Bridging traditional knowledge and modern science: A systematic review of Ampelopsis japonica with emphasis on novel anti-cancer compounds, polypharmacology and clinical translation potential.

EZH2 (enhancer of zeste homologue 2) inhibitors are an emerging class of drugs that target epigenetic regulation. However, their efficacy in solid tumours has been limited, partly due to drug-induced upregulation of fatty acid synthesis. Combining lipid metabolic modulation with EZH2 inhibition may offer a promising strategy to enhance antitumor activity. We conducted a screen of clinically approved lipid-lowering drugs to identify candidates that could enhance the efficacy of EZH2 inhibitors and found that fenofibrate significantly potentiated the antitumor effects of EZH2 inhibition. Mechanistic studies revealed that this synergistic effect was associated with the degradation of EZH2 protein. To uncover the underlying regulatory pathway, we performed mass spectrometry analysis, which identified the E3 ubiquitin ligase TRIM21 and the deubiquitinase OTUD4 as key mediators of fenofibrate-induced EZH2 degradation. Fenofibrate significantly enhanced the antitumor effects of EZH2 inhibitors in melanoma, independent of its conventional lipid-lowering function. TRIM21 and OTUD4 were identified as critical mediators of this synergistic effect. Fenofibrate disrupted the non-canonical functions of EZH2 by promoting its destabilization, thereby exerting dual effects-inhibiting EZH2 enzymatic activity and accelerating its degradation. Combination therapy with fenofibrate and EZH2 inhibitors resulted in a potent synergistic suppression of tumour growth. Our findings reveal a previously unrecognized role for fenofibrate in augmenting EZH2-targeted therapy. This study provides a novel strategy to improve the efficacy of epigenetic therapies in cancer by combining EZH2 inhibitors with fenofibrate, offering potential clinical benefits for precision oncology.

Magnetic nanoparticles (MNP) have gained significant attention for their potential in cancer therapy, particularly in targeted drug delivery, imaging, and hyperthermia treatments due to their unique magnetic properties, biological compatibility and applicability. This literature review focuses on recent progress in the green-synthesized MNP, explores their mechanisms of drug delivery, and critically evaluates their clinical applicability. The gaps in the literature that this review addresses include the inconsistency in nanoparticle size and surface properties, the limitations in achieving sustained and predictable drug release, and the difficulties in maintaining long-term stability in physiological conditions. It also discusses potential future development, including smart nanotechnology, individual medicine, and AI-acquired platforms. These findings show how MNPs can increase precise oncology by increasing medical effect, reducing toxicity and lightweight real-time monitoring of treatments.

Colorectal cancer (CRC) adjuvant therapy is evolving from tumor-node-metastasis stage-based strategies toward molecular-profiling-guided precision medicine. This minireview, based on a comprehensive literature search in PubMed and Web of Science using keywords related to CRC biomarkers and adjuvant therapy (from 2010 to 2025), examines how key biomarkers, including mismatch repair (MMR) status, rat sarcoma viral oncogene homolog/rapidly accelerated fibrosarcoma mutations, consensus molecular subtypes, and circulating tumor DNA, refine risk stratification and treatment selection. Despite consensus guidelines advocating individualized therapy, significant disparities persist in real-world implementation due to technical variability in testing, limited or evolving evidence for specific scenarios (e.g. , adjuvant immunotherapy for MMR-deficient/microsatellite instability-high patients, wherein phase 3 trials such as ATOMIC have yet to report mature overall survival data), and health economic barriers. The minireview analyzes gaps across testing, decision-making, and dynamic monitoring phases, and proposes integrated solutions involving technological innovation (e.g. , artificial intelligence-integrated multiomics, circulating tumor DNA monitoring), optimized clinical pathways, and supportive health policies. Bridging these gaps requires multidisciplinary collaboration to translate molecular insights into equitable, personalized adjuvant care for CRC patients.

