Gliomas and particularly glioblastomas, represent the most aggressive and treatment-resistant brain tumours. Current standard treatments, including surgical resection, radiotherapy and chemotherapy, offer only limited long-term survival benefits. The highly immunosuppressive tumour microenvironment that characterizes gliomas enables immune evasion and limits the effectiveness of anti-tumour immune response, indicating the urgent need for identification of tumour antigens with clinical relevance to improve current immunotherapeutic strategies and enhance glioma immunogenicity. Immunopeptidomics, a mass spectrometry-based identification of peptides presented by HLA molecules, is a growing field of research for understanding the immunosurveillance of gliomas. By enabling the direct identification of naturally presented HLA-bound peptides from tumour tissue for T cell recognition, immunopeptidomics provide valuable insights into tumour antigen presentation and immune targeting. This review highlights the emerging role of immunopeptidomics in gliomas, covering the mechanisms of antigen processing and presentation by HLA class I and II molecules, the identification of glioma-associated antigens, the development of personalised peptide vaccines and the discovery of new targets for T cell-based immunotherapies. The potential of plasma-derived soluble HLA (sHLA) peptidomes as minimally invasive liquid-biopsy biomarkers is further discussed for disease monitoring and response to treatment. Overall, immunopeptidomics are foreseen as a powerful tool for the discovery of new tumour antigens leading to the development of more effective personalised glioma immunotherapies.
Cigarette smoking remains a dominant, preventable driver of cancer morbidity and mortality, and clinical outcomes in smokers remain disproportionately poor even with targeted and immune therapies. Beyond mutagenesis, cigarette smoke (CS) remodels cell state by promoting stem-like programs and enriching cancer stem cells (CSCs), a subpopulation with self-renewal capacity and therapy resistance that drives tumor heterogeneity, metastasis, and treatment failure. CS activates stemness-linked pathways, including Wnt/β-catenin, Notch, Hedgehog/GLI, NF-κB, PI3K/AKT/mTOR, and TGF-β, and remodels the tumor microenvironment to further support CSC properties. While CS effects on lung tissue are well documented, its role in CSC induction at distant organs remains less understood. In this narrative, mechanistically organized review, we examine in vitro, in vivo, and clinical evidence linking CS exposure to CSC induction in primary lung cancer and secondary cancers at distant sites. We propose a unifying framework in which CS acts as a stemness-conditioning exposure that couples oncogenic signaling, epigenetic rewiring, and microenvironmental remodeling to stabilize therapy-evasive CSC states, converging on shared endpoints across tissues via tissue-specific intermediate signaling, and highlight therapeutic vulnerabilities arising from this framework.
Coactivator-associated arginine methyltransferase 1 (CARM1/PRMT4) is a signal-responsive epigenetic regulator that couples oncogenic and stress signals to chromatin, transcription, RNA processing, metabolism, and genome maintenance. Its effects arise from both asymmetric arginine methylation of histone and non-histone substrates and methyltransferase-independent scaffolding activities. This review critically synthesizes the structural basis, substrate networks, methylarginine readers, and cancer-contextual functions of CARM1. We propose that its apparently opposing oncogenic and tumor-suppressive activities are determined by lineage-specific substrates, regulatory post-translational modifications, cofactor and chromatin availability, and stage- or microenvironment-dependent stress signals. We further evaluate CARM1-directed therapy using an evidence-graded framework. Catalytic inhibitors such as TP-064 and EZM2302 differ in binding mode and substrate coverage, whereas emerging degraders can remove scaffolding functions but remain constrained by delivery, E3-ligase heterogeneity, pharmacokinetics, and therapeutic-window uncertainties. Biomarker-guided synthetic-lethal and immunotherapy combinations may therefore offer the most tractable route to clinical translation. This framework positions CARM1 as a context-conditioned signal-to-chromatin translator rather than a uniformly druggable oncogene.
