Diffuse intrinsic pontine glioma (DIPG), most commonly corresponding pathologically to diffuse midline glioma (DMG), H3 K27-altered, remains an overwhelmingly lethal pediatric brainstem malignancy, with median overall survival of approximately 11 months. We critically synthesized evidence identified through a structured search to December 31, 2025, supplemented by targeted updates of regulatory documents, clinical-trial records, and pivotal or practice-relevant publications through July 2026. We summarize epidemiology and the clinico-radiographic syndrome; examine the transition toward integrated molecular classification supported by stereotactic biopsy, with liquid biopsy emerging as a complementary tool; and distill core biology centered on PRC2 inhibition, loss of H3K27 trimethylation, developmental cell states, neuron-glioma interactions, and recurrent co-alterations involving TP53/PPM1D, ACVR1, PDGFRA, and PI3K/MAPK pathways. Radiotherapy remains the only modality with reproducible, albeit transient, clinical benefit; evidence supports hypofractionation in selected patients and reirradiation for carefully selected patients at recurrence. We appraise why cytotoxic chemotherapy and most targeted or epigenetic approaches have failed to deliver reproducible benefit, while highlighting early signals from CAR T-cell therapy, neoantigen vaccination, oncolytic virotherapy, and locoregional or ultrasound-enabled delivery. We also examine dordaviprone, the first systemic therapy to receive FDA accelerated approval for H3 K27M-mutant DMG with progressive disease following prior therapy, while emphasizing that the regulatory efficacy population excluded DIPG and therefore does not establish efficacy in classic pediatric pontine disease. Trial design must also explicitly separate anatomic phenotype from molecular taxonomy. Priorities include molecularly stratified enrollment, pharmacokinetically verified brainstem exposure, rational combinations, and endpoints integrating survival, neurologic function, and quality of life.
BACKGROUND:Immune checkpoint inhibitor (ICI)-associated myocarditis is usually considered an early toxicity, but late presentations remain poorly characterised. We aimed to describe the timing, clinical features, management and outcomes of late-onset ICI-associated myocarditis. METHODS:We conducted a PRISMA 2020 systematic review and patient-level synthesis of PubMed and Embase from inception to 25 August 2026. Late-onset myocarditis was defined as presentation ≥90 days after the first ICI dose. Borderline or diagnostically uncertain cases were examined in sensitivity analysis. RESULTS:Thirty-two studies were included; 31 provided extractable data for 39 potentially eligible cases. Thirty patients met primary-analysis criteria and nine were sensitivity-only. Median onset was 9.0 months (IQR 6.2-12.8); 6/30 (20.0%) presented at 3 to <6 months, 13/30 (43.3%) at 6 to <12 months, 8/30 (26.7%) at 12 to <24 months and 3/30 (10.0%) at ≥24 months. Among patients with known treatment status, 8/21 (38.1%) presented after ICI discontinuation. Major arrhythmic or conduction complications occurred in 10/19 (52.6%), left ventricular ejection fraction was <50% in 18/26 (69.2%), and mechanical circulatory support was required in 5/29 (17.2%). Nine of 29 patients died (31.0%), including three myocarditis/cardiac deaths. Among 19 patients with ascertainable recovery, 11 (57.9%) achieved complete recovery, four (21.1%) partial/incomplete recovery and four (21.1%) no recovery. CONCLUSIONS:Late-onset ICI-associated myocarditis can occur months to years after exposure, including after discontinuation, with heterogeneous severity.
Breast cancer (BC) and tuberculosis (TB) remain two major global health problems, representing the leading causes of cancer- and infection-related deaths worldwide. BC and TB have distinct global distributions but may coexist in individuals, particularly in settings where persistent TB burden coincides with increasing demand for BC diagnosis and treatment. The co-occurrence of BC and TB poses diagnostic and therapeutic challenges for multidisciplinary specialists, including drug-drug interactions (DDIs) and potentially overlapping toxicities. Misdiagnosis of concomitant TB with BC can result from overlapping clinical and radiologic features, and clinicians must differentiate between pulmonary metastatic disease, pulmonary TB, axillary metastases, axillary TB, primary BC lesions, and mammary TB. Rifampicin is the cornerstone of TB treatment and a potent inducer of cytochrome P450 enzymes, most importantly CYP3A4, increasing the risk of DDIs with many anti-cancer drugs. Thus, reviewing each agent's pharmacokinetics is essential to avoid loss of antitumor efficacy and to prevent increased toxicities. The main aim of this narrative review is to summarize the available evidence on the diagnostic and therapeutic considerations for patients with coexistent TB and BC.
