Glioblastoma (GBM), isocitrate dehydrogenase-WT (IDH-WT) (WHO grade 4) is the most common malignant glioma in adults and is characterized by a hypoxic and immunosuppressive tumor microenvironment (TME). Bone marrow–derived tumor-associated macrophages (TAMs) dominate the immune landscape in GBM and are recruited to the perinecrotic niche following the onset of necrosis. C-type lectin domain–containing 5A ( CLEC5A ) has the strongest association with poor clinical outcomes among immune-related genes in GBM and is preferentially expressed in hypoxic, perinecrotic TAMs. CLEC5A overexpression promotes TAM polarization toward an immunosuppressive phenotype and secretion of immunoregulatory cytokines. Using the replication-competent avian sarcoma-leukosis virus long terminal repeat with a splice acceptor (RCAS)/tumor virus A (tv-a) system GBM model with bone marrow transplantation from Clec5a –/– donor mice, we demonstrated that CLEC5A loss prolonged survival, delayed tumor progression, and attenuated TME immunosuppression. Mechanistically, podoplanin (PDPN) expressed on glioma cells directly engaged CLEC5A and triggered downstream Syk/JAK/STAT3 signaling in TAMs. Pharmacologic Syk inhibition suppressed glioma growth, diminished TAM infiltration and polarization, reversed the immunosuppressive TME, and prolonged survival in vivo. Collectively, our findings indicate that the PDPN/CLEC5A/Syk/STAT3 axis orchestrates TAM polarization and TME immunosuppression in the perinecrotic niche of GBM, highlighting CLEC5A/Syk as a promising therapeutic target for reversing the immunosuppressive TME and improving outcomes.

Background Chordomas are locally aggressive notochordal tumors with no systemic therapy options. As an ultra-rare cancer type, our understanding of its immune landscape is limited. While tumor-associated macrophages (TAMs) and T cells are critical components of the immune landscape, their functional states and interactions remain poorly understood.Methods We conducted an integrative analysis of 35 chordoma samples and six paired tumor-PBMC samples using single-cell RNA sequencing (scRNA-seq), T-cell receptor (TCR) profiling, and multiplex immunofluorescence. Immune cell phenotypes, spatial distribution, TCR motif diversity, and functional states were assessed using unbiased co-expression network analysis and predictive modeling.Results Chordomas exhibited remarkable immune cell heterogeneity, ranging from highly infiltrated to immune-desert tumors. Tumor-associated macrophages dominated the tumor microenvironment (TME) and were enriched for antigen-processing pathways. T-cell receptor profiling revealed clonal overlap between tumor-infiltrating and peripheral T cells, suggesting systemic anti-tumor responses. Exhausted CD8+ T cells exhibited restricted clonality and tumor-specific amino acid motifs. Weighted gene co-expression network analysis (WGCNA) identified gene modules associated with immune activation and suppression, underscoring the dual roles of immune cells in the TME. Spatial analysis revealed fibrous septa as immune interaction hubs, where immune cell clustering was significantly higher than in tumor regions.Conclusions This study advances understanding of the chordoma immune landscape by integrating spatial, transcriptomic, and TCR data. The findings highlight systemic and local immune dynamics, reveal tumor-specific TCR motifs, and identify potential therapeutic targets. These insights provide a foundation for developing personalized immunotherapies to overcome immune suppression and enhance anti-tumor immunity in chordomas.

Meningiomas are common tumors of the central nervous system that are typically treated with surgery or radiation, but lack established systemic therapies. Activation of the stimulator of interferon genes pathway with an agonist such as 8803 can trigger anti-tumor immune responses. Using integrated molecular approaches, here we show that this pathway is targetable in both neoplastic and immune populations within the meningioma microenvironment. Meningioma tumor cells exhibit promoter hypomethylation and increased chromatin accessibility of the STING genomic locus, associated with robust expression of this gene. Treatment of diverse patient meningiomas ex vivo with 8803 induces direct tumor cytotoxicity through inflammatory cell death pathways, including induction of gasdermin D membrane pore formation. Release of necrotic tumor debris triggered by 8803 activates macrophages and upregulates matrix metalloproteinase production, facilitating degradation of extra-cellular collagen. Injection of preclinical meningiomas with 8803 induces survival benefits, including in an immunocompetent orthotopic setting, through remodeling of the tumor microenvironment, immune infiltration, and downregulation of tumor-mediated immune suppression, thereby nominating 8803 for treatment consideration in meningiomas.