Metastasis and therapeutic resistance remain the principal causes of cancer-related mortality, reflecting the failure of current therapies to eradicate disseminated and treatment-refractory tumor cells. Long non-coding RNAs, once considered transcriptional noise, have now emerged as pivotal regulators of cancer progression, acting through diverse mechanisms to modulate signaling pathways, transcriptional programs, tumor metabolism, and the tumor microenvironment. Accumulating evidence demonstrates that lncRNAs orchestrate epithelial-mesenchymal transition, metabolic reprogramming, and immune evasion, thereby enabling metastatic dissemination and fostering resistance to chemotherapy. Moreover, recent discoveries have revealed that certain lncRNAs can encode functional micropeptides, further expanding their biological and therapeutic relevance. In this review, we systematically summarize current advances in lncRNA-mediated regulation of cancer metastasis and drug resistance, with particular emphasis on their roles in oncogenic signaling cascades, transcriptional control, immune cell reprogramming, and metabolic remodeling. we also discuss emerging therapeutic strategies targeting lncRNAs, including antisense oligonucleotides, CRISPR-based approaches, and lncRNA-encoded micropeptides interventions. Finally, we highlight key challenges, including context-dependent lncRNA functions, tumor heterogeneity, delivery, off-target effects, and biomarker standardization, and discuss multi-omics, single-cell, and spatial approaches may facilitate the translation of lncRNA biology into precision oncology.
B-MYB (MYBL2) is a transcription factor of the MYB family that plays critical roles in cell cycle progression, proliferation, and survival. Through the DREAM-MMB-FOXM1 network, B-MYB coordinates the expression of genes required for mitosis and cytokinesis (G2/M genes), while genes required for DNA replication during S phase are regulated by E2F-DP complexes. Initially identified as a regulator of normal cell cycle processes, B-MYB has emerged as a key oncogenic driver across multiple cancer types. This review addresses the physiological roles of B-MYB, the mechanisms underlying its oncogenic activation, and its contributions to tumorigenesis and clinical relevance as a prognostic biomarker and potential therapeutic target. Aberrant activation of B-MYB, driven by gene amplification, transcriptional upregulation, or post-translational modification, is reported as a recurrent feature of aggressive cancers. The consequences of B-MYB overexpression, including uncontrolled proliferation, genomic instability, apoptosis evasion, epithelial-to-mesenchymal transition, therapy resistance and metabolic reprogramming, further underscore B-MYB as a central oncogenic driver. Clinically, B-MYB overexpression correlates with poor prognosis, advanced disease and chemoresistance across multiple malignancies. Thus, we aim to emphasise the biological roles of B-MYB in physiological and cancer mechanisms, alongside the growing evidence establishing it as both a biomarker of disease and a potential therapeutic target. While previous reviews have addressed isolated aspects of B-MYB biology, this review provides a comprehensive and updated integration of recent mechanistic advances (A-MYB/B-MYB functional redundancy and YAP/TAZ-TEAD crosstalk) and the therapeutic potential of non-canonical DNA structures at the B-MYB promoter. We further review current trends and methodologies for targeting B-MYB and outline new perspectives for future therapeutic research.
Breast cancer is the most frequently reported cancer in women, with high mortality and morbidity globally. Paclitaxel, doxorubicin, tamoxifen, cisplatin, and 5-fluorouracil are cornerstones of standard-of-care treatment for primary and advanced breast cancers, targeting distinct molecular mechanisms. However, the evolution of acquired resistance primarily leads to treatment failure and progression to metastasis, ultimately to patient mortality. Furthermore, their effectiveness is limited by potential toxicities in various organs. These limitations present an extreme challenge for the management of breast cancer at the advanced stage. This review uncovers recent updates on acquired resistance mechanisms toward standard-of-care treatments driven by deeply rooted heterogeneity and aggressive nature through direct counteracting of its core action, hyperactivation of survival pathways, silencing of core cell death pathways, derepressing the expression of multidrug resistance proteins, metabolic reprogramming, epigenetic modifications, and exosome-mediated horizontal transfer of resistance phenotype. In addition, we discuss recent updates on potential strategies to overcome resistance and toxicities induced by standard-of-care treatments. Ultimately, this review helps to identify novel strategies targeting pathways to reverse resistance and reduce toxicity in breast cancer patients.