T cell senescence significantly impairs the efficacy of immune checkpoint blockade (ICB) therapy in cancer. Metabolic reprogramming is a crucial factor in T cell senescence in tumor microenvironment (TME). Ovarian cancer (OvCa) patients derive limited benefit from ICB treatment, probably related to T cell senescence. OvCa cells metastasize to the abdominal cavity rich in omental fat and raise ascites, forming a unique TME, adipocyte-rich TME. In this study, we investigated the effects of adipocyte-rich TME on T cell senescence. Using the single-cell RNA sequencing of OvCa and clinical samples, we found that adipocyte-rich TME is strongly associated with the formation of senescence CD8+T (CD8+Tsen) cells. Mechanistically, adipocyte-derived factors (MATES) and oleic acid (OA)-the predominant fatty acid in OvCa ascites-promoted tumor-induced CD8+Tsen formation by enhancing fatty acid (FA) uptake via FABP4, triggering lipid peroxidation rather than energy production. Inhibition of FABP4 (using the inhibitor BMS309403 or siRNA knockdown) blocked CD8+Tsen cell formation, reduced lipid peroxidation, restored CD8+T cell effector function, and suppressed immunosuppressive cytokines. Moreover, using an OvCa mouse model, we found that in OvCa mice BMS309403 treatment partially diminished CD8+Tsen formation by reducing FA uptake, and improved anti-tumor immunity, and prolonged the survival time of OvCa mice when combined with chemotherapy. Our work suggests FABP4-mediated FA metabolism as a therapeutic target to counteract T cell senescence in adipocyte-rich TME, providing a novel immunotherapeutic strategy for OvCa.

Traditional Chinese Medicine (TCM) and ultrasound-based therapy techniques have emerged as viable complementary approaches to cancer treatment, since both have modulatory effects on the tumor microenvironment (TME). TCM is distinguished by its multicomponent and multitarget processes, whereas ultrasonic treatments provide noninvasive biophysical modification to improve medication transport, immunological activation, and vascular permeability. Despite growing recognition of the synergistic potential of these modalities, no comprehensive bibliometric examination of their confluence in TME research has yet been done. CiteSpace and VOSviewer were used to evaluate publications from the Web of Science Core Collection spanning from 2014 to 2024. A total of 771 relevant publications were used to create visual knowledge maps, highlight research hotspots, collaborative networks, and emerging trends, with a particular emphasis on studies that combined TCM and ultrasonography in cancer-related TME regulation. Over the last decade, research at the interface of TCM and ultrasonic therapy has expanded rapidly. China has dominated this sector in terms of publication volume and worldwide influence, with strong partnerships with the United States and the United Kingdom. The core institutions include the Shanghai University of Traditional Chinese Medicine, Guangzhou University of Chinese Medicine, Zhejiang University, Shanghai Jiao Tong University, and the Chinese Academy of Sciences. The research field has shifted from basic studies on "cell proliferation" and "apoptosis" to more sophisticated inquiries into "immune microenvironment regulation," "ultrasound-assisted drug delivery," "nanomedicine," and "synergistic therapy." The combination of TCM and ultrasonic therapy in TME research represents a new multidisciplinary frontier that combines molecular biology, materials science, and clinical oncology. This bibliometric and knowledge atlas study emphasizes the expanding body of data supporting ultrasound-enhanced TCM therapies as a promising paradigm in cancer therapy. To fully realize their combined promise in precision oncology, future initiatives should focus on mechanistic validation, standardized clinical evaluation, and worldwide collaboration.

