Diffuse midline gliomas (DMGs) are highly aggressive, WHO grade 4 glial tumors that arise in midline central nervous system structures and are defined by K27M mutations in histone H3 genes. These K27M mutations shape intratumoral myeloid cell composition in DMG. In H3.1K27M DMGs, genetic ablation of monocyte recruitment reshapes the tumor microenvironment (TME) by reducing monocyte-derived macrophages (MDMs) and increasing microglia and neutrophil presence, with overall survival remaining unchanged, indicating compensatory myeloid remodeling is occurring. Here, by using CRISPR/Cas9-based genome editing, we generated a mouse model deficient for CCR1/CCR2/CCR3/CCR5 (Δ1235). Using this strain, we effectively abolished monocyte and MDM infiltration and reversed compensatory recruitment of CCR1+ neutrophils. Abolishing MDMs in tumors skewed remaining neutrophils and microglia toward a homeostatic state, reduced expression of immune checkpoint molecules on T cells, and extended the survival of H3.1K27M DMG-bearing mice. In contrast, H3.3K27M DMG showed independence from MDM recruitment, suggesting reliance on other TME-driven signaling. Last, H3.1K27M DMGs exhibited reduced microglia presence and a dose-dependent increase in MDM infiltration postirradiation. MDM depletion did not further enhance radiation efficacy, potentially due to compensatory recruitment of classical neutrophils. Collectively, these data reveal histone mutation-specific myeloid dependencies in DMG, highlighting MDM-independent mechanisms in H3.3K27M tumors and MDM-dependent pathways in H3.1K27M tumors.

Reduced skeletal muscle mass may impair outcomes of immune checkpoint inhibitors in recurrent or metastatic head and neck squamous cell carcinoma. We evaluated whether temporal muscle thickness (TMT) on routine head computed tomography was associated with treatment response and survival.

Smoking cessation decreases lung cancer progression; however, its effects on precancerous lesions and the underlying mechanisms remain unclear. This study established a mouse model of precancerous pulmonary nodules and employed single-cell RNA sequencing (scRNA-seq) and immune repertoire sequencing (IR-seq) to elucidate the regulatory mechanisms by which smoking cessation influences the development of lung precancerous lesions.

Myelosuppression is common during chemoradiotherapy for nasopharyngeal carcinoma (NPC), but the prognostic impact of multilineage cytopenia remains unclear. This retrospective study evaluated a three-lineage cytopenia score in 576 patients with locally advanced NPC. The score (0-3) was defined as the number of lineages (leukocytes, hemoglobin, platelets) below normal limits. During a median follow-up of 74 months, higher cytopenia grades were significantly associated with worse overall survival, locoregional relapse-free survival, and distant metastasis-free survival (all P < 0.001). The score was an independent prognostic factor. Compared with score 0, score 3 was associated with a 7.55-fold increased risk of death (HR = 7.545, 95%CI: 3.158-18.028) and a 21.33-fold increased risk of distant metastasis (HR = 21.333, 95%CI: 5.076-89.655). The model incorporating the three-lineage cytopenia score yielded an area under the curve (AUC) of 0.593 (95% CI: 0.533-0.652, P = 0.001), indicating modest discriminatory ability. The three-lineage cytopenia score is a simple, independent prognostic indicator for locally advanced NPC with strong predictive value for distant metastasis. It may serve as a useful adjunct to traditional staging for risk stratification.

Pediatric supratentorial tumors are almost always primary brain tumors. They are defined by a relatively short list of diagnoses that can be broadly divided into tumors with high-grade and low-grade features, intraventricular lesions, and other rare tumors. The differential diagnosis can be further narrowed depending on age at presentation and particular imaging features. Treatment in most cases is surgical resection and may be followed by adjuvant therapy. Many tumors, such as high-grade glioma, ependymoma, and atypical teratoid rhabdoid tumor, are associated with specific genetic mutations that determine diagnosis and prognosis. ©RSNA, 2026 Supplemental material is available for this article.

