Heterocyclic compounds are a common subject in the field of medicinal chemistry due to their numerous pharmaceutical applications. Among these, nitrogen- and oxygen-containing five-membered heterocyclic rings, namely oxazole and isoxazole, are particularly significant, exhibiting a broad spectrum of biological activities. Molecular hybridization, the process that enables the fusion of bioactive scaffolds, is a powerful strategy for the development of novel compounds characterized by enhanced or multitarget activities. This review focuses on hybrids incorporating linked oxazole and/or isoxazole moieties (i.e., isoxazole-oxazole and isoxazole-isoxazole hybrids), drawing upon peer-reviewed research articles and international patents from 1995 to the end of 2024. The overview systematically presents the diverse biological activities reported for the isoxazole-(iso)oxazole hybrids, including anticancer, antibacterial, antitubercular, anti-inflammatory, and antidepressant effects, alongside their corresponding chemical structures. Our analysis of the literature highlights the structural versatility and therapeutic potential of this important class of heterocyclic hybrids.

Poloxamer 188 is a polymer that is used as a carrier and stabilizer of pharmacological agents. It has been demonstrated to enhance red blood cell and hemoglobin levels in healthy animals and in select clinical cases. The objective of this study was to assess the efficacy of Poloxamer 188 in CBA mice when administered repeatedly in the carboplatin-induced myelosuppression model. The mice were administered carboplatin once at a dose of 100 mg/kg, and then Poloxamer 188 was orally administered daily at doses of 10 mg/kg, 100 mg/kg, 500 mg/kg, and 1000 mg/kg for 7 and 21 days. Poloxamer 188 at a dose of 1000 mg/kg was found to bring the level of 2,3-bisphosphoglycerate in red blood cells close to control level (p = 0.1331 for the control group compared to Poloxamer at a dose 1000 mg/kg) already from day 8 of the study and in bone marrow resulted in regulation of genes responsible for hematopoiesis. G-GSF at day 8 and TNFα at day 22 gene expression was significantly decreased by 54% (p = 0.012) and 16% (p = 0.024), respectively, with Poloxamer 188 administration at a dose of 100 mg/kg. Additionally, in the bone marrow, the treatment was seen to exert a positive regulatory effect on the genes responsible for hematopoiesis. These findings are consistent with the observed increase in red blood cell by 6.7% (p = 0.001), hemoglobin by 4.7% (p = 0.0053), and reticulocyte percentage by 53.6% (p < 0.0001) following Poloxamer 188 administration at a dose of 1000 mg/kg in CBA mice with myelosuppression.

The blood-brain barrier (BBB) is a highly selective interface between the bloodstream and the brain that prevents systemically administered therapeutics from effectively reaching tumor cells. As tumors progress, this barrier undergoes structural and functional alterations, giving rise to the blood-tumor barrier (BTB)-a pathologically modified structure that, despite increased permeability, often exhibits heterogeneous and clinically insufficient drug transport. Although a new generation of therapies is promising, their therapeutic potential cannot be realized unless the challenges posed by these barriers are effectively addressed. Various pharmacological strategies were explored to enhance brain tumor drug delivery. These include receptor-mediated disruption, inhibition of efflux transporters, and the engineering of delivery platforms that leverage endogenous transport pathways-such as carrier-mediated, adsorptive-mediated, and receptor-mediated mechanisms-as well as cell-mediated drug delivery. This review synthesizes (1) the BBB and BTB's structural characteristics; (2) the influence of the tumor microenvironment (TME) on drug delivery; (3) pharmacological strategies to enhance drug accumulation within brain tumors; (4) the integration of pharmacological methods with neurosurgical techniques to enhance drug delivery. As efforts to improve drug delivery across the BBB and BTB accelerate, this review aims to map the current landscape of pharmacological approaches for enhancing drug penetration into brain tumors.