Cancer therapies have well-documented adverse effects on cardiovascular and respiratory health which could increase cancer survivors' susceptibility to poor air quality. We describe the risk of cardiovascular and respiratory healthcare visits following acute air pollution exposures among adolescent and young adult (AYA) cancer survivors. We identified all Utah AYAs diagnosed at 15-39 years of age with thyroid, melanoma, lymphoma, breast, or testicular cancer from 1998-2016 (N=8,016). AYAs were linked by residential location to daily particulate matter (PM2.5), nitrogen dioxide (NO2), and ozone (O3) for 2000-2016. Case-crossover models in a distributed lag non-linear model framework estimated odds ratios (ORs) and 95% confidence intervals (95% CIs) for cardiovascular and respiratory healthcare visits with exposure over the 6 days preceding an event, adjusting for temperature and relative humidity. A total of 3,143 AYAs (39%) experienced ≥1 respiratory/cardiovascular event. O3 was associated with cardiovascular events (ORlag4=1.08, 95% CI: 1.02-1.14; ORlag5=1.05, 95% CI:1.01-1.09) and NO2 was associated with respiratory events (ORlag1=1.05, 95% CI: 1.01-1.10). Breast cancer survivors showed elevated risk for cardiovascular and respiratory visits; melanoma, lymphoma, and testis survivors displayed increased risk for cardiovascular visits. O3 was linked with elevated risk of cardiovascular events while respiratory events were associated with NO2. Associations between air pollutants and healthcare visits varied by primary diagnosis site, indicating that susceptibility to air pollution could differ due to cancer-specific treatment factors. AYAs face increased risk for cardiovascular and respiratory events with exposure to ambient air pollution and may benefit from interventions to reduce exposures.

Epidermal growth factor receptor (EGFR) mutation is a significant driving factor in the occurrence and progression of lung cancer. How to effectively block the abnormal expression of EGFR remains a key issue that urgently needs to be addressed, as it is of vital importance for the effective treatment of this cancer. Here, we report a recombinant targeted bionanoparticle that in vitro expresses Cas9 protein (tBioNP vitro-Cas9) for gene editing of EGFR mutant lung cancer. The nanoparticle was developed by transfection of four plasmids (Gag-Cas9, Gag, sgRNA, VSV-G Azi) into 293T cells to form a type of bionanoparticle and modifying it with a targeted polymer material (DBCO-PEG-FA), and it showed a cancer-targeted property, faster cancer cellular uptake, higher gene editing efficiency with lower off-target effects, and therapy efficacy in mice, indicating a translational prospect. In conclusion, the study provides a recombinant bionanoparticle in vitro expressing a Cas9 gene editing system and offers a potential strategy for gene therapy of EGFR mutant lung cancer.

Radical cystectomy (RC) with pelvic lymphadenectomy followed by urinary diversion is the standard treatment for muscle-invasive bladder cancer (MIBC). Perioperative systemic therapy can improve the oncological outcome of RC. Despite the use of modern surgical techniques, RC is still associated with ahigh rate of perioperative complications and reduced quality of life. As an alternative to RC, organ preserving trimodal therapy can be performed in selected patients. In light of newer and more effective systemic therapies and the associated higher response rates to neoadjuvant systemic therapy, interest in novel organ-preserving concepts for appropriate patients with MIBC has increased. These approaches aim to better preserve quality of life while achieving oncological outcomes that are at least comparable to those of RC. Clinical re-evaluation after initial systemic therapy requires establishment of robust surrogate parameters for complete pathological and systemic response. To this end, existing combined restaging methods (transurethral resection of bladder tumor [TUR-BT], urinary diagnostics, imaging techniques, liquid biopsies) need to be further developed and validated. This narrative review outlines current developments and challenges that must be considered for the successful implementation of organ-preserving approaches in MIBC and defines the prerequisites under which organ preservation may be feasible.