Breast biopsy markers have evolved from simple metallic markers to sophisticated multimaterial devices that serve critical purposes throughout the breast cancer care continuum. This evolution began at The University of Texas MD Anderson Cancer Center in the 1960s for gynecologic and head and neck tumors. After the MicroMark (Biopsys) clip was approved by the U.S. Food and Drug Administration in 1995, markers were subsequently adapted for patients with breast cancer in 1999. By 2003, markers had become the standard of care. Modern markers serve multiple clinical functions: marking biopsy sites, facilitating cross-modality imaging correlation, guiding surgical planning and radiation therapy targeting, and ensuring continuity of care across health care facilities. Long-term studies demonstrate excellent safety profiles with minimal adverse events and significant cost-effectiveness through improved surgical precision and reduced re-excision rates. Despite the widespread adoption of these markers, contemporary challenges persist, including marker migration, allergic reactions to metallic components or embedding materials, and visibility limitations on US images. However, recent technological advances address these concerns through improved marker designs, nonmetallic alternatives, and innovative detection methods. Current best practices emphasize optimal placement timing, appropriate marker selection based on patient-specific factors, migration prevention techniques, and use of Doppler US "twinkling" artifacts for enhanced US visualization. © The Author(s) 2026. Published by the Radiological Society of North America under a CC BY 4.0 license. Supplemental material is available for this article.

Despite recent therapeutic advances, treatment options for advanced, therapy-resistant, and metastatic prostate cancer (PCa) remain limited. Here, we developed and prospectively validated an integrated chemoinformatics and machine learning (ML) workflow with ligand-based similarity filtering. Validation on independent external data sets showed that this applicability-domain-guided integration strategy can reduce false positives and improve virtual screening performance. Screening of DrugBank identified five repurposing candidates with confirmed antiproliferative activity in both 2D and 3D PCa models. Among them, the antifungal agent chlormidazole emerged as the most promising candidate, displaying tumor-selective and predominantly cytostatic activity associated with p57 upregulation, reduced Rb phosphorylation, and G1 arrest. Chlormidazole also enhanced the antiproliferative activity of docetaxel in both models, achieving comparable efficacy at substantially lower docetaxel concentrations. These findings identify chlormidazole as a promising repurposing candidate for PCa and demonstrate the value of integrating chemoinformatics with ML for drug repurposing and virtual screening.

Microtubules are core cytoskeletal components for cellular activities. Their interaction with microtubule-associated protein 7 (MAP7) is crucial for cell proliferation, cellular component transport, and morphological regulation. The conserved microtubule surface region binds tightly to MAP7's microtubule-binding domain (MTBD). Its function relates closely to tumorigenesis and progression. Using structure-based drug design, we first designed peptides 1-3, peptide inhibitors targeting microtubule-MAP7 interaction. These peptides disrupt microtubule-MAP7 interaction by specifically binding to microtubules. After multiple optimizations, peptide-3's binding affinity to microtubules reaches 0.12 μM. Further studies show that it effectively inhibits the proliferation, migration, and invasion of colorectal cancer cells (HCT116 and SW480) and enhances cell damage. Animal experiments confirm its potent in vivo antitumor activity with no obvious toxicity. In summary, peptide-3 specifically disrupts microtubule-MAP7 interaction, acting as a promising lead compound for inhibiting colon cancer cell proliferation.

Resistance to monotherapy remains a major challenge in the treatment of nonsmall cell lung cancer (NSCLC), highlighting the need for innovative therapeutic strategies. To address this issue, we developed a dual-targeting strategy aimed at simultaneously inhibiting the oncogenic protein-protein interaction (PPI) between UBE2M and DCN1─which is critical for neddylation-dependent activation of cullin-RING ligases (CRLs)─and histone deacetylase (HDAC) activity. Inspired by the synergistic antitumor effects observed with combined inhibition of UBE2M-DCN1 and HDAC, we designed hybrid molecules integrating pharmacophores targeting both pathways. Our preferred compound JN210 effectively disrupts the UBE2M-DCN1 interaction and inhibits HDAC, demonstrating significantly enhanced cytotoxicity compared to the parent compounds in vitro and potent tumor growth suppression in vivo. Mechanistic studies revealed dual blockade of CRL neddylation and induction of histone hyperacetylation, resulting in impaired DNA damage repair and synergistic apoptosis. As a novel DCN1/HDAC dual inhibitor, JN210 represents a promising therapeutic candidate for NSCLC.