Hereditary cancer carrier tissues are difficult to sample before transformation, limiting direct study of early disease evolution. Induced pluripotent stem cells (iPSCs) preserve inherited genetic context and enable controlled reconstruction of susceptible lineages and defined second hits. Across hereditary breast and ovarian cancer, mismatch repair deficiency, Li-Fraumeni syndrome and familial adenomatous polyposis, current evidence is strongest but uneven for BRCA1/2/PALB2-, MMR-, TP53- and APC-associated models. Collectively, these systems show that lineage state, contextual stress and acquired second hits shape DNA-repair defects, clonal selection and premalignant evolution. However, developmental immaturity, incomplete stromal and immune context, clonal drift and protocol variability constrain interpretation. iPSC models should therefore be used as mechanistic filters for testing causality, comparing lineage vulnerability and prioritising biomarkers or prevention hypotheses, rather than as stand-alone predictors of individual cancer risk or clinical outcome. Their outputs require validation in adult tissues, patient-derived models and carrier cohorts.
Recent breakthroughs highlight a previously underappreciated role of the nervous system in tumor biology, drawing attention to the emerging interdisciplinary field of tumor neuroscience. Foundational discoveries have elucidated complex bidirectional interactions between neurons and cancer cells, redefining the tumor microenvironment as a dynamic neurobiological niche. A major recent breakthrough is the discovery that tumor cells can form direct synaptic or pseudo-synaptic contacts with neurons, extending the concept of synaptic communication beyond the nervous system. In this Review, we summarize current knowledge of neuronal regulation in cancer across three layers: direct synaptic communication, neuron-derived paracrine signaling, and neuroimmune modulation. We further discuss the functional consequences of these interactions, including perineural invasion, tumor-associated epilepsy and cancer pain, together with emerging therapeutic strategies targeting tumor-neuron crosstalk, highlighting these overlooked therapeutic opportunities for highly aggressive tumors. Finally, we propose a translational framework to bridge basic discoveries with clinical application.
Prostate cancer (PCa) is one of the most prevalent malignancies affecting male health globally, ranking as the fifth leading cause of cancer-related mortality in men. Post-translational modifications (PTMs), encompassing a diverse array of biochemical alterations such as methylation, acetylation, phosphorylation, ubiquitination, SUMOylation, glycosylation, and lactylation, constitute a critical category of epigenetic regulatory mechanisms that modulate numerous cellular processes in both physiological and pathological contexts. Despite their fundamental importance, the precise functional implications of PTMs in PCa pathogenesis remain incompletely elucidated. Current evidence has established that multiple oncogenic signaling pathways (including AR, PTEN/PI3K/AKT, CDK4/6-RB, Wnt/β-catenin, and JAK/STAT3), key transcription factors (such as AR, p53, ERG, NKX3.1, FOXA1, HOXB13, KLF, and MYC), and specific histone modification patterns are intimately associated with PCa progression. Furthermore, emerging studies have implicated PTMs in mediating drug resistance and immune suppression in PCa, representing two major clinical challenges in contemporary PCa management. Beyond these canonical regulatory mechanisms, metabolism-associated and emerging PTMs further connect metabolic reprogramming with AR variant splicing, lineage plasticity, immune modulation, and therapeutic resistance. We also discuss the clinical implications of PTMs in PCa, including PTM-directed clinical trials, targeted protein degradation strategies, and diagnostic or prognostic biomarker development. In light of these critical findings, this review systematically synthesizes current research elucidating the mechanistic roles of PTMs in regulating these molecular determinants of PCa progression, with the aim of providing a comprehensive understanding of PTM-mediated regulatory networks and offering translational insights for potential clinical applications.
