Adrenocortical carcinoma (ACC) is a rare malignancy in which overexpression of steroidogenic factor-1 (SF-1/NR5A1) and aberrant activation of canonical Wnt/β-catenin signaling are important oncogenic events. However, the extent to which these regulatory axes converge or interact at the transcriptional level remains unclear. We investigated their relationship using bulk transcriptomic and regulatory-network approaches.

Regulatory network inference using RTN/ARACNe was applied to the TCGA-ACC cohort. NR5A1 and β-catenin-associated TCF/LEF regulon activities were evaluated in perturbation datasets and tested for associations with CpG island methylator phenotype (CIMP), overall survival, and gene-level interaction effects. Candidate modulators of NR5A1 activity were assessed using the MINDy algorithm. The effects of cBAF inhibition on NR5A1 regulon activity were also evaluated in H295R and CU-ACC1 cells.

NR5A1 knockdown repressed steroidogenic pathways, whereas β-catenin knockdown predominantly suppressed Wnt/β-catenin signaling. In TCGA-ACC, NR5A1 regulon activity was associated with CIMP-high status and overall survival. In contrast, β-catenin-related regulons were not significantly associated with CIMP-high status after adjustment for NR5A1 activity, and no significant multiplicative interaction effects were identified. Fewer than 3% of protein-coding genes showed improved fit in models including NR5A1 × TCF/LEF interaction terms, without enrichment for steroidogenic or Wnt/β-catenin-related pathways. CTNNB1 was identified as a statistically significant but low-ranking positive modulator of NR5A1 activity, whereas CTNNBIP1 was a top-decile negative modulator. cBAF inhibition was associated with NR5A1 regulon repression in both cell models.

These findings indicate limited detectable global transcriptional convergence between NR5A1 and canonical β-catenin-related regulons in the evaluated bulk transcriptomic frameworks. Potential relationships between these pathways may depend on more localized, chromatin-dependent, protein-level, or context-specific regulatory mechanisms. NR5A1 regulon activity showed more consistent associations with CIMP-high status and clinical outcome than the β-catenin/TCF-LEF regulons in the evaluated TCGA-ACC models. The modulation patterns associated with CTNNB1 and CTNNBIP1, together with the repression of NR5A1 regulon activity following cBAF inhibition, raise the possibility that NR5A1 acts as a context-dependent regulatory node connecting oncogenic signaling and chromatin-remodeling mechanisms in ACC. These findings support further investigation into the role of chromatin-remodeling complexes in sustaining NR5A1-driven transcriptional programs in ACC.

Background: Successful translation of cancer immunotherapy is underscored by the efficacy of PD-1/PD-L1 and CTLA-4 inhibitors in the treatment of various malignancies. However, their limited efficacy in glioma indicates alternative immune escape mechanisms. We investigated B and T Lymphocyte Attenuator (BTLA), a co-inhibitory receptor structurally and functionally analogous to PD-1, to determine if it constitutes a key, unaddressed mechanism of immune escape and a novel therapeutic target in glioma. Methods: We analyzed BTLA expression and function within the tumor microenvironment of a Moroccan cohort (n = 44). This was complemented by multiparameter flow cytometry on peripheral blood from glioblastoma (GBM) patients (n = 8) to assess circulating T cell profiles. Findings were corroborated using independent transcriptomic datasets from TCGA and CGGA cohorts. Single-cell RNA-seq and citeSeq identified specific BTLA-expressing cell populations. Results: Elevated BTLA expression was significantly associated with aggressive features and poor overall survival in glioma patients. Mechanistically, BTLA levels were positively correlated with pro-tumorigenic factors, immune infiltration, and immunosuppressive checkpoints. Single-cell and citeSeq analyses revealed that BTLA was primarily expressed by exhausted T cells and conventional type 1 dendritic cells (cDC1) within the GBM microenvironment. Crucially, this phenotype was translated systemically; BTLA defined dysfunctional circulating CD8⁺ and CD4⁺ T cells characterized by diminished IFN-γ production, alongside reduced granzyme B and perforin in CD8⁺ T cells. Conclusions: Our findings indicate that BTLA may represent a relevant pathway associated with an immunosuppressive glioma microenvironment. The therapeutic potential of targeting this pathway, particularly in combination with PD-1/PD-L1 blockade, warrants further investigation.

