Selective activation of chemotherapeutics at the tumor site via bioorthogonal catalysis is a promising strategy to reduce collateral damage to healthy tissues and organs. Despite significant advances in this field, targeted drug activation by transition-metal catalysts is still limited by insufficient spatiotemporal control over the metal-mediated uncaging process. Herein, we report the development of anisotropic Pd@Au plasmonic nanorods with the capacity to accelerate dealkylation reactions under near-infrared (NIR) irradiation, thereby enabling precise control over when and where these catalytic devices are switched on. We also show that the stability and in cellulo chemical properties of Pd@Au nanorods are enhanced by Au-S functionalization with PEGylated phospholipids and report the development of a novel masking group for prodyes and prodrugs: the POxOC group, designed to improve physicochemical properties and the rate of the Pd-triggered dye/drug release process. NIR-photoactivation of lipo-Pd@Au nanorods is able to catalyze the uncaging of inactive drug precursors and release heat to the environment, killing cancer cells in culture and xenografted in zebrafish. This work provides a novel targeted strategy for photothermal chemotherapy by NIR-laser focalization.

Immunogenic cell death (ICD) is a form of regulated cell death that engages the immune system by releasing damage-associated molecular patterns, making it a promising target for cancer immunotherapy. Presented here is the synthesis and evaluation of a series of asymmetric redox-active water-soluble Au(I) bis-N-heterocyclic carbenes (Au(I) bis-NHCs). We explore the structure-activity relationships between redox activity, water solubility and ICD induction, building on our previous work with a redox-active Au(I) bis-NHC (1) that effectively induced ICD but suffered from poor water solubility. To overcome this limitation, we synthesized several water-soluble redox-active Au(I) bis-NHCs, derivatives 2-4, by modifying the imidazole moiety. Compound 2 was identified as the lead, balancing water solubility and ICD induction efficacy. This compound, featuring a naphthoquinone moiety, and was found to generate reactive oxygen species (ROS) and trigger key ICD biomarkers, including calreticulin (CRT) translocation, ATP release, and high mobility group box 1 (HMGB1) secretion. A control compound lacking the redox active naphthoquinone failed to elicit these ICD markers or promote ROS production. Across the series 1-4 a correlation was observed between ROS generation and ICD biomarker expression. In vivo studies in syngeneic immunocompetent mice demonstrated that compound 2 not only prevents CT26 colorectal cancer tumor growth upon challenge with live cancer cells but also elicits a long-lived immune response upon rechallenge 12 months later.

G1 to S phase transition 1 (GSPT1, also known as eRF3a) is a crucial translation termination factor that plays a vital role in acute myeloid leukemia (AML) and MYC-driven lung cancer. Degrading GSPT1 can induce apoptosis in cancer cells and reduce their viability, thus making GSPT1 a potential therapeutic target. This perspective aims to introduce the current research status of the mechanism of molecular glues targeting GSPT1, summarize the recent progress in and challenges for existing molecular glues, bifunctional degraders, and antibody-enabled molecular glues targeting GSPT1, and outline the development strategies for targeting GSPT1 in the treatment of cancer.

Two-photon absorption (TPA) technology has emerged as a promising approach for precise drug delivery due to its deep tissue penetration and high spatial selectivity. This study introduces a rational design approach to enhance TPA-mediated drug delivery by incorporating an increasing number of heavy bromine atoms into the hydroxymethylquinoline (HMQ) framework. The resulting molecules exhibit significantly improved TPA properties (TPA cross section of up to 130 GM), enabling efficient tumor and nuclear targeting in triple-negative breast cancer (TNBC) models. Structural modifications incorporating heavy Br atoms optimized electronic transitions, enhancing TPA cross sections and photostability. Biological evaluations revealed selective accumulation in TNBC cells, efficient nuclear localization, and enhanced therapeutic efficacy (∼75% cell killing) with minimal off-target effects. This strategy highlights the synergy between molecular design and photophysics for advancing theranostic applications. The study provides a blueprint for developing multifunctional TPA-based drug delivery systems, offering new avenues for the treatment of aggressive cancers, such as TNBC.