Selpercatinib and pralsetinib are targeted therapies for non-small cell lung cancer. However, their adverse reaction profiles remain incompletely understood. This study aims to evaluate the post-marketing adverse events (AEs) associated with selpercatinib and pralsetinib in real-world populations. We conducted a comprehensive analysis of AEs linked to selective RET inhibitors using advanced data mining techniques on the FDA Adverse Event Reporting System. Disproportionality analysis was performed to quantify the association between these drugs and AEs. Key metrics for disproportionality assessment included the reporting odds ratio (ROR), proportional reporting ratio, information component, and empirical Bayesian geometric mean. A total of 522 and 917 AE reports were identified for selpercatinib and pralsetinib in lung cancer patients, with 209 and 312 preferred terms recorded for each drug. The most frequent AEs for selpercatinib included hepatobiliary disorders (ROR=10.71) and cardiac disorders (ROR=2.33). For pralsetinib, the most common AEs were hepatobiliary disorders (ROR=2.57) and gastrointestinal disorders (ROR=1.53). Compared to pralsetinib, selpercatinib had a more increased risk of serious outcomes (P<0.05). This study provides critical insights into the established and potential adverse events associated with selpercatinib and pralsetinib. The findings offer valuable evidence to guide the clinical use of RET inhibitors.

Background and Objectives: Gynecological cancers frequently require radiation therapy (RT) in primary, adjuvant, or salvage settings. However, photon-based RT is associated with non-negligible toxicity, and treatment of pelvic recurrences after prior irradiation remains challenging. Proton beam therapy (PBT), due to its favorable dose distribution and reduced exposure of organs at risk (OARs), has emerged as a potential alternative, particularly in re-irradiation scenarios. Despite its expanding use in other malignancies, evidence supporting PBT in gynecologic cancers remains limited. This systematic review aims to investigate the use of PBT in gynecological cancers and its associated complications. Materials and Methods: This systematic review was conducted according to PRISMA guidelines and registered in PROSPERO. A comprehensive search (2000–2025) identified studies investigating PBT in gynecologic cancers. Eligible designs included randomized trials and prospective and retrospective series. Reported adverse events were categorized as GI, GU, or other, and only grade ≥3 CT-CAE complications were considered. Results: Of 580 records screened, 9 studies comprising 232 patients met inclusion criteria. Most patients were treated for endometrial (n = 147) or cervical (n = 75) cancer; 90 received chemotherapy. Overall, severe toxicity occurred in 15.2% of patients. GI complications ranged from 0–14% and GU from 0–33%. Complication rates were lowest in adjuvant or de novo treatment series (0–10%), whereas re-irradiation cohorts showed higher rates (up to 33% GU). Comparative studies suggested a possible advantage of PBT over IMRT, particularly for GI toxicity, though data remain limited. Conclusions: Severe GI and GU toxicity after PBT in gynecologic cancers appears infrequent, particularly in primary and adjuvant settings, though re-irradiation remains challenging. Current evidence is restricted to small and heterogeneous studies. Ongoing phase II trials will provide prospective data to clarify feasibility, toxicity, and long-term outcomes. Until then, PBT in gynecologic oncology should be regarded as investigational.

The efficacy of cancer therapies is often limited by inefficient drug delivery due to the highly heterogeneous tumor microenvironment (TME) and various cellular resistances, such as uptake and lysosomal escape. To overcome these challenges, we designed and synthesized three integrated polyesters through BODIPY-initiated ring-opening block copolymerization, BSN1-BSN3, which incorporate an SN38 prodrug and a cationic positively charged ([12]aneN3) unit. The optimized polyester BSN3 was co-assembled with DOPE, DSPE-PEG-iRGD, and Bcl-2-siRNA into multifunctional nanoparticles, BSN3-DR/Bcl-2 siRNA NPs. This system achieves spatiotemporally controlled activation within tumors through iRGD-mediated targeting for enhanced cellular uptake, followed by 660nm light-triggered photochemical internalization (PCI) to enable lysosomal escape, as well as high GSH/esterase-triggered disassembly of NPs for sequential release of siRNA and SN38. The combination of Bcl-2 protein silencing, chemotherapy, and PDT led to significant tumor growth inhibition at 95% in vivo in HCT116 models, without observable systemic toxicity. This work not only presents a novel cascade-responsive combination strategy to overcome the limitations of monotherapy and physical combination of different therapeutic components but also offers valuable experimental evidence and theoretical support for the development of highly efficient and safe polymeric nanodrugs.