Breast cancer, especially triple-negative breast cancer (TNBC) and endocrine-resistant disease, remains difficult to treat because of limited effective targeted therapies. In this study, we evaluated the antitumor activity and potential mechanism of MHO7, a marine-derived ophiobolin metabolite, in ER-positive ZR-75-30 cells, tamoxifen-resistant LCC2 cells, and TNBC MDA-MB-231 models. MHO7 dose-dependently reduced cell viability, wound closure, and clonogenic growth in ZR-75-30 and LCC2 cells, with IC₅₀ values of 11.53 and 10.43 μM, respectively. MHO7 also promoted apoptotic cell death, accompanied by increased reactive oxygen species accumulation and altered expression of apoptosis-related proteins, including Bcl-2 and caspase-3. N-acetyl-L-cysteine partially attenuated MHO7-induced apoptosis and YAP reduction in MDA-MB-231 cells, suggesting a contribution of oxidative stress. Molecular docking predicted that MHO7 could occupy the conserved TEAD palmitoylation pocket, and subsequent in vitro analyses showed suppression of YAP/TAZ-TEAD signaling, including reduced YAP nuclear accumulation and decreased TEAD4 expression. In an MDA-MB-231 xenograft model, MHO7 significantly inhibited tumor growth, reduced CD31-positive microvessel density, and decreased Hippo pathway-related transcriptional readouts. These findings indicate that MHO7 exerts broad antitumor activity in breast cancer models through oxidative stress-associated apoptosis and modulation of YAP/TAZ-TEAD signaling, supporting its further development as a lead compound for treatment-resistant breast cancer.

Sea cucumber cooking liquid contains water-soluble macromolecules, but its bioactive polysaccharide fractions remain insufficiently characterized. In this study, a polysaccharide-rich fraction, P0.7, was isolated from sea cucumber cooking liquid and evaluated for its antitumor activity against HCT-15 colorectal cancer. P0.7 was characterized as a relatively homogeneous sulfated acidic heteropolysaccharide-rich fraction containing 83.61 ± 3.65% total sugar, 13.67 ± 2.48% sulfate, 9.98 ± 1.22% uronic acid, and 5.11 ± 0.34% protein. It was mainly composed of galactose, mannose, and glucose, accounting for 34.12%, 26.93%, and 17.99%, respectively. Among the tested tumor cell lines, HCT-15 cells showed the highest sensitivity to P0.7, with inhibition rates of approximately 45% and 63% at 100 and 200 μg/mL, respectively. P0.7 promoted apoptosis, induced G2/M-phase accumulation, increased ROS production, disrupted mitochondrial membrane potential, regulated Bax, Bcl-2, and cleaved caspase-3 expression, and enhanced γ-H2AX-related DNA damage-response signaling in HCT-15 cells. In an HCT-15 xenograft mouse model, P0.7 reduced terminal tumor volume and tumor weight without causing obvious body weight loss. Histological and immunohistochemical analyses further showed reduced Ki67 staining, increased TUNEL-positive signals, and enhanced γ-H2AX staining in tumor tissues. These findings indicate that P0.7 suppresses HCT-15 colorectal cancer growth in vitro and in vivo, possibly through mechanisms associated with ROS accumulation, mitochondrial apoptosis, and γ-H2AX-related DNA damage response. These findings provide additional experimental evidence supporting the investigation of sea cucumber-derived polysaccharides for potential pharmaceutical applications.

Primary intra-axial cerebral schwannomas are exceptionally rare benign tumors that arise within the brain parenchyma without any association with cranial nerves. Their nonspecific clinical and radiological features frequently mimic high-grade gliomas, making preoperative diagnosis challenging.

