TNBC is a highly invasive and aggressive type of BC, which is characterized by the absence of ER, PR and HER2 expression. TNBC represents almost 20% of all diagnosed BC, being associated with resistance to chemotherapy, a predisposition to metastasis, poor prognoses and reduced survival rates [19]. Over the years, researchers have studied the molecular signatures of TNBC using advanced techniques and, according to gene expression profiles, Lehmann et al. [20], Burstein et al. [21] and Jezequel et al. [22] have all proposed different classification of TNBC in order to investigate possible therapeutic targets to improve the outcomes of TNBC (Table 1). Moreover, according to Lehmann et al., TNBC can be subdivided into six groups: basal-like 1, basal-like 2, mesenchymal, mesenchymal stem-like, immunomodulatory, and luminal androgen receptor TNBC [20]. Burstein et al. proposed a TNBC classification divided into four subtypes: basal-like immune-activated, basal-like immune-suppressed, mesenchymal, and luminal androgen receptor TNBC [21], while Jezequel et al. divided triple-negative tumors into three clusters: C1 (22.4%), C2 (44.9%) and C3 (32.7%) [22]. Classifying and understanding the particularities of TNBC allow for the development of personalized medicine, because each subtype has different characteristics and responses to anti-tumor therapy [23].

The breast tumor microenvironment (TME) is associated with chronic inflammatory reactions, with inflammatory infiltrate being a prognostic marker of cancer. Pro-inflammatory molecules together with their specific receptors are involved in the development of TNBC due to their capability to promote cell differentiation and angiogenesis, to recruit immune cells and to influence the immune system [46]. Lymphocytes, macrophages and fibroblasts are the most common cell types of the TME and secrete different factors (such as cytokines, chemokines, enzymes, growth factors, etc.), which are associated with an aggressive malignancy and high risk of metastasis. Pro-inflammatory mediators (IL-6, CCL2, COX2, and TNF-α) are generally up-regulated in breast tumor stroma; IL-1, IL-6, IL-8, IL-11, IL-18 and IL-23 are among the most studied inflammatory factors involved in inflammation, TNBC, invasion and metastasis [47]. In close correlation with the development of inflammatory reactions and TNBC is the activation of the NLRP3 inflammasome complex, with IL-1β and IL-18 being the two major cytokines activated by NLRP3 inflammasome, which promote tumor cell proliferation and invasion [48].

Over the years, new signaling pathways within breast TME have been discovered, which have opened up new perspectives for the development of strategies that aim to block these signals that promote tumorigenesis, angiogenesis and metastasis. Specifically, conventional therapeutic strategies are the gold standard for neoadjuvant treatment represented by a combination between anthracyclines and taxanes, capecitabine and taxane and ixabepilone monotherapy (paclitaxel, 5-fluorouracil, doxorubicin, cisplatin, carboplatin, abraxane, bevacizumab, cyclophosphamide, ixabepilone, capecitabine, etc.), adjuvant treatment (anthracycline-based drugs), surgery (mastectomy and lumpectomy) and radiotherapy [49].

Despite the heterogeneity and aggressiveness of TNBC, the corresponding standard of care (SOC) requires neoadjuvant chemotherapy, followed by surgery and adjuvant chemotherapy (Table 2). There are several treatment schemes for early diagnosed TNBC that are based on anthracycline and taxane administration, but which cause numerous adverse effects (nausea, fatigue, gastrointestinal toxicity, myelosuppression, alopecia, hypothyroidism, hyperthyroidism, pneumonitis, skin reactions, adrenal insufficiency, peripheral neuropathy, neutropenia, pyrexia, anemia, thrombocytopenia, electrolyte abnormalities, infection, etc.) and do not lower the relapse rate [50].

Although neoadjuvant chemotherapy is the standard treatment approach for diagnosed TNBC, the therapeutic potential of other agents that interfere with various molecular mechanisms (such as angiogenesis, the immune response, the cell cycle, etc.) have been tested or are currently under testing and approval (Table 3). The optimal treatment scheme for TNBC is a great challenge due to the disease’s heterogeneity and increased risk of relapse, so the researchers have explored several promising anti-tumor agents (pembrolizumab, bevacizumab, olaparib, sacituzumab govitecan, etc.) [53]. Other therapeutic approaches are represented by platinum salts (carboplatin, cisplatin, etc.) immunotherapies that target the programmed cell death-1 (PD-1) receptor/PD-L1 pathway, immune-checkpoint inhibitors, poly-adenosine diphosphate ribose polymerase (PARP) inhibitors or AKT inhibitors [54].

The molecular characteristics of TNBC tumors (heterogeneity and the chemoresistance mechanism) raise difficulties in establishing an effective conventional therapeutic strategy; therefore advanced therapeutic strategies have been developed. There are two main types of advanced therapeutic treatments: passive transport (or enhanced permeability and retention (nanoparticles)) and active transport (miRNA and aptamers) [49].