EGFR is the most frequently altered driver gene in non-small-cell lung cancer (NSCLC), and its overexpression is also associated with breast cancer. In the present study, we synthesized 18 new compounds (B-1, B-2, B-6, B-7, and BP-1-14). The cytotoxicity of these compounds was evaluated in A549 NSCLC and MCF-7 breast cancer cells, as well as in Jurkat cells and PBMCs (healthy). The most potent compounds were further examined for their ability to induce apoptosis in A549 and MCF-7 cells, as well as their EGFR inhibitory activity. Molecular docking was conducted at the ATP-binding site of EGFR, and key pharmacokinetic and toxicity parameters were predicted in silico. B-2 demonstrated the strongest cytotoxicity against A549 and MCF-7 cells (IC50 = 2.14 ± 0.83 μM and 8.91 ± 1.38 μM, respectively), displaying selective cytotoxicity between Jurkat cells and PBMCs (SI = 23.2). B-2 induced apoptosis in A549 and MCF-7 cells at rates of 16.8% and 4.3%, respectively. B-2 inhibited EGFR by 66% at a 10 μM concentration and showed a strong binding affinity to the ATP-binding site of EGFR. Furthermore, B-2 exhibited drug-like characteristics and was not identified as carcinogenic, genotoxic, or mutagenic. B-2 shows promise as an apoptosis inducer and EGFR inhibitor for future anti-NSCLC and anti-breast cancer research.

Background/Objectives: Vitex agnus-castus has been traditionally used to treat hormonal disorders, and recent evidence suggests its potential anticancer properties. However, its effects on gastric cancer remain unclear. Methods: This study examined the cytotoxic, apoptotic, and anti-metastatic effects of hydroalcoholic Vitex agnus-castus seed extract in gastric cancer cells. Antioxidant capacity (DPPH, ABTS) and total phenolic and flavonoid contents were analyzed. Cytotoxicity was assessed using the MTT assay in HGC27, MKN45, and AGS gastric cancer cell lines and CCD-1072Sk fibroblasts. Apoptosis, mitochondrial membrane potential (MMP), and cell cycle changes were evaluated via Annexin V-FITC/PI, Rhodamine 123, and PI staining, respectively. RT-qPCR and gene enrichment analyses were conducted to investigate the molecular mechanisms. Apoptosis-related protein expression was analyzed through enzyme-linked immunosorbent assay (ELISA). Results: The extract exhibited high antioxidant activity and a significant phenolic and flavonoid content. It reduced cell viability in a dose-dependent manner in gastric cancer cells, while exerting low toxicity in fibroblasts. It significantly increased apoptosis, induced G0/G1-phase cell cycle arrest, upregulated pro-apoptotic genes (CASP3, CASP7, TP53, BCL2L11), and downregulated anti-apoptotic genes (XIAP, NOL3). Gene enrichment analysis highlighted pathways like apoptosis, necrosis, and cysteine endopeptidase activity. The extract also disrupted MMP, inhibited migration and spheroid formation, suppressed EMT markers (SNAIL, SLUG, TWIST1, N-CADHERIN), and upregulated E-CADHERIN. The expression of Caspase 3 and Bax proteins increased and Bcl2 protein decreased. Conclusions: These findings suggest that Vitex agnus-castus seed extract exerts strong anticancer effects in gastric cancer cells by promoting apoptosis, reducing proliferation, and inhibiting migration. Further studies are warranted to explore its clinical relevance.