Triple-negative breast cancer (TNBC) remains a formidable clinical challenge due to its aggressive phenotype and limited therapeutic options. Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, is evolving as a highly promising approach to combat TNBC. However, tumor cells deploy redundant ferroptosis defense systems including glutathione peroxidase 4 (GPX4) and dihydroorotate dehydrogenase (DHODH) systems to evade this lethal process. Here, doxorubicin (DOX) and teriflunomide (Tfm) were used as therapeutic building blocks for the self-assembly of tumor-targeting, excipient-free nanoassemblies (DoT) that enhance ferroptosis induction in TNBC. After being trapped in cancer cells, the FDA-approved antitumor drug DOX could not only disrupt the GPX4 defense system by inhibiting Nrf2 but also ignite an intracellular reactive oxygen species storm to unleash a lipid peroxidation spark. Simultaneously, Tfm further devastated the intracellular ferroptosis defense system by suppressing DHODH and crippling the radical-trapping antioxidant capacity, thus evoking robust ferroptotic cell death in TNBC cells. The work presents a synergistic co-disruption strategy against dual ferroptosis defense systems, exhibiting significant potential for clinical applications.

Wilms' tumor 1-associated protein 1 (WTAP) is an epitranscriptomic regulator with multifaceted roles in cancer biology. Acting beyond its function in the m6A methyltransferase complex, WTAP governs RNA splicing, stability, and translation, influencing oncogenic signaling, immune modulation, and therapy resistance. Recent evidence reveals its dynamic involvement in diverse malignancies, where it can act as both an oncogene and tumor suppressor depending on the cellular context. WTAP promotes tumor progression through epithelial-mesenchymal transition (EMT), metabolic reprogramming, angiogenesis, and immune evasion, and contributes to resistance against chemotherapy and immunotherapy by regulating DNA repair, ferroptosis, and immune checkpoint pathways. However, studies have also demonstrated that WTAP can exert tumor-suppressive effects under specific physiological conditions, such as hepatocyte-specific WTAP loss leading to extracellular-signal regulated kinases (ERK)-driven hepatocarcinogenesis, and WTAP-mediated m6A regulation restraining oncogenic signaling in some prostate cancers. Moreover, by enhancing ferroptosis resistance, WTAP may weaken ferroptosis-driven antitumor immunity and contribute to immune-checkpoint resistance. Understanding these mechanisms offers opportunities for exploiting WTAP as a biomarker and therapeutic target across multiple cancer types. This review explores the multifaceted role of WTAP in cancer, focusing on its mechanisms of action in tumorigenesis, immune modulation, and therapy resistance, and offers insights into potential therapeutic strategies targeting WTAP in cancer treatment.

Covalent organic frameworks (COFs) represent a rapidly expanding class of porous crystalline materials with exceptional potential in cancer diagnosis and therapy. Their ordered π-conjugated backbones, tunable pore architectures, and abundant functional sites provide unique advantages for drug loading, controlled release, and biointerfacing. Unlike conventional porous carriers, COFs exhibit intrinsic optical, electrical, and chemical properties that enable them to act both as delivery scaffolds and as active therapeutic platforms. Recent advances demonstrate their integration into drug delivery systems, photodynamic therapy (PDT), photothermal therapy (PTT), biosensing, and bioimaging. In cancer sensing and imaging, nanoscale COFs improve probe stability, enhance detection sensitivity, and enable responsive diagnostic platforms with reduced signal quenching. Furthermore, COFs can stabilize or directly function as photosensitizers and photothermal agents, thereby facilitating multimodal, imaging-guided therapeutic interventions. Despite these advances, key challenges remain, including scalable synthesis, long-term biocompatibility, precise drug-release control, and overcoming tumor heterogeneity. This review highlights emerging strategies to optimize COF stability, pore design, and functionalization, while exploring their potential applications across oncology. Finally, perspectives on clinical translation underscore the importance of interdisciplinary approaches to position COFs as next-generation platforms for precision cancer medicine, addressing urgent needs in early detection, therapeutic resistance, and metastasis management. Finally, the unique properties of COFs make them promising applicants for improving therapeutic products in cancer treatment.

