# New Achievements for the Treatment of Triple-Negative Breast Cancer
## 2 Therapeutic Treatments  
Several therapeutic strategies have been proposed for early and advanced TNBC and are summarized in Figure 1[60]. This disease differs in several characteristics from other BC subtypes, and it is more likely than other BC subtypes to benefit from immune checkpoint blockade [61]. Immunotherapy is a useful strategy for the treatment of TNBC [62; 63], and immune checkpoint inhibitors (ICIs) can block immunosuppressive receptors to improve the cytotoxicity and proliferative capacity of tumor-infiltrating lymphocytes (TILs) [64; 65]. ICIs include monoclonal antibodies against PD-1 (e.g., pembrolizumab, nivolumab, cimplimab) [66; 67], PD-L1 (e.g., atezolizumab, durvalumab, avelumab) [68], and CTLA-4 (e.g., ipilimumab and tremelimumab) [69; 70]. TNBC has more TILs and thus better responds to ICIs; moreover, high levels of TILs in TNBC are associated with improved prognosis in early-stage TNBC. Futher, TNBC has higher levels of PD-L1 expression on both tumor and immune cells, thus providing direct targets for ICIs. However, immune checkpoint inhibitors are not able to hamper the ex-novo expression of oncoprotein such as PD-L1 in tumoral cells. Instead, microRNA-based gene therapy leads to the restoration of specific microRNAs, which can downregulate tumoral PD-L1 expression, inhibiting TNBC development. This approach suppresses tumor proliferation and migration and regulates different oncogenic signaling pathways in TNBC cells [71].  
Taxane-based chemotherapy is still the mainstay of treatment in early stages of TNBC. Among taxanes, paclitaxel protein-bound is a well-known microtubule inhibitor used for TNBC treatment, even if there are some limitations, including the barriers to effective drug delivery of highly lipophilic agents. In order to overcome the latter limitation, a next-generation taxane, _nab_-paclitaxel, was specifically designed and showed a therapeutic index higher than paclitaxel, as demonstrated in Phase III trials [72]. Docetaxel (Taxotere(r)), discovered in the 1980s, has been one of the most significant chemotherapeutic medicines used to treat cancer [73], but it may present side effects on the normal microbial flora of the body, leading to antibiotic resistance. Since the phosphatidylinositol 3-kinase (PI3K)/ AKT signaling pathway is frequently activated in TNBC, Capivasertib (AZD5363) [74], a potent selective oral inhibitor of all three isoforms of the serine/threonine kinase AKT, demonstrated preclinical activity in TNBC models, and drug sensitivity has been associated with activation of PI3K or AKT and/or deletions of PTEN [75]. Vinblastine, a Vinca alkaloids [76], shows various biochemical effects, such as microtubule disorganization, inhibition of protein and nucleic acid synthesis, increased oxidized glutathione, alteration of lipid metabolism and the lipid content of membranes, elevation of cyclic adenosine monophosphate (cAMP) and inhibition of calcium-calmodulin regulated cAMP phosphodiesterase. Particularly, it induces the assembly of tubulin into non-microtubule polymers such as para-crystals or spiral proto-filamentous structures [77]. Finally, dasatinib, an approved second-generation inhibitor of multiple tyrosine kinases (Src, BCR-ABL, c-KIT, PDGF-\(\alpha\), PDGFR-\(\beta\) and ephrin receptor kinase), was suggested in preclinical studies as a potential targeted treatment for TNBC. However, in Phase II clinical trials it showed limited single-agent activity in patients with locally advanced or metastatic TNBC, thus further studies are needed.