Cancer immunotherapy, including immune checkpoint blockade (ICB), often has limited efficacy due to inadequate neoantigen exposure. Although neoantigen vaccines can enhance immune sensitization, their clinical application is hindered by high identification costs and tumor heterogeneity. Alternatively, heteroantigen presentation by cancer cells offers a promising strategy to improve immunotherapy. Herein, hyaluronic acid (HA)-modified bacterial membrane vesicles were developed as heteroantigen reservoirs (HLGV) and then further loaded with PD-L1 siRNA (siPD-L1) for immune checkpoint blockade. Intracellularly, HLGV released heteroantigens and siPD-L1 into the cytoplasm via early endosomal membrane fusion. The heteroantigens were presented by MHC class I molecules, while siPD-L1 escaped lysosomal degradation and effectively silenced PD-L1 expression. When administered peritumorally, the synergistic therapeutic effect of heteroantigen presentation and ICB significantly inhibited both subcutaneous CT-26 tumors and distant metastases. For colorectal cancer immunotherapy, HLGV@siPD-L1 was encapsuled into chondroitin sulfate hydrogel microspheres (HEBV@siPD-L1) and administered through oral gavage. Ultimately, HEBV@siPD-L1 increased the infiltration of macrophages and CD8+ T cells and effectively suppressed the growth of orthotopic colorectal cancer, with the tumor inhibition rate reaching 91.6%. These findings demonstrated the potential of bacterial membrane vesicles as heteroantigen reservoirs to activate antitumor immune responses, which could further synergize with ICB for promoted immune efficacy.

Daidzin (DZN), a naturally occurring isoflavone extracted from leguminous plants such as soybeans, has gained significant attention for its anticancer properties. This study provides a comprehensive overview of the pharmacokinetics (PKs), botanical sources, and therapeutic potentials of DZN, focusing on its mechanistic insights into cancer prevention and treatment. For the study, data were collected from databases such as PubMed, Google Scholar, Web of Science, and other reputable sources. In results, DZN induces oxidative stress, apoptosis, cytotoxicity, and cell cycle arrest while inhibiting proliferation, migration, invasion, and angiogenesis across various cancer cell lines, including breast, prostate, cervical, hepatocellular, and colon cancers. Its anticancer efficacy is mediated through modulation of key pathways: Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-κB), which promotes inflammation and survival; Janus Kinase/Signal Transducer and Activator of Transcription (JAK/STAT), essential for proliferation and immune evasion; and Rat Sarcoma virus/Rapidly Accelerated Fibrosarcoma (RAS/RAF), a critical regulator of cell growth and chemoresistance. By inhibiting these pathways, DZN enhances apoptosis and chemotherapy sensitivity. Additionally, DZN's pharmacokinetic profile reveals favorable absorption, distribution, metabolism, and excretion (ADME) properties, with minimal toxicity in preclinical studies. Its ability to modulate pathways and enhance chemotherapy sensitivity positions DZN as a potential therapeutic candidate. Despite promising preclinical findings, the lack of clinical validation underscores the need for well-designed human trials to confirm its efficacy and safety, paving the way for its translational application in oncology.

This study aims to investigate the cellular response of Glioblastoma (GBM) to adhesion and metabolic inhibitors, focusing on cell migration and matrix adhesion properties. GBM is the most common incurable brain tumor. Despite decades of research into GBM's chemical and molecular classification, identifying mechanisms of drug resistance has been challenging. Studies on inhibitors targeting cancer cell migration and proliferation rarely consider the heterogeneous migration properties among cells, which may impact patient responses to treatment. In this work, tissue samples were obtained from spatially distinct locations with different 5-aminolevulinic acid (5-ALA) fluorescent intensities-including strongly fluorescent tumor cores, a weakly fluorescent tumor rim, and non-fluorescent tumor margins. These samples were previously shown to be associated with significantly different motility and adhesion properties. We tested the response of tumor cells to adhesion and metabolic inhibitors using metabolic MTT and Cell Titer Glo viability assays, respectively. We also monitored cell survival using time-lapse microscopy, while culturing them on low-modulus polydimethylsiloxane (representing the stiffness of brain tissue). Metabolic viability assays revealed substantial heterogeneity in drug potency across cells from different regions of the tumor. Highly fluorescent tumor core cells were significantly more resistant to an F0F1 ATP synthase inhibitor (Gboxin), and a FAK inhibitor (GSK2256098), while their proliferation ceased post-treatment in vitro. In contrast, cells derived from non-fluorescent tumor margins exhibited higher potency for the ATP synthase inhibitor (Gboxin), but their proliferation persisted post-treatment. Our study demonstrates a correlation between the adhesive and migration properties of cells and their sensitivity to therapeutics in different regions of the tumor within individual patients and between patients with GBM.