Cisplatin (CIS) remains a cornerstone of chemotherapy but is limited by resistance and systemic toxicity. Combining DNA-damaging agents with epigenetic modulators such as vorinostat (VOR) offers a promising strategy to enhance efficacy. However, the co-delivery of these drugs is challenging due to their distinct physicochemical properties. The aim was to develop and characterize niosomal nanoparticles co-loaded with CIS and VOR (NIO-CIS-VOR) and to assess their physicochemical characteristics and in vitro anticancer activity. Niosomes were prepared using ethanol injection, with CIS entrapped in the aqueous core and VOR in the lipid bilayer. Characterization included particle size, polydispersity index (PDI), and zeta potential by DLS, morphology by TEM, and encapsulation confirmation by FTIR. Encapsulation efficiency (EE%) and drug release were determined by HPLC. Cytotoxicity, caspase-3/7 activation, colony formation, and wound healing assays were conducted in HT-29, A549, and PANC-1 cancer cell lines. Optimized NIO-CIS-VOR nanoparticles exhibited a mean diameter of 152.7 nm, PDI of 0.12, and zeta potential of -9.79 mV, with spherical morphology. Encapsulation efficiency of NIO-CIS-VOR reached 89.3% for CIS and 52.1% for VOR. The formulation showed sustained release over 72 h, with cumulative release of 62% (CIS) and 38% (VOR) at 6 h. Cytotoxicity assays demonstrated markedly reduced IC50 values for NIO-CIS-VOR compared with free drugs: 1.8 µM vs. 4.47 µM (CIS) and 3.4 µM (VOR) in HT-29; 0.95 µM vs. 3.8 µM and 3.1 µM in A549; and 2.37 µM vs. 13.9 µM and 3.66 µM in PANC-1. Enhanced apoptosis and reduced colony formation further confirmed superior anticancer activity.In Conclusion the Co-loaded niosomes achieved efficient co-delivery, sustained release, and synergistic anticancer effects, highlighting NIO-CIS-VOR as a promising nanocarrier for combination cancer therapy.

Colorectal cancer (CRC) remains difficult to eradicate locally because chemotherapy, photothermal therapy (PTT), and radiotherapy each have distinct limitations when used alone. Here, we engineer an injectable, mucoadhesive hydrogel-mediated tri-modal nanoplatform designed for localized CRC therapy by integrating smart chemotherapy delivery with externally activatable PTT and radiosensitization. Core-shell AuNP@mesoporous silica nanoparticles were loaded with 5-fluorouracil (5-FU) and functionalized with a pH/ROS-responsive linker and hyaluronic acid (HA) to enable CD44-mediated tumor targeting and microenvironment-triggered "uncapping"/drug release. The targeted nanocarriers were embedded within a chitosan/acellular fish skin (CS/AFS) hydrogel to form a local depot intended to prolong tumor-site residence and reduce systemic exposure. In vitro, the complete nine-group panel demonstrated stepwise gains from targeting, hydrogel confinement, and external activation. The tri-modal condition (Gel-tNP + 808-nm NIR + 2-Gy X-ray) produced the strongest cytotoxicity, approaching near-complete ablation in HCT-116 cells and reproducing the efficacy hierarchy in a second CRC line (SW480), while normal colon epithelial cells (NCM460) maintained higher viability across matched conditions, supporting an initial therapeutic window. Mechanistically, the tri-modal regimen generated the highest intracellular ROS levels, amplified early γH2AX DNA double-strand break signaling and increased damage persistence, and drove extensive cell death consistent with synergistic chemo-photothermal-radiotherapy action (e.g., ~ 9% viability and ~ 5.6-fold LDH release vs. control in the tri-modal group). Collectively, this work advances an engineering framework for localized, externally programmable tri-modal CRC therapy using a stimuli-responsive, HA-targeted nanocarrier embedded in an injectable bioadhesive hydrogel depot.