Background/Objectives: This study evaluated the in vitro probiotic potential of Lactiplantibacillus plantarum Probio87 (Probio87), focusing on its physiological robustness, safety, antimicrobial properties, and anticancer activity, with relevance to vaginal and cervical health. Methods: Tests included acid and bile salt tolerance, mucin adhesion, and carbohydrate utilization. Prebiotic preferences were assessed using FOS, GOS, and inulin. Antibiotic susceptibility was evaluated per EFSA standards. Antimicrobial activity of the cell-free supernatant (CFS) was tested against Staphylococcus aureus, Escherichia coli, and Candida species. Effects on Lactobacillus iners and L. crispatus were analyzed. Anticancer properties were assessed in HeLa, CaSki (HPV-positive), and C-33A (HPV-negative) cervical cancer cell lines through proliferation, apoptosis, angiogenesis, and cell cycle assays. Results: Probio87 showed strong acid and bile tolerance, efficient mucin adhesion, and broad carbohydrate utilization, favoring short-chain prebiotics like FOS and GOS over inulin. It met EFSA antibiotic safety standards. The CFS exhibited potent antimicrobial activity, including complete inhibition of Candida albicans. Probio87 selectively inhibited L. iners without affecting L. crispatus, indicating positive modulation of vaginal microbiota. In cervical cancer cells, the CFS significantly reduced proliferation and angiogenesis markers (p < 0.05), and induced apoptosis and cell cycle arrest in HPV-positive cells, with minimal effects on HPV-negative C-33A cells. Conclusions: Probio87 demonstrates strong probiotic potential, with safe, selective antimicrobial and anticancer effects. Its ability to modulate key microbial and cancer-related pathways supports its application in functional foods or therapeutic strategies for vaginal and cervical health.

Background/Objectives: Colorectal cancer (CRC) is among the most prevalent malignant neoplasms globally. Chemotherapeutic treatment strategies have demonstrated minimal improvement over the past decade. Combination therapies, including those with nutraceuticals, are currently being investigated as promising alternatives to enhance therapeutic efficacy. The organosulfur garlic extract diallyl disulfide (DADS) has demonstrated anti-tumoral activity in several types of cancer. This study aimed to investigate the effects of DADS and 5-fluorouracil (5-FU), both individually and in combination, on the human CRC cell lines Caco-2 and HT-29. Methods: Caco-2, HT-29, and non-tumoral human umbilical vein endothelial cells (HUVEC) were exposed to DADS (25-600 µM) and 5-FU (5-100 µM), either individually or in simultaneous combination (DADS 100 µM + 5-FU 100 µM), for 24 h. Cytotoxicity was evaluated in all three cell lines. In addition, the effects of these treatments on oxidative stress, cell migration, genotoxicity, cell death, global DNA methylation, and gene-nutraceutical interactions were assessed in both tumor cell lines. Results: DADS demonstrated cytotoxic effects at high concentrations in Caco-2, HT-29, and HUVECs and induced DNA damage in both colorectal cancer cell lines. The combination of DADS and 5-FU significantly promoted apoptotic cell death, increased genotoxicity, elevated global DNA methylation, and inhibited cell migration, with these effects being particularly pronounced in HT-29 cells. Conclusions: We provide evidence that DADS combined with 5-FU is potentially useful in the therapy of CRC. However the combination of nutraceuticals and chemotherapy must consider the distinct molecular and phenotypic characteristics of each tumor cell line.

Urtica Dioica (UD) or stinging nettle has been widely used for its therapeutic benefits and biological activities. Recent studies have reported its beneficial effect in treating cancer, most importantly when combined with chemotherapeutic drugs. To our knowledge, no studies investigated the potential effect of UD to enhance the sensitivity of ovarian cancer cells to cisplatin. In this study we aim to investigate whether this combination might possess anti-proliferative, pro-apoptotic, and anti-metastatic properties on one of the most aggressive ovarian cancer cell lines, SKOV-3 cells, in vitro. To elucidate its therapeutic values, cytotoxicity and DNA fragmentation assays were performed along with cell cycle and apoptosis assays using flow cytometry, RT-qPCR, and western blot analysis. Additionally, wound healing and trans-well migration assays were used to study the effect of this combination on the motility of ovarian cancer cells. Results showed that the combination of nettle extract and cisplatin significantly decreased the proliferation of SKOV-3 cells in a dose and time-dependent manner compared to each treatment alone by inducing cellular death as revealed by major apoptotic markers including phosphatidylserine translocation to the outer membrane leaflet, DNA fragmentation, and the upregulation of cleaved PARP protein. Further evaluation verified the activation of extrinsic apoptosis via the caspase-dependent pathway as demonstrated by the upregulated expression levels of caspases 3 and 8. Finally, the combination of nettle tea and cisplatin showed an inhibitory effect on the motility and migratory capacities of SKOV-3 cells. As a result, Urtica Dioica leaf infusion was found effective in enhancing cisplatin-induced apoptosis while inhibiting the tumor progression of one of the most aggressive ovarian cancer cells in vitro.