The profound intratumoral heterogeneity and the highly dynamic spatiotemporal evolution of its immunosuppressive microenvironment in glioblastoma (GBM) are major factors underlying the limited efficacy of the standard-of-care treatment (SOC). Although immunotherapy has revolutionized the treatment of many solid tumors, it has produced limited clinical benefit in patients with GBM. This limited efficacy is closely associated with the abundance, distribution, and functional state of T cells, which constitute the core effector population mediating antitumor immune responses. However, previous studies have largely focused on the static characteristics of T cells in GBM, whereas the mechanisms governing their spatiotemporal dynamics remain poorly defined, thereby impeding clinical translation. In this review, we delineate the spatiotemporal dynamics of T cells in GBM and re-evaluate the mechanisms underlying immunotherapy failure, thereby identifying potential therapeutic opportunities. Furthermore, we aim to provide new insights into patient stratification, the development of precise targets that modulate T-cell spatiotemporal dynamics, and personalized combination strategies for patients with GBM.
Ubiquitin-specific protease 2 (USP2), a pivotal member of the deubiquitinating enzyme family, has emerged as a critical but context-dependent regulator in cancer, exhibiting paradoxical tumor-suppressive and oncogenic functions. This duality is governed by its ability to stabilize specific substrate proteins, thereby modulating central signaling hubs including the p53, Wnt/β-catenin, PI3K/Akt, and cell cycle networks. Through these axes, USP2 profoundly influences hallmark cancer phenotypes such as sustained proliferation, metabolic reprogramming, metastatic progression, immune evasion, and therapy resistance. This review systematically synthesizes the mechanistic roles of USP2 across various cancers, highlighting its function as a double-edged sword. We detail how specific interactions between USP2 and its substrates dictate its pro-tumorigenic or anti-tumorigenic outcomes, depending on the tissue and microenvironment. Furthermore, we comprehensively evaluate the landscape of emerging USP2 inhibitors, discussing their therapeutic potential and the significant challenges posed by USP2's functional duality, substrate promiscuity, and isoform diversity. Targeting USP2 presents a promising yet intricate avenue for cancer therapy, necessitating future research focused on patient stratification, combination strategies, and the development of context-specific inhibitors.
Immunotherapy has reshaped the treatment landscape of colorectal cancer (CRC), with the clearest and most durable benefit established in mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) disease. However, framing CRC immunotherapy simply as "MSI-H responsive versus microsatellite stable (MSS) resistant" is no longer sufficient. Recent studies indicate that a subset of proficient mismatch repair (pMMR) colon cancers, particularly in the neoadjuvant setting, can mount clinically meaningful responses to immune checkpoint blockade, suggesting that disease stage, local immune organization, and treatment timing critically influence immunotherapy sensitivity. In parallel, emerging evidence has expanded the relevant immune landscape beyond the tumor bed itself, showing that spatially organized stromal and adipose niches can actively divert tumor-reactive lymphocytes and promote immune escape. These advances shift the central challenge in CRC immunotherapy from simply identifying new agents to defining when and in whom immune resistance is reversible, and which biological bottlenecks-such as vascular dysfunction, myeloid suppression, and spatial immune exclusion-must be overcome. In this context, alternative checkpoint inhibitors, bispecific antibodies, cellular therapies, vaccines, nanotechnology-enabled platforms, and microbiome-targeted approaches remain important, but their translational maturity and evidentiary support differ substantially. Biomarker development is likewise evolving from static genomic classification toward dynamic and mechanism-informed stratification incorporating circulating tumor DNA (ctDNA), chromosomal instability, immune architecture, and treatment-induced response trajectories. This review synthesizes recent advances in CRC immunotherapy while emphasizing evidence hierarchy, biomarker-guided patient selection, and the mechanistic basis of combination strategies. We argue that the next phase of CRC immunotherapy will depend less on the indiscriminate addition of novel agents and more on the rational deployment of immunotherapy across molecularly, spatially, and temporally defined disease states.