Abstract Glioblastoma (GBM) presents a major clinical challenge due to its highly invasive nature and resistance to treatment. We previously developed Bvax, a novel B-cell-based cancer therapy. In preclinical models of GBM, Bvax elicited robust antitumor immunity by enriching a subpopulation of CD8+ T cells characterized by high TCF1 and low PD-1 expression. Additionally, Bvax differentiated into plasma cells that secreted antibodies targeting tumor-associated proteins involved in motility and matrix remodeling, suggesting the disruption of tumor progression and enhanced immune infiltration. A first-in-human (FIH) Phase I clinical trial at Northwestern University evaluates the safety and feasibility of Bvax in patients with newly diagnosed GBM. Given the encouraging preclinical results in GBM, we explored therapeutic potential of Bvax for other solid tumors, namely lung and prostate cancer. This study aims to characterize the effects of Bvax on tumor growth, survival, and the preferential migration of Bvax in these new models. To assess Bvax in a lung cancer model, we utilized an orthotopic KP (Kras/p53 mutated) lung tumor model that recapitulates KRAS-driven non-small cell lung cancer (NSCLC). Bvax treatment resulted in a marked survival extension (median 39 vs. 17 days) in tumor bearing mice compared to controls (Wilcoxon p = 0.046). To further assess biodistribution, we used B cell knockout (muMt) mice and observed enriched Bvax infiltration within the tumor, confirming strong tumor tropism within the lung microenvironment. We next evaluated Bvax in a subcutaneous prostate tumor model known for immune exclusion and poor immunotherapy responsiveness. Twenty one days after tumor induction, Bvax was administered and tumor volumes were measured regularly until they reached the defined size endpoint. At peak treatment response, tumor volumes were reduced by 68% relative to controls, accompanied by a higher percentage of MHC-II tumor-infiltrating B cells. These results suggest Bvax retains efficacy across several tumor types with restricted immune infiltration. Ongoing work is now evaluating Bvax in combination with standard-of-care regimens across both tumor models to determine whether its therapeutic activity can be enhanced. In parallel, we are performing immunophenotyping analyses to define how Bvax reshapes the immune landscape within the tumor and surrounding tissue, and better quantify Bvax infiltration across tumor compartments. Additionally, to support translational relevance, we are extending these investigations into patient-derived samples to assess Bvax function in human disease contexts. Citation Format: Hanxiao Wan, Joshua L. Katz, Yotam D. Hahn, Si Wang, Grace V. Jones, Alina R. Murphy, Rebecca Du, Jeffrey Bacha, Roger Stupp, Catalina Lee-Chang. Expanding the therapeutic potential of Bvax: A B-cell-based vaccine for solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4386.

BackgroundPatients with glioblastoma experience a substantial symptom burden that negatively affects functioning in daily life. Symptoms frequently co-occur and may form symptom clusters, yet the robustness, generalizability, and temporal stability of these clusters remain insufficiently studied. This is particularly relevant given the dynamic disease course and treatment-related effects in glioblastoma.MethodsWe used data from the CODAGLIO 2.0 database, comprising adult patients with newly diagnosed or recurrent glioblastoma from seven randomized controlled trials not included in previous clustering studies. Symptoms were assessed using 18 symptom scales from EORTC QLQ-C30 and QLQ-BN20 questionnaires at baseline and 3-month follow-up. Symptom prevalence and multi-symptom co-occurrence were described. Symptom clusters were identified using Spearman correlations, partial correlations, and hierarchical cluster analysis and compared with previously reported clusters. Cluster stability over time was evaluated using cophenetic correlation, tanglegrams, entanglement, and adjusted Rand index scores.ResultsAmong 1,795 patients with baseline HRQoL data, 1678 patients (94%) reported multi-symptom co-occurrence at baseline and 1045 patients (96%) at follow-up. Fatigue, communication deficits, motor dysfunction, drowsiness, insomnia, and visual disorder were most prevalent. Four clinically meaningful symptom clusters were identified: pain–headache, motor dysfunction–weakness of the legs, fatigue–drowsiness, and a seizure-related cluster. These clusters largely aligned with previously reported findings and showed moderate stability over time (cophenetic correlation 0.84; adjusted Rand index 0.41), with greatest variability observed in seizure-related symptoms.ConclusionSymptom clusters in glioblastoma are robust yet dynamic. Incorporating cluster-based and longitudinal symptom assessment may enhance symptom monitoring and support more personalized supportive care strategies.