We report the case of a 17-year-old male who presented with recent-onset right-sided visual disturbance and bilateral early papilledema. Magnetic resonance imaging demonstrated a lobulated, contrast-enhancing left occipitoparietal intra-axial mass with restricted diffusion, hyperperfusion, extensive vasogenic edema, and adjacent calvarial remodeling, raising suspicion for glioblastoma, gliosarcoma, or pleomorphic xanthoastrocytoma. The patient underwent gross-total resection through a left occipital craniotomy. Histopathological examination revealed a well-circumscribed cellular spindle-cell neoplasm with alternating hypercellular and hypocellular areas, perivascular hyalinization, and an absence of mitotic activity or necrosis. Immunohistochemistry demonstrated diffuse positivity for S100 and SOX10, negative Olig2 staining, retained INI-1 expression, and a low Ki-67 proliferation index of approximately 5%, establishing the diagnosis of a WHO grade 1 cellular schwannoma.

Intra-axial cerebral schwannoma should be considered in the differential diagnosis of enhancing supratentorial brain lesions in children and adolescents, particularly when imaging suggests a high-grade glioma. Definitive diagnosis relies on histopathological and immunohistochemical evaluation. Gross-total resection is associated with excellent outcomes and durable disease control, although continued radiological surveillance remains advisable given the rarity of the condition.

The rapid expansion of biologic therapies for immune-mediated inflammatory diseases has raised significant clinical concerns regarding malignancy risk, particularly for patients with a history of cancer. This narrative review explores the safety of targeted therapies across dermatology, rheumatology, respiratory medicine, and gastroenterology to guide clinicians in these therapeutic dilemmas. We conducted a non-systematic review of the literature, prioritising longitudinal registry and real-world cohort data over clinical trials to better capture malignancy outcomes with long latency periods. Results indicate that tumour necrosis factor (TNF) inhibitors, which have the most extensive evidence base, do not consistently demonstrate an increased risk of overall incident malignancy or recurrence across specialties. Newer agents, including interleukin (IL)-17 and IL-23 inhibitors, show reassuring safety profiles in both trial and registry data. While dupilumab is associated with the potential diagnostic 'unmasking' of pre-existing cutaneous T-cell lymphoma, overall cancer rates remain stable among users. Most clinical guidelines support an individualised, multidisciplinary approach involving oncology consultation. We conclude that biologic agents can be used cautiously in certain patients with a history of malignancy following multidisciplinary discussion; however, in those with active malignancy there are no meaningful data that exist. Most evidence is heterogenous and excludes patients with a history of malignancy. Future management requires validated decision frameworks and mandatory participation in real-world patient co-created registries which leverage developing artificial intelligence tools to refine long-term safety assessments.

In the current work, a new series of novel Δ²-pyrazoline-1H-1,2,3-triazole derivatives (6a-6j and 7a-7f) were synthesized, followed by in situ biological evaluation to assess their antiproliferative and immunomodulatory potential against breast cancer cells (MDA-MB-231 and MCF-7), HUVECs, and PBMCs. The compounds demonstrated antiproliferative effects with IC₅₀ values ranging from 116.92 to 549.73 µM. Seven compounds (6c, 6f, 6h, 6i, 7b, 7e, and 7f) exhibited promising antiproliferative activities with IC₅₀ values below 140 µM in both MDA-MB-231 and MCF-7 cancer cell lines. Compound 7f demonstrated the highest antiproliferative effect with IC₅₀ values of 116.92 µM in MDA-MB-231 and 124.72 µM in MCF-7, with an acceptable cytotoxicity profile in normal HUVEC cells (IC₅₀ = 208.41 µM); thus, immunomodulatory effects of 7f on checkpoint signaling were further evaluated. Compound 7f showed a dose-dependent increase of TIGIT, PD-1, and LAG-3 expression in CD3⁺ T cells. These changes may enhance responsiveness to checkpoint-targeted therapies while reflecting complex regulation of T-cell function. In silico target fishing and molecular docking reflect calpain as a probable target for 7f, while DFT analysis indicates electrophilic and nucleophilic positions within 7f may help its interaction with the target. Molecular dynamics (MD) simulation supports strong binding of 7f with binding energy (-22.259 ± 4.71 kcal mol^-1).