Circulating tumor DNA (ctDNA) increasingly guides adjuvant therapy and surveillance in urothelial carcinoma (UC), yet whether its prognostic effect is adequately summarized by a single pooled hazard ratio (HR), which assumes proportional hazards (PH), has not been formally evaluated. We searched five sources for studies reporting ctDNA prognostic associations across non-muscle-invasive, muscle-invasive (MIBC), upper-tract and metastatic UC. HRs for unfavorable versus favorable ctDNA were pooled by Bayesian random-effects meta-analysis, with subgroups by stage and assay strategy. Where individual patient data could be reconstructed, PH was tested under four decision rules and restricted mean survival time (RMST), a PH-independent estimand, estimated at 12, 24 and 36 months. Twenty-five studies were synthesized qualitatively and 17 quantitatively. The pooled HR was 3.85 (95% credible interval 2.92-5.26; I² = 50.7%; prediction interval 1.67-9.38), and was higher in MIBC (4.89) than metastatic UC (2.52; p = 0.034) and for tumor-informed (5.46) than tumor-agnostic (2.68) assays (p = 0.009); neither survived multiplicity adjustment, and the latter is confounded with setting and sponsorship. PH was not supported in 5 of 11 cohorts under the pre-specified rule (2-5 across rules); pooled RMST loss in the unfavorable stratum was 2.2, 6.6 and 12.2 months at 12, 24 and 36 months (11, 8 and 5 cohorts), with certainty falling as the horizon lengthened. Unfavorable ctDNA was consistently associated with worse survival, particularly in perioperative MIBC, but non-proportional hazards in many cohorts indicate that its prognostic value should be reported with time-axis estimands alongside HRs.
Relapsed or refractory neuroblastoma (R/R NB) is one of the most challenging pediatric cancers, with long-term survival rates below 20%. Both standard chemotherapy and single-target immune cell therapies are associated with significant limitations. Chemotherapy is unable to clear minimal residual disease in the majority of cases, and engineered cell therapies lose efficacy when tumors drop the target antigen because of intratumoral heterogeneity. Thus, tumor-infiltrating lymphocyte (TIL) therapy offers an alternative approach. TILs are polyclonal and have previously engaged with the tumor, so they can recognize a broad spectrum of patient-specific antigens and are less likely to be compromised by the loss of a single antigen. Nevertheless, early efforts to evaluate TIL therapy in R/R NB have encountered important challenges. The primary obstacles include unsuccessful TIL manufacturing, immunosuppressive tumor microenvironment (TME), and defective antigen presentation due to MYCN-driven loss of MHC class I and impaired interferon signaling. These challenges necessitate novel approaches, such as antigen enrichment or MHC-independent engineering. This review summarizes the results of preclinical research over three decades, categorizing studies into three major periods with distinctive determinants of TIL therapy efficacy in NB. Key clinical studies are also summarized to inform the development, safety, and feasibility of TIL therapy in pediatric NB patients. Finally, a translational roadmap is proposed that integrates γδ TIL enrichment, cell engineering, TME modification, and biomarker-driven patient selection to guide early-phase clinical trials in R/R NB.
Exosomes are 30-150nm extracellular vesicles released via fusion of multivesicular bodies with the plasma membrane and enriched in selectively sorted proteins, lipids and nucleic acids that reflect both donor-cell state and regulated packaging pathways. In central nervous system (CNS) tumours, exosome-mediated communication is increasingly recognised as a scalable mechanism by which malignant cells coordinate adaptation to therapy across cellular and anatomical barriers, including the blood-brain barrier. This review synthesises current evidence linking exosome biogenesis and cargo selection (ESCRT-associated factors, tetraspanins, Rab GTPases, RNA-binding proteins) with key resistance phenotypes in glioblastoma and other CNS tumour entities. We outline four convergent routes by which exosomes blunt therapeutic efficacy: horizontal transfer of resistance determinants, rapid activation of pro-survival signalling hubs, tumour-microenvironment remodeling, vesicle-enabled "drug scavenging", where cytotoxic agents and/or efflux machinery are sequestered and exported, lowering effective intracellular drug exposure. Finally, we discuss translational opportunities and constraints, highlighting exosome-based liquid biopsy strategies in CSF and blood and therapeutic concepts targeting vesicle biogenesis, release or uptake, while emphasizing the need for rigorous EV characterization and reporting standards to accelerate clinical implementation.