Abstract Immunotherapy shows limited efficacy in brain tumours, where restricted immune access, antigenic heterogeneity and local immunosuppression constrain durable responses. Low-intensity pulsed ultrasound with microbubbles (LIPU+MB) transiently modulates the blood–brain barrier (BBB) and is widely assumed to enhance immunotherapy by facilitating drug and immune cell penetration into the central nervous system (CNS). However, whether increased anatomical access alone is sufficient to generate effective CNS immunity remains unclear. Here, using a transgenic mouse model with astrocyte-restricted antigen expression, we showed that BBB modulation alone is insufficient to generate functional T-cell immunity in the CNS. Although LIPU+MB enabled rapid T-cell entry, accumulation required prior T-cell activation and integrin-dependent mechanisms, indicating that entry remains governed by canonical immune processes. Moreover, T-cells failed to persist owing to insufficient activation of antigen-presenting cells (APCs) within the CNS. Systemic immune adjuvants (poly-ICLC and IL-2; PI) induced APC activation, promoted tissue-resident-memory-like differentiation and supported durable T-cell responses. LIPU+MB further enhanced these responses by increasing T-cell recruitment, resulting in greater accumulation than with PI alone. Mechanistically, antigen presentation by bone marrow–derived APCs was more critical than that by microglia for the accumulation and persistence of antigen-specifc T-cells in the CNS. In antigenically heterogeneous glioma models resistant to CAR T-cell therapy, combining PI with BBB modulation enhanced the efficacy of immunotherapy, which was mirrored by prolonged survival and endogenous tumour-specific T-cell responses, consistent with epitope spreading. Together, these findings define key limitations of LIPU+MB in enabling effective T-cell therapy and establish that BBB modulation must be coupled to systemic immune activation to support T-cell-mediated antitumour immunity in the CNS.

Bispecific T cell engagers (BTEs) induce MHC-independent cytotoxicity by bridging T cells to tumor cells via binding a T cell-activating receptor and a tumor-associated antigen. BTEs have proven effective in hematologic malignancies and some solid tumors, yet their potential in glioblastoma (GBM) is largely unexplored. We developed a fully humanized BTE (hBTE) targeting interleukin-13 receptor alpha 2 (IL13RA2), a tumor-associated antigen widely expressed in GBM and associated with poor prognosis. In vitro, hBTE activated T cells and induced antigen-dependent cytokine release and cytotoxicity against IL13RA2-positive GBM cells. In vivo, hBTE showed robust target-specific activity and markedly prolonged survival in primary and recurrent GBM xenograft models, without detectable off-target local or systemic toxicity. Beyond GBM, hBTE also exhibited antitumor activity in IL13RA2-expressing solid tumors, demonstrating selective tumor accumulation and therapeutic efficacy in models of breast cancer brain metastases and extracranial lung cancer. This work highlights the therapeutic potential of BTEs in IL13RA2-expressing tumors and establishes a strong preclinical rationale for advancing hBTE therapy toward clinical translation in GBM and other tumors.

Abstract Purpose: We conducted a phase I trial to evaluate radiotherapy (RT) and nivolumab with the further addition of an indoleamine 2,3-dioxygenase 1 (IDO1) enzyme inhibitor (BMS-986205) in newly diagnosed patients with glioblastoma (GBM) IDH wild-type. Patients and Methods: In the current study, there were two primary cohorts of individuals. Cohort A included patients with O6-methylguanine-DNA methyltransferase (MGMT)–unmethylated GBM who received RT with concurrent and adjuvant nivolumab with escalating BMS-986205 doses. Cohort B included patients with MGMT-methylated GBM who received BMS-986205 at 25 mg daily with RT, nivolumab, and temozolomide (TMZ) followed by adjuvant TMZ. Patient outcomes were correlated with flow cytometric, transcriptome, general metabolite, and microbial metabolite analyses. Results: The treatments for both cohorts were moderately safe and tolerable. The treatment-emergent adverse events (TEAE) were mostly related to RT, TMZ, or the underlying disease and tumor progression. In cohort A, serious adverse events and TEAEs were predominantly lower grade, with no differences between the IDO1 enzyme inhibitor dosing cohorts. Dose-limiting toxicities reflected by increased transaminases (grade 3) were observed in two and three patients at the 50 and 100 mg levels of BMS-986205, respectively, with malaise observed in the 50 mg arm only. The 50 mg daily schedule was established as the recommended phase II dose (RP2D) in combination with RT and nivolumab. A number of exploratory correlative studies were also conducted. Conclusions: This single-arm, small phase I trial establishes a safety profile and RP2D for RT in combination with nivolumab and BMS-986205 for newly diagnosed patients with MGMT-unmethylated GBM (ClinicalTrials.gov: NCT04047706).

