Triple-negative breast cancer (TNBC), characterized by the absence of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), remains a therapeutic challenge due to its aggressive nature, limited treatment options, and high recurrence rates. Current therapies, including chemotherapy and immune checkpoint inhibitors, face resistance driven by tumor heterogeneity, immunosuppressive signaling, and dysregulated redox pathways. This review explores silibinin’s potential to modulate the tumor immune microenvironment (TIME) and overcome therapeutic resistance in TNBC. Silibinin exerts multifaceted anticancer effects by suppressing PD-L1 expression through the inhibition of JAK/STAT3 signaling and MUC1-C interaction, attenuating NF-κB-driven inflammation, and downregulating CCL2-mediated recruitment of tumor-associated macrophages (TAMs). Additionally, silibinin disrupts redox adaptation by targeting the Nrf2-EGFR-MYC-TXNIP axis, enhancing oxidative stress and chemosensitivity. Preclinical studies highlight its ability to inhibit epithelial–mesenchymal transition (EMT), reduce cancer stem cell (CSC) populations, and synergize with existing therapies like PD-1 inhibitors. Despite its low bioavailability, advanced formulations such as liposomes and nanoparticles show promise in improving delivery and efficacy. By reshaping TIME through dual antioxidant and immunomodulatory mechanisms, silibinin emerges as a viable adjunct therapy to reverse immunosuppression and chemoresistance in TNBC.

Triple-negative breast cancer (TNBC) is one of the most aggressive and non-responsive subtypes regarding standard treatment options for breast cancer

Triple-negative breast cancer (TNBC) remains one of the most challenging subtypes of breast cancer to treat, defined by its molecular heterogeneity, absence of hormone receptors, and poor clinical outcomes. While this difficulty with cancer cells persists even in the presence of chemotherapy and immune checkpoint inhibitors (ICIs), one critical factor linked to both chemoresistance and immune escape is autophagy. Autophagy is a cellular process with lysosomal recycling function. In TNBC, autophagy paradoxically shifts from tumor-suppressive to a tumor-promoting role. Autophagy was initially known to maintain genomic stability and alleviate oxidative damage. In TNBC, cancer cells use autophagy to detoxify platinum-induced DNA. damage, clear damaged mitochondria via mitophagy, recycle critical macromolecules, and sustain dormancy in cancer stem-like cells (CSCs). At the same time, the process of autophagic flux facilitates immune evasion, including PD-L1 expression stabilization, MHC-I degradation, and the establishment of an immunosuppressive tumor microenvironment (TME). The review encapsulates the progressive concepts of molecular regulation of autophagy, which involve key factors such as ULK1, VPS34, and non-coding RNAs (ncRNAs). These factors play a significant role in chemoresistance, taxanes, anthracyclines, and platinum compounds. The review also discusses various strategies for translation that aim to circumvent or suppress autophagy-mediated chemoresistance, including autophagy inhibitors, natural compounds, and nanoparticle-based formulations, with a focus on their synergistic potential with ICIs and chemotherapeutic agents. Targeting autophagy has shown considerable potential for effectively addressing chemoresistance in TNBC. Future studies should focus on addressing chemoresistance and immunoresistance through autophagy-based therapies.

Background: Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer characterized by poor prognosis, high metastatic potential, and limited targeted therapies. Methods: This study evaluates the anticancer activity of kaempferol in two genetically and ethnically distinct TNBC models: MDA-MB-231 (Caucasian) and MDA-MB-468 (African American) cells, utilizing cell viability, cell proliferation, apoptosis, cell cycle arrest, qPCR, and Abby analysis assays. Results: Kaempferol inhibited TNBC cell viability and proliferation in a dose- and time-dependent manner, in both 2D monolayer and three-dimensional (3D) cell cultures, and induced apoptosis and S phase cycle arrest. This investigation demonstrated that kaempferol affects cancer cells by inhibiting CDK1, CDK4, CDK6, and CDK7 at both the gene and protein levels in MDA-MB-231 cells, and specifically CDK6 and CDK7 in MDA-MB-468 cells. It reduced expression of PD-L1, JAK1, STAT3, MUC-1, and NF-κB1 (p50), indicating that the underlying pathway of PD-L1 inhibition may involve targeting the JAK1/STAT3 pathway and downregulating MUC-1, while inhibiting NF-κB1 levels. Kaempferol also inhibited the overexpression of CCL2 and TGM2, which are responsible for the development of resistance to targeted therapies, such as anti-PD-L1 immunotherapy, in TNBC. Conclusion: Kaempferol acts as a multi-target modulator of CDKs and PD-L1-associated signaling in TNBC, extending prior reports of its antiproliferative and pro-apoptotic effects in MDA-MB-231 and, significantly, providing comparative evidence across MDA-MB-231 versus MDA-MB-468 models. Since the levels of PD-L1 have been previously shown to be regulated by CDKs, this study is the first to report the dual inhibitory effect of a flavonoid of natural origin on CDKs and PD-L1 levels in TNBC cells.