We systematically reviewed prognostic models for recurrence after curative-intent locoregional treatment of colorectal liver metastases (CRLM) and quantitatively synthesized prognostic factors associated with recurrence-free survival (RFS). From 2,208 records across 26 years of literature, 293 studies were included, encompassing 85,150 patients in development cohorts and 5,549 patients in validation cohorts. Most models targeted risk stratification rather than clinically actionable prediction, and Cox proportional hazards regression remained the dominant modelling approach despite increasing use of artificial intelligence and machine learning terminology. External validation was uncommon (33/293 studies), performance reporting was heterogeneous, and overall methodological quality was limited, restricting cross-study comparability and clinical translation. Imaging-based modelling represented a small subset (19 studies; 23 RFS models), generally characterized by small cohorts and predominantly conventional regression-based pipelines. Meta-analysis identified several clinicopathological, molecular, and treatment-related predictors consistently associated with recurrence, including primary lymph node positivity (HR 1.58), multiple liver metastases (HR 1.49), positive resection margins (HR 1.73), postoperative carcinoembryonic antigen >5ng/mL (HR 2.79), poor response to neoadjuvant therapy according to RECIST criteria (HR 2.76), and postoperative circulating tumor DNA positivity (HR 4.78), the strongest prognostic factor identified. Adjuvant and peri-operative systemic therapies were associated with lower recurrence risk. The study showed that current prognostic models incompletely capture the biological heterogeneity underlying CRLM recurrence. Dynamic biomarkers and treatment-response indicators may support future multimodal prognostic frameworks and improve risk stratification following curative-intent treatment.
Spatio-temporal heterogeneity within the tumour immune microenvironment (TIME) underpins therapeutic resistance to cancer immunotherapy across solid malignancies, yet the mechanistic drivers governing such heterogeneous immune landscapes remain incompletely defined. Biophysical mechanical cues constitute pervasive microenvironmental regulators that dynamically remodel immune homeostasis throughout tumour initiation, local progression and distal metastatic colonisation. As core mechanotransductive effectors, YAP and TAZ integrate extracellular mechanical inputs into cell-intrinsic transcriptional programmes, functioning as a central molecular nexus bridging physical microenvironment remodelling and TIME specification. Mechanosensory activation of YAP/TAZ remodels the functional phenotypes of malignant epithelial cells, cancer-associated fibroblasts (CAFs) and multiple immune subsets, thereby dictating the spatial distribution, polarisation status and effector competence of tumour-infiltrating immune cells to establish spatially segregated immune-suppressive niches. Fueled by advances in single-cell transcriptomics and spatial multi-omics, recent findings have unravelled YAP/TAZ regulatory circuits that sculpt divergent TIME landscapes in mechanical pathways. Here, we synthesise contemporary progress delineating how YAP/TAZ-dependent mechanotransduction programmes establish TIME spatiotemporal heterogeneity, highlight translational therapeutic strategies centred on perturbing this mechanochemical axis to dismantle mechanical immune suppression, and discuss outstanding challenges to unlock targeted TIME remodelling for overcoming clinical immunotherapy failure in solid tumours.
Poly (ADP-ribose) polymerase inhibitors (PARPi) have revolutionized in precision oncology, particularly in tumors harboring homologous recombination deficiency (HRD), such asovarian and breast cancers. Despite their clinical success, both primary and acquired resistance substantially limit the durability and breadth of therapeutic benefit, indicating that tumor-intrinsic DNA repair defects alone are insufficient to fully explain treatment outcomes. Accumulating evidence highlights the tumor microenvironment (TME) as a critical determinant of PARPi sensitivity and resistance. This review provides a comprehensive and mechanistic overview of the bidirectional crosstalk between PARPi and the TME. We first summarize both classical and non-classical mechanisms of PARPi action, extending beyond synthetic lethality to include PARP trapping, replication stress, immune activation, and metabolic reprogramming. We then systematically dissect how key TME components-including immune cells, cancer-associated fibroblasts (CAFs), extracellular matrix (ECM), hypoxia, and metabolic networks-modulate PARPi efficacy. Importantly, we highlight the dual nature of PARPi-mediated TME remodeling: while PARPi can activate cGAS-STING-dependent antitumor immunity, normalize tumor vasculature, and soften stromal barriers, they may simultaneously induce adaptive resistance through immune checkpoint upregulation, immunosuppressive cell recruitment, and metabolic compensation. Finally, we discuss emerging translational opportunities, emphasizing the development of TME-informed biomarkers and rational combination strategies, including immunotherapy, anti-angiogenic therapy, and metabolic interventions. A deeper understanding of TME-mediated mechanisms will be essential to optimize PARPi-based therapies and overcome resistance in the clinical setting.