The use of sodium-glucose cotransporter protein 2 (SGLT2) inhibitors, specifically canagliflozin and dapagliflozin, has expanded from diabetes treatment to promising anticancer applications. Epidemiological links between diabetes and certain cancers highlight the potential of these agents in oncology, as SGLT2 is highly expressed in various tumor types. By inhibiting glucose uptake, canagliflozin and dapagliflozin disrupt glycolysis-dependent tumor growth, promoting apoptosis and reducing proliferation across multiple cancer models, including liver, prostate, and lung cancers. Key pathways involved in these effects include PI3K/AKT, mTOR, and AMPK signaling. Importantly, the combination of SGLT2 inhibitors with chemotherapy or radiotherapy has been shown to enhance antitumor efficacy and reduce treatment resistance, underscoring their potential as adjunctive therapies. However, adverse effects, such as increased risk of infection, and the need for more comprehensive mechanistic studies limit current applications. Future research should focus on expanding the understanding of these mechanisms, evaluating efficacy in additional tumor types, and optimizing combination therapies to mitigate side effects. SGLT2 inhibitors thus represent a novel class of metabolic modulators with potential for significant impact in cancer therapeutics.

Ion interference therapy (IIT) has emerged as a promising antitumor strategy by disrupting intracellular ion homeostasis. However, balancing physiological ion stability with tumor-responsive ion release remains a critical challenge. Herein, we present a crystal-phase engineering approach to program montmorillonite nanoclay with thermally responsive lattice strain, which enables tumor microenvironment (TME)-triggered crystal-phase aluminum (Al) liberation. Hyperthermia-induced lattice distortion amplifies the surface Al-OH density by 1.7-fold, promoting pH-responsive crystal-phase Al liberation in the acidic TME. Systematic investigations reveal that the engineered nanoclay maintains physiological stability while achieving 87.5% tumor-selective crystal-phase Al liberation (increased by 70%), which destroys tumor cell membranes by interacting with membrane phospholipids, thereby accelerating intracellular uptake. Furthermore, the intracellular liberation of crystal-phase Al causes mitochondrial dysfunction through oxidative stress, ultimately inducing tumor cell death and awakening the systemic immune response. This work pioneers crystal-phase modulation in nanoclay-based therapeutics, providing a roadmap for the development of spatially controlled ion interference agents.

Telomerase is an attractive therapeutic target due to its expression in most cancer cells. This study focuses on harnessing the potential of telomerase to alter telomeres as a therapeutic modality. We designed and synthesized divalent dinucleotide prodrugs comprised of 6-thio-2'-deoxyguanosine (6-thio-dG; THIO) and 5-fluoro-2'-deoxyuridine (5-FdU) nucleosides. Although dinucleotides containing 5-FdU pharmacophores showed better activity in vitro versus compounds containing only THIO pharmacophores, we observed greater activity for THIO-containing compounds in vivo. The homopurine compounds MAIA-2022-12 and MAIA-2021-20, with two 6-thio-dG pharmacophores, linked by 3', 5'- and 5', 5'-phosphodiester bonds, respectively, demonstrated the greatest anticancer efficacy among the compounds tested and induced host immune-memory responses in vivo. The sequential combination of MAIA-2022-12 or MAIA-2021-20 with the immune anti-PD-1 or anti-PD-L1 checkpoint inhibitors demonstrated superior anticancer efficacy compared with the corresponding monotherapies. We conclude that MAIA-2022-12 and MAIA-2021-20 are promising candidates for future preclinical and potential clinical studies.