IgG4 monoclonal anti-CD47 for cancer immunotherapy resulted in anemia necessitating red cell (RBC) transfusions. Although the antibody readily binds to CD47 on RBCs, the mechanism underlying the anemia associated with IgG4 is poorly understood. We investigated samples from patients receiving Hu5F9-G4 (magrolimab) with positive reactivity in compatibility tests using a monocyte-monolayer assay (MMA). For RBC opsonization, patient plasma was diluted to avoid direct agglutination and to give a 4+ indirect antiglobulin test (IAT) and >103 mean fluorescent intensity (MFI) by flow cytometry. Fcγ receptor blocking used F(ab')2 antibodies. Antibody-dependent cellular cytotoxicity (ADCC) used purified natural killer (NK) cells. Recombinant IgG4 anti-K and polyclonal anti-D were tested by MMA concurrent with blocking of CD47 with a deglycosylated antibody. Five of six samples showed significant erythrophagocytosis (phagocytosis index [PI] = 20-60; PI > 5 clinically significant) with the exception having 30-fold lower MFI. Phagocytosis was not increased in the presence of complement. Fcγ receptor blocking showed FcγRI and FcγRIIa were involved but not FcγRIIIa, supported by negative results when tested for NK ADCC. IgG4 anti-K also showed significant erythrophagocytosis (PI = 30). Blocking of CD47 increased phagocytosis, 1.7 to 3.9-fold, respectively, of RBCs opsonized with IgG4 anti-K or polyclonal anti-D. IgG4 RBC antibodies, generally not considered clinically significant for transfusion, can result in erythrophagocytosis providing an explanation for anemia related to anti-CD47 mediated by FcγRI and FcγRIIa. Enhanced phagocytosis of alloantibody-coated RBCs with concurrent blocking CD47 suggests potential for enhanced complications for patients who develop RBC alloantibodies while receiving cancer therapies targeting CD47.

ABSTRACT Introduction Endoglin has been extensively studied as an anti-angiogenic target, with preclinical work highlighting its critical role in tumor vasculature. TRC105 (carotuximab), a monoclonal antibody against endoglin, progressed through multiple clinical trials and was well tolerated, yet outcomes were disappointing, revealing a gap between preclinical findings and patient benefit. Recent insights into endoglin biology in the tumor microenvironment suggest that more precise, informed strategies are needed to fully realize its therapeutic potential. Areas covered This review summarizes key advances in endoglin biology, including its endothelial and non-endothelial roles and context-dependent effects across tumor and stromal compartments. We discuss preclinical therapeutic strategies and clinical trial experience with TRC105 and examine the translational challenges and future considerations needed to achieve potential clinical benefit. Expert opinion Preclinical studies have greatly advanced our understanding of endoglin biology, but the key challenge lies in identifying the biologic context where endoglin drives tumor progression. Future progress requires a deeper mechanistic resolution of endoglin’s roles across tumor type and disease stage, along with the development of biomarkers incorporating spatial expression patterns. Successful translation will depend on matching endoglin-targeted therapy to patients and tumor ecosystems most likely to benefit, shifting from broad anti-angiogenic application to precision stromal targeting.

Gut microbiota has emerged as a determinant of cancer therapy efficacy, shaping immune responses both systemically and locally within the tumor microenvironment. In this piece, we discuss current insights into the mechanistic basis of these interactions, with a focus on type I interferon as a central mediator of microbiota-driven immune modulation.