Giant cell-rich tumors encompass a heterogeneous group of bone and soft tissue neoplasms with overlapping morphologic features but distinct molecular drivers and clinical behaviors. Recent studies have identified a unique subset of giant cell-rich tumors characterized by recurrent HMGA2::NCOR2 gene fusions, variably described as xanthogranulomatous epithelial tumor or keratin-positive giant cell tumor. In this paper, we emphasize the clinicopathologic, histologic, and molecular features that distinguish these rare neoplasms from conventional giant cell tumors of bone, soft tissue giant cell tumors, and tenosynovial giant cell tumors. Although these tumors generally exhibit an indolent clinical course, their optimal management remains undefined due to limited published experience. Emerging data suggest signs of therapeutic activity with targeting the CSF1 signaling pathway, and there may be a role for tyrosine kinase inhibitors such as imatinib in selected cases. In contrast, the role of denosumab in this molecularly distinct entity remains unclear. Given the rarity of HMGA2::NCOR2-rearranged tumors, improved recognition and molecular confirmation are essential to refine diagnostic criteria and guide future therapeutic strategies.
Glutathione S-transferase P1 (GSTP1), a canonical phase II detoxification enzyme, has long been recognized for its role in drug resistance via glutathione (GSH)-mediated conjugation and clearance of chemotherapeutic agents. However, accumulating evidence has uncovered its multifaceted non-canonical functions that critically contribute to cancer progression beyond detoxification. This review systematically synthesizes the latest advances in understanding GSTP1's divergent roles in cancer biology, including regulation of oncogenic signaling pathways, maintenance of redox homeostasis, modulation of metabolic reprogramming, and shaping of the tumor immune microenvironment. GSTP1 also plays important roles in key cancer hallmarks including tumorigenesis, metastasis, cancer stemness maintenance, and resistance to chemotherapy, targeted therapy, radiotherapy, and immunotherapy. Clinically, GSTP1 promoter hypermethylation serves as a valuable epigenetic biomarker for cancer diagnosis, prognosis stratification, and therapeutic response prediction via liquid biopsy. Furthermore, the development of GSTP1-targeted inhibitors, either as monotherapy or in combination with other anticancer modalities, has shown promising preclinical efficacy in overcoming treatment resistance. Despite these advances, critical questions remain regarding the precise molecular mechanisms underlying GSTP1's nuclear functions, its context-dependent roles (oncogenic versus tumor-suppressive), and the translation of targeted therapies to clinical practice. Future research focusing on these unresolved areas will deepen our understanding of GSTP1's complex biology and facilitate the development of novel personalized therapeutic strategies for cancer therapy.
Cancer is among the leading causes of death worldwide, and its development has been a consistent focus of research. Many investigations have demonstrated the close relationship between epigenetic mechanisms and cancer development. Posttranslational modifications (PTMs) are pivotal regulators of cancer biology, orchestrating protein functional diversity, epigenetic reprogramming, and metabolic adaptation to drive tumor initiation and progression.In addition to classical phosphorylation and acetylation, advancements in mass spectrometry have led to the discovery of more forms of protein modification. These modifications bridge metabolic dysregulation and oncogenic reprogramming. In this review, we summarize current knowledge on the molecular mechanisms underlying nine novel acylations in cancer, including the roles of acyltransferases, deacylases, and metabolic enzymes in generating acyl-CoA donors. We highlight preclinical and clinical evidence linking aberrant acylation to cancer progression, with a focus on emerging therapeutic strategies targeting acylation enzymes and their combination with immunotherapy or metabolic interventions. Key research gaps are identified, including the need for high-resolution profiling of acylation dynamics, tissue-specific biomarkers, and mechanistic studies on rare types of acylation. By integrating basic research and translational insights, this review highlights the translational potential of novel types of acylation as both a prognostic marker and a therapeutic target in precision oncology.