BACKGROUND:We assessed the clinical relevance of age and sex as risk factors for health-related quality of life (HRQoL) in patients with adult-type diffuse glioma. MATERIALS AND METHODS:The CODAGLIO 2.0 database contains 16 randomized trials from 5369 patients with glioma. Patients' HRQoL was assessed using EORTC QLQ-C30 and QLQ-BN20 questionnaires. In 8 HRQoL scales, we compared mean HRQoL at baseline with the general population and evaluated factors associated with HRQoL over time using linear mixed models (LMMs). We used the anchor-based minimally important difference to interpret clinically relevant changes. RESULTS:We included 4301 patients with baseline HRQoL followed up to 3 months. Compared to the general population, patients with glioma at baseline had statistically and clinically relevant worse HRQoL, which was still evident after stratifying by age and sex groups. In LMMs, compared to patients aged ≤60 years, those >60 years had statistically significant associations with worse physical functioning: -2.40 (95% confidence interval [CI] -4.14 to -0.71), better social: 4.88 (2.68-7.30) and role: 3.79 (1.39-6.16) functioning, and less fatigue: -3.43 (-5.44 to -1.33) and pain: -4.56 (-6.18 to -2.93). Compared to men, women had statistically significant associations with worse physical and social functioning and more fatigue and pain. Associations between age, sex, and HRQoL were not clinically relevant. Performance status had clinically relevant associations in 5/8 scales. CONCLUSION:Patients with glioma have clinically relevant worse HRQoL compared to the general population. There are statistically but not clinically significant associations between age, sex, and certain HRQoL scales.

An expanded access program of depatuxizumab mafodotin for patients with progressive glioblastoma explores the relationship between tumor EGFR expression and outcomes.

Radiation therapy (RT) is the standard of care for glioblastoma but is not curative. Triggering the cGAS/stimulator of interferon genes (STING) pathway with potent agonists, such as 8803, exerts activity across high-grade glioma preclinical models. To determine if the combination of 8803 with RT warrants consideration in the up-front treatment setting and to clarify the underlying mechanisms of therapeutic activity, C57BL/6J mice harboring intracerebral CT-2A or QPP8v gliomas were treated with RT, intratumoral 8803, or both. The treatment with the combination resulted in 80% long-term survival in the CT-2A model but not in the radiation-resistant QPP8v model. This therapeutic effect was maintained in Sting-/- CT-2A cells, highlighting the direct role of the immune system in mediating the survival benefit. Single-cell RNA-Seq identified increased nitric oxide synthase 2 (Nos2) in inflammatory tumor-associated macrophages; however, the therapeutic effect was maintained in Nos2-/- mice. Additionally, 8803 reprogrammed the blood-brain barrier (BBB) by altering the Pecam and Cd147 pathways in endothelial cells; intracranial injection of 8803 induced bihemispheric BBB opening for up to 24 hours. Sting activation was visualized longitudinally using 3'-deoxy-3'-[18F]-fluorothymidine ([18F]-FLT) PET, which peaked 72-96 hours after 8803 administration. In summary, 8803 combined with RT triggers distinctive antiglioma immune reactivity, facilitates BBB opening, and warrants consideration for up-front clinical trials in glioblastoma, where treatment effects can be monitored using [18F]-FLT PET imaging.