Two copper(II) complexes, (1) [CuCl2(tmp-terpy)] and (2) {[CuCl(tmp-terpy)]·PF6}n, (tmp-terpy-4'-(3,4,5-trimethoxy-phenyl)-2,2':6',2″-terpyridine) were designed, characterized, and evaluated for cytotoxicity in 2D human cell models (HCT116, HCT116-DoxR, and in normal primary fibroblasts), and 3D colorectal cancer (CRC) spheroids and patient-derived organoids (PDOs). Both complexes demonstrated potent antiproliferative effects, alone and in combination with the FOLFOX (FF), across all 3D models. Importantly, the cytotoxic effects of complex 1 were significantly more pronounced in tumor-derived PDOs than in normal tissue-derived PDOs. Complex 1 induced reactive oxygen species (ROS) production, triggering intrinsic apoptosis and autophagy, consistent with a multimodal anticancer mechanism. It also exerted a cytostatic effect, as shown by delayed cell-cycle progression, and antiangiogenic activity in vivo without systemic toxicity. Notably, cotreatment of complex 1 with FF significantly potentiated cytotoxicity in 3D tumor spheroids and PDOs tumor-derived-PDOs. [CuCl2(tmp-terpy)] alone or in combination with the FF regimen warrants further evaluation in advanced preclinical models.

Estrogen receptor α (ERα) remains a pivotal therapeutic target for ER-positive (ER+) breast cancer, yet resistance to endocrine therapies driven by ligand-binding pocket (LBP) mutations demands novel strategies. To integrate the complementary strengths of binding modalities of the orthosteric LBP and the allosteric coactivator binding site (CBS) against endocrine resistance, we designed a series of ERα LBP/CBS dual-targeting proteolysis-targeting chimeras (PROTACs). The lead compound P5 demonstrated high binding affinities for LBP and CBS sites, potent antiproliferative activity, and efficient ERα degradation efficacy across a panel of breast cancer cell lines via the ubiquitin-proteasome system. Mechanistically, P5 triggered S-phase cell cycle arrest and apoptosis in LCC2 cells. In vivo, P5 exhibited significant tumor growth inhibition in the LCC2 xenograft model, with efficacy comparable to fulvestrant, and a favorable safety profile. Our findings validate the LBP/CBS dual-targeting PROTAC strategy as a promising avenue for overcoming resistance in ER+ breast cancer.

SHP2 (Src homology 2 (SH2)-containing protein tyrosine phosphatase 2) is a tyrosine phosphatase that plays a critical role in numerous physiological and pathological cellular processes, including cell proliferation, survival, and migration through the regulation of multiple signaling pathways, such as RAS-RAF-mitogen-activated protein kinase, phosphatidylinositol 3-kinase (PI3K)-AKT, Janus tyrosine kinase (JAK), and signal transducer and activator of transcription pathways (STAT) in response to cytokines and growth factors. Through extensive structure-based optimization, we identified I-0436650, a preclinical candidate with an excellent pharmacological profile. I-0436650 is a low nanomolar allosteric inhibitor of human wild-type (wt) SHP2 and strongly inhibits ERK phosphorylation in cells. It exhibits antiproliferative activity in EGFR- and RAS-dependent cell lines, suppresses tumor growth as a single agent in xenograft models, and delays tumor relapse when combined with inhibitors of the same pathway, demonstrating the potential of vertical inhibition strategies.

Rho-associated coiled-coil-containing kinase 2 (ROCK2) is a key regulator of cellular motility and invasion and represents a promising therapeutic target for metastatic breast cancer. Through systematic structure-activity relationship (SAR) studies, we designed and synthesized a novel series of 1-methyl-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-dione derivatives as selective ROCK2 inhibitors. Strategic deuterium incorporation during structural optimization was employed to enhance pharmacokinetic profiles. This effort led to the identification of compound 22d, a highly potent deuterated analog with excellent ROCK2 inhibitory activity (IC50 = 13 nM) and remarkable selectivity (≥769-fold over ROCK1). In functional assays, 22d exhibited robust antimetastatic activity in vitro and significantly suppressed tumor metastasis in MDA-MB-231 breast cancer xenograft models. Mechanistically, its antimetastatic effects were attributed to selective inhibition of STAT3 phosphorylation at tyrosine 705 (Y705). Collectively, these findings establish 22d as a novel lead compound that impairs breast cancer metastasis through targeted disruption of the ROCK2-STAT3 signaling axis, providing a promising foundation for further therapeutic development against metastatic breast cancer.

Selective lysine-specific demethylase 1 (LSD1) inhibition has emerged as a robust strategy for small cell lung cancer (SCLC) eradication. Herein, we describe the structural design, synthesis, and biological evaluation of novel reversible LSD1 inhibitors containing a carboxamido pyrazole core with a pyrrolidine-substituted phenyl ring. Notably, compound 10q demonstrated potent LSD1 inhibition with an IC50 value of 7.2 nM and effective H1417 cell growth inhibition with a GI50 value of 20.0 nM. Moreover, it showed notable selectivity against homologous proteins and demethylases. The oral administration of compound 10q demonstrated encouraging pharmacokinetic profiles and remarkable antitumor efficacy in the NCI-H1417 SCLC xenograft model using NOD/Shi-scid/IL-2Rγnull mice without notable toxicity. Furthermore, the potential of compound 10q is proposed by combinatorial therapy with chemotherapeutic agents for treating SCLC. Therefore, compound 10q can be considered a promising candidate as a selective and orally bioavailable LSD1 inhibitor.