MDM2, a key negative regulator of the tumor suppressor p53, has emerged as a compelling therapeutic target in human cancer. This Viewpoint summarizes the discovery of a potent and orally bioavailable MDM2 degrader that demonstrates unprecedented single dose antitumor efficacy. The compound holds substantial potential as a cancer therapeutic and warrants thorough preclinical evaluation.

This study presents a macrophage-mimetic nanoplatform (MPMs@Cur-BDTA NPs) for dual-mode intervention. Curcumin simultaneously amplifies Förster resonance energy transfer (FRET) to enhance phototherapy and inhibits heat shock protein 70 (HSP-70) to dismantle the thermal defense. By coprecipitating curcumin with a finely tuned excited-state dynamic luminogen BDTA, we establish synergistic FRET pairs for energy redistribution. Within this configuration, curcumin functions dually: as a photonic amplifier, it elevates the photothermal conversion efficiency to 87.6% and enhances singlet oxygen generation 1.7-fold; as a biochemical modulator, it downregulates HSP-70 expression by 50%, sensitizing glioblastoma cells to thermal attack. This triple-modal treatment strategy (photothermal therapy/photodynamic therapy/chemotherapy), guided by NIR imaging, extends the median survival time from 14.5 days to 19.4 days in orthotopic glioblastoma models. Collectively, this work introduces a new paradigm of "energy channeling hijacking" combined with "molecular defense disarmament", redefining how natural molecules like curcumin can actively orchestrate phototheranostic responses in brain tumor theranostics.

This is a protocol for a Cochrane Review (intervention). The objectives are as follows: To assess the beneficial and harmful effects of sorafenib, with or without co-interventions, versus placebo, no intervention, or the same co-interventions for adults, aged 18 and over, with hepatocellular carcinoma.

Cancer remains a leading global health challenge, with high mortality rates persisting despite significant advancements in therapeutic interventions. Major obstacles, including systemic toxicity, therapy resistance, metastasis, and relapses, emphasize the urgent need for safer, more effective, and readily accessible treatment strategies. Among emerging alternatives, natural bioactive compounds have gained considerable attention because of their diverse therapeutic potential and lower toxicity profiles. Urolithin A (UA), a metabolite derived from ellagic acid through gut microbiota metabolism, has emerged as a compelling anticancer agent. UA has multiple mechanisms of action, including the regulation of autophagy, enhancement of mitochondrial function, and inhibition of tumor progression and metastatic pathways. Additionally, its chemo-, immuno-, and radio-sensitization properties further increase its therapeutic advantages. Nanotechnology-driven approaches, such as nanoparticle formulations, lipids, and powder formulations, have successfully increased the solubility, stability, bioavailability, precise targeted delivery to cancer tissues, and overall therapeutic benefits of these materials. This review comprehensively explores the anticancer mechanisms of UA, its modulatory role, and advances in nanoformulation strategies, highlighting its potential as a next-generation therapeutic agent for improved cancer treatment and prevention.

Mitophagy has been implicated in chemoresistance in various cancers. Worenine, an active compound derived from Coptidis rhizome, has exhibited anti-tumor activity. We aimed to clarify the impacts of worenine on regulating the cisplatin (DDP) sensitivity and mitophagy in DDP-resistant non-small cell lung cancer (NSCLC) cells. The DDP-resistant NSCLC cell line (A549/DDP) were established via exposure to escalating DDP concentrations. Its resistance characteristics were confirmed by CCK-8 and flow cytometry assays. Moreover, the effects of worenine and/or DDP on the A549/DDP cells viability, colony formation abilities, apoptosis, and mitophagy-related proteins were evaluated. The A549/DDP cells were successfully established, with markedly higher IC50 value than A549 cells (25.67 μM vs. 9.555 μM). We noted that the HIF-1α/BNIP3-mediated mitophagy was clearly activated in A549/DDP cells. Worenine decreased A549/DDP cell viability and colony formation abilities, promoted apoptosis, and suppressed HIF-1α/BNIP3-mediated mitophagy. Importantly, worenine enhanced the responsiveness of A549/DDP cells to DDP. Besides, the suppressive impacts of worenine on A549/DDP cells were reversed by HIF-1α overexpression. Our findings indicate that worenine may enhance the sensitivity of A549/DDP cells to DDP via suppressing HIF-1α/BNIP3-mediated mitophagy. Targeting mitophagy may be a promising therapeutic strategy for addressing chemoresistance in NSCLC.