Hypusination of eukaryotic translation initiation factor 5 A (eIF5A) is a highly conserved post-translational modification. This process uniquely depends on spermidine and is catalyzed sequentially by deoxyhypusine synthase (DHPS) and deoxyhypusine hydroxylase (DOHH). Recent studies have established eIF5A hypusination as a key translational regulatory mechanism linking polyamine metabolism to tumor progression. By relieving ribosomal stalling in selected difficult-to-translate targets, hypusinated eIF5A directly controls defined translational outputs. Through these direct mechanisms, as well as broader downstream signaling and phenotypic effects whose immediate translational targets remain incompletely resolved, the hypusination pathway has been linked to tumor cell proliferation, invasion and metastasis, angiogenesis, therapeutic resistance, and adaptive stress responses. This review critically distinguishes sequence-resolved translational mechanisms from target-level regulatory associations and indirect phenotypic consequences through which eIF5A hypusination is linked to these cancer hallmarks and further examines pharmacological and genetic strategies targeting the polyamine-eIF5A axis, including inhibitors of polyamine metabolism, DHPS, and DOHH. It also discusses the potential translational significance of these strategies in cancer therapy. Overall, eIF5A hypusination may act as a central effector that converts metabolic inputs into oncogenic protein outputs and represents a promising therapeutic target across diverse tumor types.
Perineural invasion (PNI) is associated with tumor progression, therapeutic resistance, and poor prognosis. However, the mechanisms driving tumor-nerve interactions remain incompletely understood. Emerging evidence suggests that macrophages function as key regulators within the perineural niche by linking inflammation, neural remodeling, extracellular matrix reorganization, and immunometabolic signaling. This review proposes a macrophage-centered framework for understanding PNI progression and summarizes macrophage-mediated mechanisms involved in nerve invasion, perineural homeostasis disruption, and tumor-nerve crosstalk. We further discuss recent advances in macrophage-targeted therapeutic strategies and highlight current challenges, including limited direct evidence and barriers to clinical translation. Understanding macrophage-mediated PNI may provide new insights into therapeutic interventions targeting the neural-tumor-immune microenvironment.
Drug resistance remains a major obstacle in cancer therapy, underscoring the urgent need to identify new targets and therapeutic strategies to overcome resistance. The integrated stress response (ISR), an evolutionarily conserved mechanism that enables cells to adapt to various internal and external stresses, plays a critical role in determining cell fate and has emerged as a key player in therapy resistance. However, targeting the ISR to overcome treatment resistance remains challenging. In this review, we systematically outline the regulatory mechanisms of the ISR in cancer cells and its crosstalk with other oncogenic signaling pathways. We further summarize the molecular mechanisms by which ISR signaling contributes to therapeutic resistance, along with recent advances in targeting the ISR and the current landscape of drug development. In addition, we explore the potential of leveraging ISR-induced cell death pathways to sensitize tumors to therapy and overcome resistance. We also discuss the current status, challenges, and future directions for clinical translation of ISR-targeting strategies, and provide perspectives aimed at advancing their therapeutic application.
Glioblastoma (GBM) is the most aggressive type of primary brain tumor, and recurrence remains virtually inevitable despite standard treatment. The prevention of recurrence represents a critical unmet need. However, the evolutionary characteristics of GBM recurrence patterns and their determinants are incompletely understood, limiting improvements in multimodal treatment. We systematically reviewed studies on GBM recurrence patterns from 1980 onward. Recurrence patterns were harmonized using two classification systems-anatomical distance and radiation isodose overlap-and dichotomized into local versus nonlocal recurrence for a pooled analysis. Although local recurrence predominates, nonlocal recurrence has steadily increased and correlates with therapeutic advances (e.g., extended resection, precision chemoradiotherapy, and tumor treatment fields). MGMT promoter methylation, EGFR aberrations, and the involvement of the cortex or cerebellum promote nonlocal recurrence. Oligodendroglial progenitor cell-like, neuron-like, neural progenitor cell-like, and mesenchymal-like GBM cells undergo distal invasion along white matter tracts through multiple mechanisms. Distant recurrence, a representative nonlocal subtype, only prolongs progression-free survival without prolonging overall survival. Current therapies remain insufficient to prevent distant dissemination, and the underlying mechanisms require further elucidation. Therefore, building a multiparametric recurrence risk stratification system and developing targeted adjuvant strategies are essential for improving the long-term survival of patients with GBM.