Resistance to single-target therapies has spurred interest in multitarget strategies for acute myeloid leukemia (AML). Heat shock protein 90 (HSP90), a chaperone that stabilizes numerous oncogenic client proteins, represents an attractive therapeutic target for AML; however, the clinical development of early HSP90 inhibitors was limited by dose-limiting toxicities and an excessive heat-shock response (HSR). Through structural optimization of the marine aaptamine scaffold and target identification, ap-a48 was identified as a novel HSP90-targeting anti-AML lead that exhibits potent anti-AML activity and acceptable preliminary tolerability while inducing only a modest HSR. In rats, ap-a48 showed favorable pharmacokinetics with 65.3% oral bioavailability, and in HL-60 xenograft mouse models, it suppressed tumor growth (71.2% inhibition at intraperitoneal 40 mg/kg; 67.3% at oral 60 mg/kg) without significant hepatotoxicity or major organ abnormalities. These findings identify ap-a48 as a promising marine-natural-product-derived HSP90-targeting lead for AML therapy.

The development of cyclin-dependent kinase 7 (CDK7) inhibitors represents a promising therapeutic strategy for triple-negative breast cancer (TNBC). Herein, we designed and synthesized 21 novel CDK7-targeted small molecules and identified ZJC-11 as a potent lead candidate. ZJC-11 demonstrated significant antiproliferative activity against TNBC both in vitro and in vivo, with reduced toxicity compared to the reported CDK7 inhibitor THZ1. Molecular docking, Kinact/KI tests, kinase selectivity profiling, and pharmacokinetic studies confirmed that ZJC-11 selectively and covalently targets CDK7 with favorable pharmacokinetic properties. RNA sequencing and functional analyses revealed that ZJC-11 not only suppresses transcription and G2/M cell cycle checkpoint pathways but also induces DNA damage-driven cellular senescence, ultimately leading to TNBC cell death. Moreover, ZJC-11 not only exhibited a synergistic anti-TNBC effect when combined with doxorubicin but also alleviated doxorubicin-induced cardiotoxicity, a clinically significant adverse effect, highlighting its promise as a therapeutic candidate for TNBC treatment.

Age at diagnosis is an independent prognostic variable for breast cancer-specific and overall survival (OS). We previously developed a novel prognostic staging system that incorporates age and demonstrated refined risk stratification compared with the current American Joint Committee on Cancer (AJCC) staging schema. We now aim to externally validate this staging system.

This study aimed to links between ATP7B, CTR1, GPX4, 53BP1, p-H2AX and p-ATM expression, platinum sensitivity and prognosis in patients with epithelial ovarian cancer (EOC).

Accurate preoperative radiological assessment is essential in breast-conserving surgery (BCS) to achieve clear margins while minimizing unnecessary healthy tissue excision. Discrepancies between radiological and pathological tumor size may contribute to re-excision. This study evaluated factors associated with radiology-pathology discordance and their impact on re-excision.

R-loops are three-stranded nucleic acid structures comprising a DNA: RNA hybrid and a displaced single-stranded DNA strand. Their abnormal persistence can trigger transcription-replication conflicts, replication-fork stalling, DNA damage, chromosomal instability, inflammatory signalling, and epigenetic reprogramming. These effects are particularly relevant to colorectal cancer (CRC), which is frequently characterised by replication stress, defective DNA repair, genomic instability, and treatment resistance. This review summarises current evidence linking altered R-loop homeostasis to CRC initiation, progression, metastasis, molecular heterogeneity, and therapeutic response. We discuss key regulators with evidence in CRC or intestinal models, including RNASEH1/2, DDX21, DHX9, TOP1, POLD1/POLD3, and ATR, while distinguishing them from emerging mechanisms requiring CRC-specific validation. We also evaluate major R-loop detection strategies and their limitations. R-loop-associated vulnerabilities may influence responses to irinotecan, ATR/CHK1 and WEE1 inhibitors, PARP-related strategies, and immunotherapy. However, most evidence remains preclinical, highlighting the need for orthogonal detection methods, patient-derived models, and clinically annotated cohorts.