Isocitrate dehydrogenase (IDH) mutant gliomas represent a unique molecular subset of gliomas with distinct metabolic and microstructural characteristics. The recent approval of targeted IDH inhibitors marks a significant advancement in glioma therapy, thereby necessitating robust, quantitative methods for noninvasive assessment of treatment response. This review provides an overview of advanced multiparametric imaging techniques-including proton MR spectroscopy, diffusion and perfusion MRI, amide proton transfer imaging, and amino acid positron emission tomography imaging-and their role in detecting IDH-mutations and monitoring therapeutic response to IDH inhibitors. Special emphasis is placed on metabolic imaging of the oncometabolite D-2-hydroxyglutarate (2-HG), a hallmark signature of IDH-mutant gliomas, and how its quantification serves as a surrogate biomarker for diagnosis and treatment monitoring. We also highlight the potential of advanced diffusion MRI-based models, which capture microstructural alterations beyond conventional apparent diffusion coefficient metrics. Some limitations of these techniques in clinical translation are also considered, along with future directions to integrate them into prospective clinical trials.

Abstract Background: Glioblastoma recurrence is inevitable despite aggressive surgical resection of contrast enhancing (CE) tumor. Unlike the deep molecular characterization of CE glioblastoma, unresected infiltrating tumor, representing minimal residual disease (MRD) has not been well profiled. Increasingly, clinical trials are being conducted in the MRD setting for glioblastoma patients, necessitating understanding of unresected infiltrating tumor for targeted therapeutic development. Methods: Visium HD spatial transcriptomics was used to profile a cohort of newly diagnosed, treatment-naïve glioblastoma patients that underwent supramaximal resection, with both core and infiltrating in situ components. Spatial profiles generated expression signatures of infiltrative and CE tumor. For in silico prediction of therapeutics targeting the MRD, expression signatures of infiltrative and CE tumor were compared with drug perturbation signatures from the NIH L1000 database using the sRGES method to predict reversal of disease expression patterns. IC50 data from human cell lines were aggregated from the Genomics of Drug Sensitivity in Cancer or individual study data while blood-brain barrier (BBB) penetrance was predicted using the CNS-MPO approach. Findings: Infiltrative tumor expression profiles were enriched for genes corresponding to neural and oligodendrocyte progenitor like cells. In contrast CE glioblastoma displayed mesenchymal and astrocytic programs, suggesting spatial concentration of glioblastoma states within MRD and CE tumor. For CE glioblastoma, proteasome inhibitors and glucocorticoid receptor agonists were predicted to have the highest antitumor activity. In contrast, histone deacetylase inhibitors (HDACi) were highly ranked for MRD while exhibiting low predicted efficacy in CE tumor. Synergy analysis of drug candidates provided multiple dual treatment options for both the CE and MRD contexts. Conclusions: Cumulatively, these data indicate that the resected tumor does not reflect the MRD state, providing clarity on why targeted therapeutics for glioblastoma have not been particularly successful. Spatial profiling of the MRD demonstrates vulnerability to unique drug targets, which if utilized in the correct setting could confer greater survival benefit. Citation Format: Harrshavasan Congivaram, Shashwat Tripathi, Mateo Gomez, Katy McCortney, Ching Man Wai, Ruochen Du, Thomas K. Sears, Jianzhong Zhang, Daniel J. Brat, Craig M. Horbinski, Mark W. Youngblood, Jared T. Ahrendsen, Adam M. Sonabend, Stephen T. Magill, Matthew C. Tate, Maciej S. Lesniak, Sean Sachdev, Timothy Sita, Priya Kumthekar, Karan Dixit, Robin Buerki, Ditte Primdahl, Mustafa Khasraw, John de Groot, David A. Reardon, Rimas V. Lukas, Roger Stupp, Amy B. Heimberger. In silico screening of therapeutics candidates targeting minimal residual disease in glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 2496.