Poly (ADP-ribose) polymerase (PARP) inhibitors (PARPis) are effective agents in different tumor types. A typical class of adverse events (AEs) associated with these agents, often leading to treatment modifications and discontinuations of treatment, is hematological toxicity. In our systematic review and safety meta-analysis, we investigated the incidence and risk of all grades and ≥ grade (G) 3 hematological AEs, including anemia, neutropenia, thrombocytopenia, and acute myeloid leukemia (AML)/myelodysplastic syndrome (MDS) due to PARPis, used alone or in combination, in patients diagnosed with solid tumors. This systematic review and meta-analysis followed the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement. We systematically searched the PubMed, EMBASE, and Cochrane databases, the American Society of Clinical Oncology, and the European Society of Medical Oncology meeting abstracts for randomized clinical trials (RCTs) concerning the use of PARPis in patients with solid tumors. The search deadline was April 30, 2024. We calculated risk ratios (RRs) for all-grade and ≥ G3 AEs of PARPis versus non-PARPis. 31 phase II/III RCTs were included. Anemia was the most common all-grade (49.2%) and ≥ G3 AE (25.0%). The administration of PARPis significantly increased the risk of developing all grades of anemia (RR = 2.15, p < 0.00001), neutropenia (RR = 1.50, p = 0.0002), and thrombocytopenia (RR = 2.59, p < 0.00001) compared to non-PARPis. Similarly, a significant increase in the risk of ≥ G3 anemia (RR = 5.43, p < 0.00001), neutropenia (RR = 1.70, p = 0.002), and thrombocytopenia (RR = 5.42, p < 0.00001) was detected. PARPis did not increase the risk of AML/MDS (p = 0.86). PARPis increase the risk of hematologic toxicity compared to other treatments in solid tumors. Clinicians should be aware of this risk, especially given the expected increase in PARPis use in the next year in different tumor types.

Herein, we report graphene nanosheets fabricated using liquid-phase exfoliation of graphite employing cetyltrimethylammonium chloride (CTAC) in an aqueous medium. The salient features of CTAC-assisted graphene nanosheets are as follows: (i) the concentration of graphene dispersed in water is found to be 26.01 mg/mL at 50 mg with a Critical Micelle Concentration (CMC) Value of 3 mg/mL (9.375 mM); (ii) rapid exfoliation is assisted by CTAC via sonication, which develops hydrophilic micelles on graphitic surface; (iii) the strong repulsive force of CTAC prevents re-aggregation of graphene sheets by means of electrostatic interaction as revealed by zeta potential measurement (+ 33.8 mV); (iv) the graphene nanosheets display excellent anticancer properties against MCF-7 (IC50 - 205.5 ng/mL) and MDA-MB-231 (IC50 - 216.9 ng/mL) breast cancer cells; (v) the CTAC assisted graphene nanosheets induce PI3K/Akt mediated apoptosis in breast cancer cells. Based on the results, CTAC-assisted graphene nanosheets are expected to be a potential candidate for therapeutic applications in the near future.