Brain-metastatic breast cancer (BMBC) is a severe complication of advanced breast cancer, affecting 15-30% of metastatic patients, particularly those with HER2-positive or triple-negative subtypes, and is associated with dismal prognosis and median survival under 12 months. Therapeutic resistance, driven by the central nervous system's sanctuary role, poses a major barrier to effective treatment, often resulting in discordant intracranial versus extracranial responses. This comprehensive review highlights BMBC resistance mechanisms, drawing from preclinical models, clinical studies, and genomic analyses. Key drivers include genetic/epigenetic alterations, BBB-mediated drug exclusion via efflux transporters, and microenvironmental interactions with astrocytes and immune cells that promote survival signaling. Additional factors encompass cancer stem cell plasticity/dormancy enabling therapy evasion, metabolic reprogramming and extracellular matrix remodeling that shields tumor from drugs. We highlight how these interconnected pathways create a protective niche for metastatic cells. Promising strategies to overcome resistance include BBB-penetrant agents, antibody-drug conjugates, nanomedicine, and combination therapies targeting the tumor microenvironment and epigenetics. By integrating mechanistic insights with translational opportunities, this review emphasizes the potential for personalized, multi-targeted approaches to improve patient outcomes in BMBC.
Chimeric antigen receptor (CAR)-T cell immunotherapy is one of the emerging advancements in personalized treatment of cancer, whose design is based on the genetic modification of T cells to express chimeric antigen receptors (CARs) to generate CAR-T cells, specifically targeting cancer tissues. Despite the fact that immunotherapy provides significant antitumor activity, only a limited number of therapies reached the market after their FDA approval because of the accompanying challenges including tumor resistance, side effects, high cost of production, possible toxicities during CAR-T cells engineering, and poor selectivity. Nanotechnology has emerged as a promising approach for improving drug targeting, selectivity and reducing their side effects. In this context, recent advances highlight the innovative integration of nanomaterials for enhancing CAR-T cell engineering, delivery, and in vivo functionality. Nanotechnology-enabled strategies such as nanoparticle-based gene delivery systems, nanoformulations for controlled CAR expression, and tumor microenvironment modulation have demonstrated significant potential in overcoming current therapeutic limitations. Therefore, substantial research efforts are currently focused on integrating this technology in developing CAR-T cell immunotherapy. This review article focuses on CAR-T cell bioengineering, antitumor mechanism of action, challenges and limitations, as well as the latest innovative nanotechnological solutions for complementing CAR-T cell immunotherapy. It also emphasizes the translational applications and design innovations of nanotechnology, including precision targeting platforms and multifunctional nanocarriers, highlighting that nanotechnology may play an important role in advancing the efficacy, safety, and clinical applicability of personalized CAR-T cancer immunotherapy.
Pancreatic cancer features a dense desmoplastic stroma that drives therapeutic resistance and immune evasion. Traditionally viewed as inert scaffolds, keratan sulfate proteoglycans (KSPGs) now emerge as active signaling modulators within this tumor microenvironment. This review elucidates the multifaceted roles of KSPGs and their specific sulfation patterns in pancreatic ductal adenocarcinoma (PDAC). We detail how KSPG core proteins orchestrate collagen fibrillogenesis and tissue biomechanics, while highly sulfated keratan sulfate (KS) chains act as biochemical traps sequestering oncogenic ligands and chemokines. This biochemical interplay synergistically reprograms signaling cascades to govern tumor plasticity and metastasis. Crucially, KSPGs mediate immune exclusion by impeding CD8+ T cell infiltration and sustaining chronic inflammation via damage-associated molecular patterns (DAMPs). Finally, we highlight the translational potential of targeting KS sulfation via carbohydrate sulfotransferases (CHSTs) as a promising strategy for stromal normalization to overcome current therapeutic bottlenecks in PDAC.
