Breast cancer is the most frequent cancer and the leading cause of cancer death in women. Oxidative stress and the generation of reactive oxygen species (ROS) have been related to cancer progression. Compared to their normal counterparts, tumor cells show higher ROS levels and tight regulation of REDOX homeostasis to maintain a low degree of oxidative stress. Traditionally antioxidants have been extensively investigated to counteract breast carcinogenesis and tumor progression as chemopreventive agents; however, there is growing evidence indicating their potential as adjuvants for the treatment of breast cancer. Aimed to elucidate whether antioxidants could be a reality in the management of breast cancer patients, this review focuses on the latest investigations regarding the ambivalent role of antioxidants in the development of breast cancer, with special attention to the results derived from clinical trials, as well as their potential use as plausible agents in combination therapy and their power to ameliorate the side effects attributed to standard therapeutics. Data retrieved herein suggest that antioxidants play an important role in breast cancer prevention and the improvement of therapeutic efficacy; nevertheless, appropriate patient stratification based on “redoxidomics” or tumor subtype is mandatory in order to define the dosage for future standardized and personalized treatments of patients.

Triple-negative breast cancer (TNBC) is the most aggressive type of breast cancer which presents a high rate of relapse, metastasis, and mortality. Nowadays, the absence of approved specific targeted therapies to eradicate TNBC remains one of the main challenges in clinical practice. Drug discovery is a long and costly process that can be dramatically improved by drug repurposing, which identifies new uses for existing drugs, both approved and investigational. Drug repositioning benefits from improvements in computational methods related to chemoinformatics, genomics, and systems biology. To the best of our knowledge, we propose a novel and inclusive classification of those approaches whereby drug repurposing can be achieved in silico: structure-based, transcriptional signatures-based, biological networks-based, and data-mining-based drug repositioning. This review specially emphasizes the most relevant research, both at preclinical and clinical settings, aimed at repurposing pre-existing drugs to treat TNBC on the basis of molecular mechanisms and signaling pathways such as androgen receptor, adrenergic receptor, STAT3, nitric oxide synthase, or AXL. Finally, because of the ability and relevance of cancer stem cells (CSCs) to drive tumor aggressiveness and poor clinical outcome, we also focus on those molecules repurposed to specifically target this cell population to tackle recurrence and metastases associated with the progression of TNBC.

Esophageal squamous cell carcinoma (eSCC) is a highly aggressive malignancy with poor prognosis and limited therapeutic options. Although immune checkpoint inhibitors such as nivolumab have shown clinical benefit, particularly in patients with high PD-L1 expression, this subgroup represents only a small fraction of eSCC cases. CDK4/6 inhibitors such as palbociclib have only been tested as second-line agents in eSCC, often in combination with EGFR inhibitors, with minimal benefit. Our study evaluates palbociclib as a first-line therapy in treatment-naive eSCC models. Using a panel of 22 eSCC cell lines with integrated multi-omics and phenotypic assays, we identified three response subtypes, resistant, delayed, and arrested, correlated to Rb-pathway status. Interestingly, in delayed responders, palbociclib treatment was associated with DNA damage accumulation and unprotected micronuclei enriched for cGAS, triggering activation of interferon-stimulated genes. Consistent with this, palbociclib enhanced immune cell infiltration in delayed eSCC spheroids within a preclinical vascularized 3D microfluidic system. Our study demonstrates that first-line palbociclib treatment unmasks intrinsic vulnerabilities in the CDK4/6-Rb axis and triggers innate immune activation in molecularly defined eSCC. Using a translationally relevant 3D vascularized microfluidic system, we provide evidence that early CDK4/6 inhibition not only stall cancer cell growth but also promotes immune cells recruitment. In conclusion, our study identifies palbociclib as a viable first-line therapeutic candidate in selected eSCC patients and uncover its immunomodulatory potential.

Esophageal squamous cell carcinoma (ESCC) accounts for 90% of esophageal cancer cases worldwide and carries a poor prognosis, with overall survival below 20%. Chemotherapy remains the standard of care, yet acquired resistance is a critical barrier and the programs that establish and stabilize it are still poorly defined. Using an in vitro model of cisplatin resistance, we show that sustained platinum exposure does not drive a single, uniform resistant state but a continuum of adaptive transcriptional states. Most resistant clones presented a drug-tolerant persister (DTP)-like phenotype with stemness traits and slow-cycling behaviour. The DTP phenotype persisted after cisplatin withdrawal and was accompanied by markers of resistance, suggesting consolidation into a stable, acquired-resistance state. Unexpectedly, the effect of this reprogramming extended beyond cisplatin. Resistant clones displayed impaired cytostatic control and failed to suppress cell cycle programs upon CDK4/6 inhibition (CDK4/6i), revealing collateral cross-resistance. Multiomic profiling revealed an attenuation of the immune and inflammatory signaling expected from CDK4/6i, upregulation of immune-evasive markers and a dysregulated IFN pathway activation at baseline in cisplatin-resistant clones, reflecting an immune-evasive state consequent to cisplatin-induced reprogramming. A signature-based approach identified HDAC inhibitors as candidates for reversing resistance, and functional validation confirmed that HDACi combined with cisplatin fully restored parental-level sensitivity while also enhancing CDK4/6i efficacy, supporting epigenetic reprogramming as a strategy to counteract cross-resistance. Together, our findings define cisplatin resistance in ESCC as a reversible, epigenetically encoded and immune-evasive state, and provide a mechanistic rationale for HDACi-based combinations to restore sensitivity to both cisplatin and CDK4/6 inhibitors. Statement of Significance: Sustained cisplatin exposure drives esophageal squamous cell carcinoma toward a drug-tolerant persister-like, immune-evasive state that survives drug withdrawal and confers cross-resistance to CDK4/6 inhibition. HDAC inhibition reverses this state, restoring sensitivity to both agents and synergizing in chemotherapy-naive cells, supporting epigenetic intervention early in treatment.