Many studies have reported the aberrant expression of lncRNAs and indicated their role in cancer progression and drug resistance across various cancers. In this study, we aimed to evaluate the effect of LINC00162 lncRNA on the chemosensitivity of thyroid cancer cells, both individually and in combination with sorafenib, on various biological processes. In this regard, we conducted our experiments in several groups: (1) LINC00162 siRNA-transfected cells, (2) Sorafenib-treated cells, (3) Cells that received both siRNA transfection and sorafenib treatment (4) Control group. MTT assay results revealed that siRNA-mediated silencing of LINC00162 reduced the viability of the B-CPAP thyroid cancer cells and increased the sensitivity of these cells to sorafenib by reducing its IC50. Flow cytometry analysis of apoptosis and cell cycle progression indicated that LINC00162 silencing induced apoptosis and Sub-G1 cell cycle arrest, while its combination with sorafenib significantly increased the apoptosis rate and also arrested cells in the G2-M phase in addition to the Sub-G1 phase. This combination treatment increased the expression of apoptosis-related genes BAX, CASP3, CASP9 while decreasing BCL2 expression. Additionally, significant inhibition of the cell-cycle related genes MYC and Cyclin D and upregulation of TP53 were observed following combination treatment. Furthermore, the combination therapy reduced the migration of B-CPAP cells through the downregulation of MMP-3 and MMP-9. Colony sizes and numbers also decreased following siRNA-mediated silencing of LINC00162 and sorafenib treatment. qRT-PCR analysis of stemness-related genes, including NANOG, SOX2, CD44, and CD133 confirmed the findings of the colony formation assay. To understand the underlying mechanisms of LINC00162 lncRNA in thyroid cancer progression, we evaluated the expression of MAPK pathway genes. Our findings indicated that LINC00162 silencing, in combination with sorafenib, reduced the expression of MAPK, KRAS, and RAF genes. From our findings, we can conclude that LINC00162 silencing, both individually and combined with sorafenib, reduced the progression and viability of thyroid cancer cells through modulating genes involved in key pathways and could be considered a new therapeutic approach for the treatment of papillary thyroid cancer (PTC).

Stress granules (SGs), which are phase-separating organelles that serve as protective cellular mechanisms in response to various harmful stimuli, have an unclear role in oxaliplatin resistance. Here, we establish a causal link between SG formation and oxaliplatin resistance in GC. Notably, we identify a key SG nucleator, namely, ubiquitin-associated protein 2-like (UBAP2L), as a previously unrecognized critical factor in mediating oxaliplatin resistance. UBAP2L-nucleated SG-mediated inhibition of apoptosis is associated with the recruitment of receptor of activated protein C kinase 1 (RACK1), a known promoter of apoptosis, to these entities. Transcriptional upregulation of UBAP2L is enhanced by oxaliplatin-induced phosphorylation and activation of heat shock factor protein 1 (HSF1) via AKT. Inhibiting either SG or HSF1 significantly overcomes oxaliplatin resistance in vivo. These findings demonstrate that UBAP2L-nucleated SGs play a vital role in mediating oxaliplatin resistance, with elevated SG levels emerging as a promising therapeutic target for overcoming this resistance.

Agents used in antitumour therapy have toxic effects on the cardiovascular system of breast cancer (BC) patients, increasing the risk of cardiovascular disease, which has become the most common non-cancer cause of death in BC patients. Exercise can effectively prevent or reduce the occurrence of cardiotoxicity, however, most BC patients have low levels of physical activity. The Health Action Process Approach (HAPA) model has been successfully applied to encourage patients to adhere to physical exercise. This study aims to explore the impact of exercise interventions based on the HAPA model on the monitoring indicators related to cardiotoxicity in BC patients during chemotherapy, aiming to prevent cardiotoxicity in BC patients and improve their physical activity level, exercise self-efficacy, exercise social support and exercise compliance.

A man in his early 40s was receiving treatment for rectal cancer with dostarlimab, an immune checkpoint inhibitor (ICI), when he developed fevers, headache and nausea. He was hospitalised with elevated liver enzymes and infectious work-up revealed an acute cytomegalovirus (CMV) infection. With concern that his dostarlimab therapy could be contributing to his inflammatory response as an ICI-induced hepatitis, the patient underwent a liver biopsy. Pathology was instead consistent with CMV hepatitis, and the patient was treated with antiviral therapy and had complete resolution of his illness. This case illustrates the importance of monitoring for immune-related adverse effects in patients taking ICIs, while still maintaining a broad differential diagnosis for other causes.

