Double-Negative Prostate Cancer: Evolutionary Mechanisms, Microenvironmental Remodeling, and Clinical Translation.

Epigenetic Plasticity in Triple-Negative Breast Cancer: Mechanisms of Therapy Resistance, Biomarkers, and Therapeutic Vulnerabilities

Triple-negative breast cancer (TNBC) is an aggressive and clinically heterogeneous breast cancer subtype characterized by the absence of estrogen receptor, progesterone receptor, and HER2 overexpression, limited targeted treatment options, early relapse, and frequent development of therapy resistance. Although TNBC often shows initial sensitivity to chemotherapy, durable responses are commonly undermined by the emergence of adaptive resistant cell states rather than solely by fixed genetic mutations. This review synthesizes the role of epigenetic plasticity as a central mechanism that enables TNBC cells to dynamically reprogram transcriptional identity, survive therapeutic stress, and transition between epithelial, mesenchymal, stem-like, immune-evasive, and drug-tolerant persister phenotypes. Key epigenetic mechanisms include aberrant DNA methylation, histone acetylation and methylation, BET/BRD4-dependent transcriptional regulation, EZH2-mediated repression, SWI/SNF-dependent chromatin remodeling, non-coding RNA networks, and three-dimensional genome reorganization. These processes regulate tumor suppressor silencing, DNA-damage repair, epithelial–mesenchymal plasticity, cancer stem-cell maintenance, metabolic adaptation, immune-checkpoint regulation, and minimal residual disease. The review also highlights the translational relevance of epigenetic biomarkers, including DNA methylation signatures, circulating epigenetic markers, chromatin-accessibility profiles, and single-cell epigenomic approaches for diagnosis, prognosis, therapy prediction, and monitoring resistance evolution. Finally, therapeutic strategies targeting epigenetic plasticity are discussed, including DNMT, HDAC, BET, EZH2, KDM, and LSD1 inhibitors, with emphasis on rational combination approaches involving chemotherapy, PARP inhibitors, immunotherapy, and metabolic targeting. Overall, epigenetic plasticity represents both a major driver of TNBC resistance and a therapeutically exploitable vulnerability, provided those future strategies account for tumor heterogeneity, adaptive cell-state transitions, biomarker-guided patient selection, and combination-based treatment design.

Overcoming cancer resistance in pancreatic cancer: toward dynamic precision oncology

The molecular underpinnings of the immune landscape in prostate cancer: decoding a “cold” tumor

Prostate cancer (PCa) remains a leading cause of cancer-related death in men, characterized by a notoriously immunosuppressive tumor microenvironment (TME) that renders it largely refractory to immune checkpoint inhibitors (ICIs). This “cold” tumor phenotype is orchestrated by a complex network of molecular mechanisms, rather than a simple absence of antigens. Here, we provide a focused review of the key molecular drivers enforcing immune evasion in PCa, moving beyond cellular descriptions to the underlying genomic and signaling aberrations. We dissect the roles of tumor-intrinsic oncogenic pathways, specifically the androgen receptor (AR) signaling axis, PTEN/PI3K/AKT activation, and loss of tumor suppressors like TP53 and RB1, in sculpting an immunosuppressive secretome. Furthermore, we explore the paradoxical role of genomic instability, where defects in mismatch repair (dMMR) and homologous recombination deficiency (HRD) create neoantigens but simultaneously foster immune exclusion through the cyclic GMP-AMP synthase/stimulator of interferon genes (cGAS/STING) pathway and immunosuppressive cytokines. We discuss emerging controversies, including the immunostimulatory versus immunosuppressive duality of AR signaling and the role of the STING pathway in promoting a pro-metastatic inflammatory state. Critically, we highlight that many of these mechanistic insights are predominantly derived from preclinical models, and their direct translation to clinical responses remains an ongoing challenge. The field is also constrained by a lack of robust, validated predictive biomarkers beyond dMMR. Moreover, the mechanisms of immune evasion in treatment-emergent neuroendocrine prostate cancer (NEPC) represent a critical knowledge gap, hindering immunotherapy development for this aggressive variant. Future therapeutic strategies must pivot from a monotherapy paradigm to rationally designed molecular combinations that leverage our deepening understanding of these intricate mechanisms to convert the TME from an immune desert into an inflamed, ICI-responsive hub.

Drug resistance in breast cancer brain metastasis: mechanisms and therapeutic strategies.

This comprehensive review highlights BMBC resistance mechanisms, drawing from preclinical models, clinical studies, and genomic analyses, and highlights the potential for personalized, multi-targeted approaches to improve patient outcomes in BMBC.

Convergent Mechanistic Pathways Driving the Anaplastic Phenotype in Thyroid Cancer

Anaplastic thyroid carcinoma (ATC) is a rare, highly aggressive follicular cell-derived malignancy characterized by rapid progression, profound dedifferentiation, and marked resistance to conventional therapy. Despite frequent involvement of major oncogenic pathways, ATC does not exhibit a universal driver mutation, suggesting that its pathogenesis reflects convergence upon shared biological hallmarks rather than dependence on a single molecular event. This review describes the principal mechanistic programs that define the ATC phenotype: disruption of cell-cycle and apoptotic control through alterations in TP53, CDKN2A/B, and aberrant MAPK activation; metabolic adaptations involving glycolysis, glutaminolysis, and mitochondrial one-carbon metabolism; reprogramming of canonical stress response pathways including ER stress and hypoxia signaling; and dynamic remodeling of the tumor microenvironment through cytokine-driven paracrine networks and immune modulation. Collectively, these processes cooperate to generate a highly proliferative, stress-tolerant, immune-inflamed yet immunosuppressed tumor state. A mechanistic understanding of these convergent pathways is essential for rational therapeutic development and for overcoming the profound clinical resistance that defines ATC.

Targeting glioblastoma epigenetics: mechanisms, microenvironmental interplay, and therapeutic potential.

The present review explores the complex epigenetic mechanisms such as DNA methylation, histone modification and RNA editing that drive GBM progression, shape the tumor microenvironment and facilitate immune evasion and highlights the therapeutic potential of targeting these epigenetic vulnerabilities through inhibitors of histone deacetylase and DNA methyltransferase.