In the pursuit of optimal medical care, treatment selection based on the molecular analysis of genomes, transcriptomes, and proteomes has been explored; however, this approach relies on data from large patient groups, resulting in limited accuracy in predicting treatment efficacy. Diseases involve complex pathological networks, requiring treatments that target multiple key molecules in these networks. Drug screening using these networks, which cannot be achieved through a gene expression analysis alone, requires animal models. Zebrafish embryos have an immature immune system, allowing for a high engraftment rate of human cancer cells transplanted within 48 h after fertilization. Consequently, the time required for engraftment is also reduced. Less than 500 human cancer cells are required for transplantation, enabling the assessment of drug efficacy from clinical samples within approximately 1 week. The cost of raising zebrafish is low, drug efficacy can be evaluated using small amounts of drugs, and their use aligns closely with animal welfare standards. This review aims to discuss the technical aspects of evaluating drug efficacy using zebrafish patient cancer tissue-derived xenograft (zPDX) models and summarize previous studies using zPDX as an avatar model for personalized medicine.

Oxaliplatin, a third-generation platinum-based chemotherapeutic agent, is widely used in the treatment of colorectal cancer (CRC). However, some patients do not respond effectively to oxaliplatin, and intrinsic resistance to the drug poses a significant challenge. Recent studies have revealed an association between the gut microbiome and the progression of CRC. We hypothesized that Citrobacter freundii, a component of the gut microbiome, contributes to oxaliplatin resistance by regulating specific gene expression in CRC cells.

The immuno-oncology-microbiome (IOM) axis, referring to the gut microbiota-regulated immune interactions on the tumor microenvironment and systemic immunity, is essential for cancer therapies. However, the cytotoxicity of chemotherapeutic agents (Chemos) disrupts the gut microbiota- and gut microbiota-manipulated IOM axis, further diminishing the therapeutic efficacy. Here, we developed oral nanoarmored live bacterial biotherapeutics (supraLBT), to reshape the tumor microenvironment and enhance chemotherapy via reestablishing the IOM axis. The cyto-adhesive polyphenol-based supraparticles, made from green tea polyphenol and food-grade milk protein, attached on microbes (Escherichia coli Nissle1917, EcN) resisted a range of clinically relevant Chemos via phenolic-mediated noncovalent interactions, enhancing supraLBT survival by 27-fold compared with bare EcN. SupraLBT restored the intestinal microbiota and the disrupted IOM axis, thereby reducing the infiltration of regulatory T cells, increasing the recruitment of cytotoxic CD8+ T cells to the tumor bed, and further inhibiting tumor proliferation and demonstrating enhanced systemic immune responses. Notably, oral supraLBT combined with chemotherapy (doxorubicin) exhibited 2.35-fold greater tumor regression than that of doxorubicin alone, indicating that oral supraLBT can enhance the chemotherapeutic effect. Further investigations revealed that supraLBT reprogrammed the immune tumor microenvironment by upregulating antitumor cytokines and altering the gut microbial composition. Given the intricate interplay between gut microbiota, host immune system, and tumor microenvironment, this work presents a facile and biomaterial-engineered microorganism-based strategy to enhance the synergistic immuno-chemotherapy effects.

Drug-induced liver injury (DILI) is a leading cause of liver damage. It is especially prevalent in haematologic malignancies, complicating treatment regimens and posing a risk for severe outcomes such as acute liver failure. Antibody-based therapies have significantly improved treatment outcomes. However, these therapies are increasingly associated with liver injury, posing challenges in clinical management.

Aneuploidy is near-ubiquitous in cancer and can decrease chemotherapy efficacy while also sensitizing cells to other drugs.