The MYC oncogene is causally involved in the pathogenesis of most human cancers. The mTORC1 complex regulates MYC translation through 4EBP1 and S6K. However, agents that selectively target mTORC1 (without affecting mTORC2) have so far failed to reactivate 4EBP1 and, thus, cannot effectively suppress MYC in vivo. In contrast, nonselective inhibitors that block both mTOR complexes can activate 4EBP1, but often lack tolerability and induce immunosuppression. Here, we introduce bi-steric mTORC1-selective inhibitors, including the clinical candidate RMC-5552, which potently reactivate 4EBP1 and decrease MYC protein expression levels. Consequently, suppression of MYC signaling occurs, resulting in tumor growth inhibition through both direct effects on tumor cells and immune activation. RMC-5552 exhibits anti-tumor activity in human patient-derived xenografts models harboring genomic MYC amplifications and reduces MYC protein levels in vivo. Furthermore, bi-steric mTORC1-selective inhibitors enhance the efficacy of immune checkpoint blockade, leading to tumor regression.

Glioblastoma (GBM) is one of the deadliest solid cancers with limited treatment options. Resistance to Temozolomide (TMZ), the most common oral anticancer drug available for GBM, develops rapidly and frequently in patients. This study reveals TMZ-sensitive GBM cells rely on glycolysis, while resistant counterparts preferentially utilize fatty acid oxidation (FAO). Hence, we developed an engineered nanoprogrammer using a metal-organic framework (MOF) coloaded with TMZ and the FAO inhibitor (etomoxir, ETO). Postengineered unsaturated Fe3+ sites adsorbed transferrin, enabling efficient blood-brain barrier traversal and tumor targeting. TMZ suppressed aggressive tumor growth by eliminating glycolysis-dependent cells during early treatment. Simultaneously, ETO inhibited FAO in resistant cells, forcing metabolic rewiring to glycolysis and restoring TMZ susceptibility. This dual-action strategy disrupted energy pathways in heterogeneous tumors, overcoming resistance. The nanoprogrammer demonstrated potent efficacy in orthotopic and patient-derived drug-resistant GBM models, achieving significant tumor suppression without notable toxicity.

The antitumor activity demonstrated by DNA damage response inhibitors (DDRis) can be partially attributed to their capacity to enhance immune responses. However, the toxicity of DDRis to lymphocytes, particularly when a DDRi is combined with other treatments targeting cell cycle checkpoint kinases, indicates a need for the development of different DDRi treatment schedules. Here, we systematically assessed changes to the tumor immune microenvironment (TIME) in response to DDRis across various treatment timelines in ovarian cancer. Using single-cell analysis, we found that the sequential treatment with an inhibitor of poly(ADP-ribose) polymerase (PARPi), followed by an inhibitor of the cell cycle checkpoint kinase WEE1 (WEE1i), resulted in more effective cancer eradication and stronger antitumor immune responses in vivo, compared with mono- and concurrent therapy. Both sequential and concurrent treatment schedules could induce lethal DNA damage and activate the cGAS-STING pathway in cancer cells, but T cell viability was greater under sequential treatment. Proteomic analysis showed that T cells more quickly recovered from DNA damage after DDRi treatment compared with cancer cells. Both immune checkpoint therapy and CAR T cells were more effective when combined with sequential treatment compared with monotherapy treatment in a syngeneic high-grade serous ovarian cancer mouse model and in a treatment-resistant ovarian cancer patient-derived xenograft model. Our study demonstrated that sequential treatment with PARPi and WEE1i spared T cells from severe DNA damage and activated the cGAS-STING pathway in cancer cells, suggesting that antitumor immunity and control of tumor growth can be optimized through changes in treatment schedules.