Immune checkpoint inhibitor (ICI) combinations are standard for metastatic renal cell carcinoma (mRCC), but evidence is uneven across distinct populations. We searched PubMed, Embase and Cochrane CENTRAL through June 3, 2026, and synthesized original studies reporting efficacy or safety in non-clear cell RCC, brain, bone or liver metastases, adults aged 75 years or older, poor performance status, trial ineligibility, frailty, renal impairment or hemodialysis, and sarcomatoid differentiation. Independent studies were the analytical unit. Proportions were pooled only when at least three studies were available, using logit random effects models with Paule-Mandel heterogeneity and modified Hartung-Knapp confidence intervals. Forty-nine studies were included, 13 prospective and 36 retrospective. The pooled objective response rate (ORR) was 37.1% (95% confidence interval [CI]: 28.8-46.2) in non-clear cell RCC, 34.9% (CI: 17.4-57.6) for systemic response in brain metastases, and 41.8% (CI: 31.8-52.5) in adults aged 75 years or older. Study-level ORRs were 30.0-35.3% in poor performance status cohorts, 41.7% in one trial-ineligible cohort, and 24.1% in one hemodialysis cohort. In sarcomatoid differentiation, ICI combinations versus sunitinib improved progression-free survival (PFS; hazard ratio 0.48, CI: 0.34-0.66) and overall survival (OS; hazard ratio 0.55, CI: 0.38-0.80). Safety was described without pooling because definitions and regimens differed. These results quantify response signals, distinguish evidence that can inform routine care, and identify settings requiring individualized judgment and prospective confirmation.
Enterotoxigenic Bacteroides fragilis (ETBF) is a pivotal pathogenic microbe associated with intestinal dysbiosis. Its major virulence factor, Bacteroides fragilis toxin (BFT), is a zinc-dependent metalloproteinase that disrupts intestinal barrier function by degrading adhesion molecules in epithelial cells, thereby triggering inflammatory signaling cascades and inducing aberrant proliferation of intestinal epithelial cells. Beyond this direct toxin-mediated pathogenicity, ETBF-induced pathogenesis also involves intercellular signal transduction mediated by outer membrane vesicles and complex epigenetic regulatory perturbations. Collectively, these pathological processes promote the development of inflammatory bowel disease (IBD) and colorectal cancer (CRC). This review elaborates on the structure-activity relationships of BFT and its multifaceted roles in inducing tissue damage, remodeling the inflammatory microenvironment, and driving carcinogenic progression. We also analyze the technical limitations of current clinical diagnostic approaches for ETBF, and prospect the development of targeted detection methodologies, including integrated multi-omics analyses and molecular diagnostic systems. Furthermore, this review systematically expounds on a variety of promising targeted therapeutic strategies against ETBF, clarifies their potential clinical application value and latest research progress, and thus provides a comprehensive theoretical framework for the clinical diagnosis, treatment and prognostic management of ETBF-associated diseases.
Tumor growth and progression depend on adequate blood supply, which is traditionally maintained through sprouting angiogenesis. However, an alternative form of vascular formation, termed vasculogenic mimicry (VM), has been identified in various tumors. A growing body of evidence suggests that VM is closely associated with tumor invasion, metastasis, and poor clinical outcomes in malignancies. Despite its significance, the precise molecular mechanisms underlying VM remain poorly understood. Recent studies have implicated multiple factors, including the tumor microenvironment, epithelial-mesenchymal transition, and epigenetics, in the regulation of this process. Although numerous anti-angiogenic therapies have been developed and achieved clinical success to some extent, certain limitations persist. This review aims to provide a comprehensive overview of the pathological mechanisms, diagnostic methods, potential clinical applications, and existing challenges associated with tumor VM.