PURPOSE:The blood-brain barrier (BBB) impedes the passage of most circulating drugs into the brain. Low-intensity pulsed ultrasound with microbubbles (LIPU/MB) transiently opens the BBB, improving parenchymal drug penetration. Parenchymal drug retention following short-lived BBB opening is unknown. We investigated the effect of LIPU/MB on the concentration of carboplatin and fluorescein over time and compared the parenchymal retention of temozolomide (TMZ), carboplatin, and fluorescein in the nonsonicated brain. EXPERIMENTAL DESIGN:We analyzed four patients who underwent intraoperative LIPU/MB with intravenous administration of carboplatin and fluorescein in the NCT04528680 clinical trial. Microdialysis catheters were implanted into sonicated and nonsonicated brain regions, and drug levels were measured over 24 hours. Published microdialysis data of TMZ without LIPU/MB were used for comparison. RESULTS:LIPU/MB led to sustained elevated parenchymal drug concentrations, achieving a 3.1-fold increase in brain-to-plasma AUC for carboplatin and fluorescein (P = 0.03). In the nonsonicated brain, TMZ concentrations remained below their plasma levels, as parenchymal drug clearance mirrored plasma clearance. In contrast, BBB-impermeable drugs such as carboplatin and fluorescein exhibited delayed parenchymal clearance, resulting in higher brain than plasma drug levels over time. Parenchymal drug clearance of carboplatin and fluorescein was not affected by sonication. CONCLUSIONS:Following LIPU/MB, BBB-impermeable drugs exhibit sustained elevated parenchymal concentrations surpassing their plasma levels, highlighting the bidirectional restriction of drug passage by the BBB. Future studies are warranted to explore drug trapping and the efficacy of sustained exposure to cytotoxic drugs for the treatment of brain-infiltrating tumors.

Glioblastoma (GBM) remains one of the most aggressive and fatal cancers, with a median survival of only 12-18 months despite standard treatments, including surgical resection, temozolomide (TMZ) chemotherapy, and radiotherapy. Tumor recurrence and therapy resistance are significant barriers to improving patient outcomes. To address this, our lab investigated the molecular mechanisms driving resistance during TMZ therapy using a single-cell RNA-sequencing screen on a patient-derived xenograft (PDX) model. This approach enabled us to study tumor evolution pre-, during, and post-therapy. Our analysis identified 149 unique genes expressed during TMZ therapy, with the ribonucleotide reductase (RNR) family, particularly Ribonucleotide Reductase Regulatory Subunit 2 (RRM2), emerging as critical players. During TMZ treatment, GBM cells preferentially utilize RRM1-RRM2 interaction to support deoxynucleoside triphosphate (dNTP) biosynthesis, whereas post-therapy recurrent GBM shifts to RRM1-RRM2B complexes. Functional studies demonstrated that RRM2 knockdown sensitized GBM cells to TMZ, reducing DNA repair capacity, as evidenced by increased yH2AX fluorescence, while RRM1 or RRM2B knockdown conferred resistance (p<0.001). Metabolomic profiling revealed that RRM2 mediates dCTP and dGTP production during TMZ treatment, critical for chemoresistance. Supplementation with these dNTPs rescued TMZ susceptibility in RRM2-deficient cells, highlighting its pivotal role in DNA repair and therapeutic resistance. Recognizing the limitations of first-generation RNR inhibitors, we explored the second-generation inhibitor Triapine (3-AP). Preclinical studies showed that 3-AP effectively inhibits RRM2 activity, enhancing TMZ sensitivity and extending survival in PDX models (p<0.0001). Mice treated with a combination of 3-AP and TMZ demonstrated significantly longer survival compared to TMZ alone. These findings underscore the potential of targeting RRM2-mediated dNTP biosynthesis to overcome chemoresistance in GBM. We are conducting a Phase 1/1b clinical trial to assess the safety, toxicity, and maximum tolerated dose (MTD) of combining 3-AP with TMZ in recurrent GBM patients. Atique U. Ahmed, Karan Dixit, Ella N Perrault, Jack M Shireman, Priya Kumthekar, Roger Stupp. David C James. RRM2-driven dNTP biosynthesis: a therapeutic vulnerability in temozolomide-resistant glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4431.

Advances in molecular biology, genetics, and epigenetics have refined our understanding of metastatic brain cancer and underscored the need for better classification and targeted approaches. The heterogeneity of brain metastases highlights the differences from their primary source of origin and contributes to therapeutic resistance. Before colonising the brain, tumour cells acquire specialised proficiencies that enable them to capitalise on the unique microenvironment of the brain. The tumour cells further orchestrate key adaptations to adjust to the brain microenvironment by manipulating the blood-brain barrier, evading immune surveillance, rewiring metabolic profiles, and reprogramming astrocytes. These adaptations facilitate tumour survival, growth, and treatment resistance. Recognising metastatic brain cancer as a distinctive CNS disease, rather than an extension of the primary cancer, would support the development of rational approaches that target its molecular and genetic features and improve research funding in this area. Here, we delve into the distinct genetic and phenotypic characteristics metastatic brain cancer, and reflect on how a change in the perception of this disease could accelerate the development of more effective therapies and drive continued progress in the field of neuro-oncology.