Overexpression of the polyspecific efflux transporter, P-glycoprotein (P-gp, MDR1, ABCB1), is a major mechanism by which cancer cells acquire multidrug resistance (MDR), the resistance to diverse chemotherapeutic drugs. Inhibiting drug transport by P-gp can resensitize cancer cells to chemotherapy, but there are no P-gp inhibitors available to patients. Clinically unsuccessful P-gp inhibitors tend to bind at the pump's transmembrane drug binding domains and are often P-gp transport substrates, resulting in lowered intracellular concentration of the drug and altered pharmacokinetics. In prior work, we used computationally accelerated drug discovery to identify novel P-gp inhibitors that target the pump's cytoplasmic nucleotide binding domains. Our first-draft study provided conclusive evidence that the nucleotide binding domains of P-gp are viable targets for drug discovery. Here we develop an enhanced, computationally accelerated drug discovery pipeline that expands upon our prior work by iteratively screening compounds against multiple conformations of P-gp with molecular docking. Targeted molecular dynamics simulations with our homology model of human P-gp were used to generate docking receptors in conformations mimicking a putative drug transport cycle. We offset the increased computational complexity using custom Tanimoto chemical datasets, which maximize the chemical diversity of ligands screened by docking. Using our expanded, virtual-assisted pipeline, we identified nine novel P-gp inhibitors that reverse MDR in two types of P-gp overexpressing human cancer cell lines, reflecting a 13.4% hit rate. Of these inhibitors, all were non-toxic to non-cancerous human cells, and six were not likely to be transport substrates of P-gp. Our novel P-gp inhibitors are chemically diverse and are good candidates for lead optimization. Our results demonstrate that the nucleotide binding domains of P-gp are an underappreciated target in the effort to reverse P-gp-mediated multidrug resistance in cancer.

The global rise of antimicrobial resistance and aggressive cancers like triple-negative breast cancer (TNBC) demands dual-functional therapies. We synthesized water-soluble ruthenium(II) p-cymene complexes (RuL1-RuL5) using quinoxaline-pyridyl ligands with strategic C6-substitutions. Structure-activity relationship studies identified halogenated RuL1 (-Br) as the most potent, showing selective activity against Gram-positive bacteria (MIC = 8 μg/mL vs Staphylococcus aureus). Mechanistic studies revealed membrane-targeted antibacterial action, supported by AFM, SEM, and fluorescence assays showing disruption, depolarization, and biofilm inhibition. RuL1 was also effective against intracellular S. aureus in HeLa cells, with good hemocompatibility and in vivo efficacy in a murine abscess model. Additionally, RuL1 exhibited strong anticancer activity against MDA-MB-231 TNBC cells (IC50 = ∼2.38 μM), while sparing HEK-293 cells. Mechanistic assays confirmed mitochondrial depolarization, ROS generation, and inhibition of migration and clonal expansion. These results position RuL1 as a promising dual-action metallotherapeutic for combating both drug-resistant bacteria and TNBC.

Radiodynamic therapy (RDT) offers a potential strategy to enhance radiation therapy (RT) efficacy by efficiently generating singlet oxygen (1O2) upon radiation. However, both RT and RDT can be compromised by tumor hypoxia. To relieve hypoxia while potentiating RT-RDT, we developed a hybrid-ligand nanoscale metal-organic framework (nMOF), LuMix, for radio-radiodynamic-chemodynamic therapy (RT-RDT-CDT) of tumors with low-dose X-ray. In LuMix, Lu effectively absorbs X-rays to generate hydroxyl radical (•OH) and transfers energy to TCPP to produce 1O2. TCPP(Fe) ligand catalyzes the degradation of H2O2 to generate O2 and •OH, alleviating hypoxia and enabling CDT. We further combined RT-RDT-CDT with checkpoint blockade immunotherapy to demonstrate the effective control of primary and distant tumor progression. In a bilateral colorectal cancer mouse model, LuMix combined with anti-PD-1 (αPD-1) effectively induced an abscopal effect under low-dose X-ray treatment (2 Gy for 3 days consecutively) with 97.3% primary tumor inhibition and 98.5% distant tumor inhibition. Notably, one of six primary tumors and two of six distant tumors were eradicated after treatment. Immunological analysis demonstrates that LuMix-enabled RT-RDT-CDT effectively promotes cytokine release and thereby enhances DC recruitment in the tumor-draining lymph nodes. Meanwhile, αPD-1 facilitates DC maturation and tumor-associated antigens presentation and increases CD8+ T cell infiltration in both the primary and distant tumors. The RT-RDT-CDT-induced damage also recruits macrophages to tumor sites and downregulates Tregs to activate the immune microenvironment. We therefore demonstrate a feasible strategy to fabricate radiosensitizers to synergize RT-RDT-CDT with checkpoint blockade immunotherapy.