Recent updates in Chronic Lymphocytic Leukemia (CLL) management guidelines emphasize three determinants for first-line treatment choice: patient age, clinical fitness, and key molecular features (IGHV and TP53/17p status). However, multiple therapeutic options are suggested within each clinical scenario, often without clear prioritization. We aimed to transparently rank host, disease and therapy-related determinants influencing frontline therapy selection in CLL, to enhance personalized prescription and clinical decision-making. To achieve this aim, a national expert panel of seven Italian key opinion leaders in Hematology participated in a structured consensus using conjoint analysis methodology. Five major treatment goals and fourteen host or disease-related determinants were selected based on literature and panelists expertise expert input. Conjoint analysis estimated determinant weights for each treatment goal: Time-to-Next-Treatment (TTNT), Rapidity of Disease Control, Infective Safety, Cardiovascular Safety, and Quality of Life. Furthermore, five commonly used regimens (ibrutinib, acalabrutinib, zanubrutinib, ibrutinib-venetoclax, venetoclax-obinutuzumab) were comparatively ranked according to their ability to accomplish each goal. Host/disease-related determinants with the highest impact on TTNT included life expectancy, cytopenias, and complex karyotype. Infective safety was mostly influenced by TP53 disruption and severe comorbidity burden, while cardiovascular safety was primarily affected by comorbidity type and frailty. Among therapies, zanubrutinib and ibrutinib-venetoclax achieved the most balanced profiles across goals. This national consensus provides a transparent, goal-oriented framework for CLL frontline therapy selection. Integrating conjoint analysis enables quantitative weighting of determinants and prioritization of treatment options beyond conventional categorical algorithms. The model supports evidence-based, individualized treatment strategies for CLL in clinical practice.
Decentralized clinical trials (DCTs) are an innovative model of clinical trials in which some or all activities take place at, or near, participants’ homes rather than at traditional clinical sites. DCTs represent a shift from a traditional site-centered approach to a more patient-centered one, leveraging digital tools, home-based services, and local healthcare networks. While DCTs can broaden participation and improve equity, they remain underutilized worldwide. The COVID-19 pandemic demonstrated their practicality, but also highlighted challenges such as uneven regulations, logistical complexity, digital literacy gaps, and data-privacy concerns. The objective of this narrative review is to critically evaluate the implementation of DCTs in oncology, examining their potential benefits and limitations and how decentralization may reshape key trial activities, including recruitment, informed consent, investigational drug delivery, monitoring, and data collection. We further assess the organizational, regulatory, technological, and equity-related conditions required for sustainable implementation and discuss the role of hybrid models. Rather than representing a universal alternative to conventional trials, DCTs should be viewed as a flexible model whose value depends on the clinical context, trial design, patient population, and healthcare infrastructure.
Persistent dysregulation of the Hippo-YAP1 signaling pathway is closely associated with tumor progression and therapeutic resistance, rendering it an exceptionally compelling yet complex target for intervention. To elucidate the potential of harnessing this pathway for cancer therapy, this review systematically integrates mechanistic and translational evidence across three interrelated dimensions. First, we outline the context-dependent roles of Hippo-YAP1 signaling in tumorigenesis, progression, and metastasis, highlighting how pathway activation or inhibition differentially impacts cell proliferation, metabolic reprogramming, epithelial-mesenchymal transition, and metastatic dissemination. Second, the current therapeutic strategies targeting the Hippo pathway are summarized, emphasizing direct inhibition of the YAP/TAZ-TEAD transcriptional complex and pharmacological modulation of upstream druggable regulators. Finally, we dissect how aberrant Hippo-YAP1 activation drives resistance to chemotherapy, radiotherapy, targeted therapies, and immunotherapy across multiple levels. Building upon these findings, we discuss combinatorial therapeutic approaches targeting YAP/TEAD and their specific partner pathways, while outlining molecular stratification strategies based on Hippo-YAP1 activation status and microenvironmental context. In summary, this review summarizes the close link between Hippo-YAP1 dysregulation and drug resistance, and highlights intervention strategies with the potential to serve as novel treatment strategies.
Glioblastoma (GBM) is the most aggressive primary malignancy of the central nervous system. Chimeric antigen receptor T (CAR-T) cell therapy has shown promising therapeutic potential against GBM, yet its efficacy remains constrained by multiple barriers, including physical barriers imposed by the blood-brain barrier and extracellular matrix, the immunosuppressive tumor microenvironment, spatiotemporal antigen heterogeneity, and safety concerns. In this review, we summarize the major obstacles limiting CAR-T therapy in GBM and discuss emerging strategies to overcome these challenges. Next-generation engineered CAR-T cells-through armored modifications, logic-gated regulation, and dual-targeting approaches-enhance specificity, persistence, and controllability. Concurrently, combinatorial approaches leveraging biomaterials enable localized delivery and sustained release of CAR-T cells, while physical modalities, such as focused ultrasound and thermal modulation, can transiently disrupt the blood-brain barrier or induce immunogenic cell death. Integration with real-time imaging further enables dynamic monitoring of therapeutic responses. Together, these synergistic strategies may enhance antitumor efficacy while minimizing systemic toxicity, paving the way for future CAR-T-based therapies in glioblastoma.
