy, PARP inhibitors, or immunotherapies such as cancer vaccines and NK cell therapy can significantly enhance therapeutic efficacy and provide more durable anti-tumor responses (Figure 3).Additionally, combining ICIs with other treatment modalities such as CDK4/6 inhibitors has shown synergistic effects in preclinical models, suggesting that multi-modal approaches could be beneficial (Teo et al., 2017). Figure 1 Current Approaches for PD-1 and PD-L1 immune checkpoint inhibition in TNBC (Adopted from Thomas et al., 2021) Image Caption: The efficacy of PD-1 and PD-L1 therapy may be hampered due to cancer cell-intrinsic interactions and/or microenvironmental factors along with the expression of immune checkpoint molecules such as PD-L1 that define a potent and durable anti-tumor immune response. Immune checkpoint blockade could be used as monotherapy or in combination with different therapeutic approaches, including chemotherapy, PARP inhibitors with or without VEGFR/CDK/MEK inhibitors, cancer vaccines, and NK cell therapy (Adopted from Thomas et al., 2021)
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