Gangliogliomas (GGs) are low-grade glioneuronal tumors that frequently present with drug-resistant epilepsy. Although their indolent course contrasts with their high epileptogenic potential, the oncogenic mechanisms sustaining neuronal precursor-like populations within the tumor microenvironment remain poorly defined.

We performed spatial transcriptomic profiling on eight histologically confirmed GGs and matched healthy cortex to map the cellular and molecular architecture of the tumor microenvironment. Integrated analysis with weighted gene correlation network analysis (WGCNA) defined recurrent oncogenic programs and spatially resolved tumor-stroma interactions.

Eight conserved gene modules emerged, encompassing physiological cortical, reactive glial, and oncopathological programs. The latter captured extracellular matrix (ECM) remodeling, vascular-immune signaling, and persistence of immature, proliferative neuronal-like states. Spatial modeling revealed that these oncopathological programs form structured niches at the tumor-brain interface, where radial glia-derived neuronal-like tumor cells coexist with immune and stromal elements engaged in ECM turnover and cytokine signaling.

Ganglioglioma represents a hybrid glioneuronal neoplasm in which developmental neuronal programs are co-opted by tumor-associated stromal and immune cues. This convergence establishes a permissive oncogenic niche that sustains precursor-like tumor cells and provides a mechanistic basis for both the tumor's benign growth and its intrinsic epileptogenicity.

Inflammatory myofibroblastic tumor (IMT) is a rare mesenchymal neoplasm for which definitive radiotherapy in the retroperitoneum remains largely undefined, particularly when dose escalation must be balanced against the preservation of adjacent critical organs. A 59-year-old woman presented with a 10-day history of fever and abdominopelvic pain. Physical examination revealed deep tenderness in the right lower quadrant, and laboratory testing demonstrated leukocytosis. Imaging identified a 9.2 cm retroperitoneal mass invading the right ureter and inferior vena cava. Biopsy confirmed IMT, and capture-based next-generation sequencing revealed no class I actionable alterations. Given the unfavorable surgical anatomy and limited response to corticosteroids, curative-intent resection was precluded. The patient was treated with definitive dose-escalated volumetric modulated arc therapy (VMAT) employing a simultaneous integrated boost strategy (66 Gy/33 fractions to the boost volume and 50 Gy to the conventional planning target volume), with spatial sparing of adjacent organs at risk. Complete radiographic response was achieved at one month, without grade ≥2 treatment-related adverse events. At 19-month follow-up, the patient remained disease-free with stable renal function. This case demonstrates that dose-escalated VMAT with spatial organ avoidance can achieve durable complete remission in unresectable retroperitoneal IMT while preserving organ function, supporting its consideration as a curative-intent strategy in this challenging clinical setting.

Magnetic hyperthermia, in which magnetic nanoparticles (MNPs) generate heat under an alternating magnetic field, has emerged as a promising strategy for cancer therapy. Among numerous magnetic hyperthermia platforms, direct intratumoral administration has achieved the greatest clinical progress because it enables localized heat generation while overcoming the limited tumor accumulation associated with systemic nanoparticle delivery. The development of functional MNPs capable of efficient cellular interaction and intracellular localization has further expanded magnetic hyperthermia beyond conventional tissue heating toward intracellular hyperthermia and cancer immunotherapy. This review summarizes the historical evolution and clinical translation of functional MNPs with particular emphasis on the design principles that have facilitated successful clinical development. We discuss how advances in nanoparticle engineering have improved intratumoral retention, intracellular delivery, thermal dose optimization, and therapeutic efficacy. We further review the emerging role of magnetic hyperthermia as an in situ vaccination strategy capable of inducing immunogenic cell death and stimulating systemic antitumor immunity, providing a biological rationale for combination with immunotherapies. Finally, we discuss current challenges limiting widespread clinical translation, together with future perspectives on multifunctional therapeutic and theranostic nanoplatforms. These advances position functional MNPs as promising platforms for next-generation cancer therapy.