Ferroptosis represents a promising antitumor strategy, yet its efficacy in colon cancer is compromised by excessive antioxidant glutathione (GSH) and insufficient reactive oxygen species (ROS). To address this limitation, we rationally designed integrated nanoplatforms (FeBMnDC NPs) by covalently conjugating albumin-MnO2 complexes with ferritin to codeliver the ROS-responsive dihydroartemisinin (DHA) dimer and photosensitizer Chlorin e6 (Ce6). This design synergistically disrupts redox homeostasis to induce ferroptosis and immune activation. Upon tumor accumulation and laser irradiation, the FeBMnDC NPs release oxygen, Mn2+, ferritin, DHA, and Ce6. Laser-triggered ROS initiates a self-amplifying feedback loop that further releases DHA and Ce6, enhancing ROS generation via chemodynamic and photodynamic therapies, while MnO2 degradation and ferric ion reduction deplete GSH. Severe oxidative stress promotes apoptosis, ferroptosis, and immunogenic cell death. In vitro and in vivo studies confirmed that FeBMnDC NPs enhance lipid peroxidation and dendritic cell maturation, achieving potent antitumor efficacy without apparent side effects. Moreover, integrated transcriptomic and proteomic analyses revealed that laser irradiation reprograms GSH metabolism and activates ferroptosis-executing pathways, identifying AMPD3 as a novel ferroptosis-associated gene in colon cancer. This work presents a self-amplifying nanoplatform enabling multimodal redox intervention, offering a mechanism-driven strategy for colon cancer treatment.

Background Esophageal squamous cell carcinoma (ESCC) remains a major cause of cancer-related mortality worldwide, with immunotherapy resistance representing a critical therapeutic challenge. This resistance is driven by profound tumor heterogeneity that fosters diverse immune evasion mechanisms, limiting the efficacy of current treatments. Thus, an urgent need exists to identify the key drivers within heterogeneous tumors that potentiate immunotherapeutic resistance. Methods Single-cell, spatial, and bulk transcriptomic data from multiple ESCC cohorts were integrated to map the cellular ecosystems and decipher the heterogeneity of immunotherapy-resistant tumors. Multi-cohort analyses were conducted to assess clinical relevance, and key findings were validated through targeted functional assays in vitro and in vivo. Results We discovered a previously unrecognized secreted phosphoprotein 1 (SPP1)-expressing malignant epithelial subpopulation that is markedly enriched in non-responders, representing a critical component of tumor heterogeneity. Elevated SPP1 expression correlated with immunotherapy resistance and poorer survival across independent cohorts. Mechanistically, SPP1 promoted tumor proliferation and migration while upregulating PD-L1 via the mTORC1–STAT3 pathway, as revealed by our RNA-sequencing data. Furthermore, SPP1 induced CD8⁺ T cell exhaustion through SPP1–CD44 signaling, accompanied by CD44-dependent MAPK activation, and polarized macrophages toward an immunosuppressive phenotype via α5β1 integrin–dependent FAK–AKT–mTOR activation. Spatial transcriptomics validation demonstrated that SPP1⁺ cells shape immunosuppressive niches within the tumor microenvironment. Therapeutically, SPP1 blockade enhanced the antitumor effect of anti-PD-1 therapy to suppress tumor growth in vivo. To directly address tumor heterogeneity, we employed drug sensitivity profiling that nominated microtubule and kinase inhibitors as potent agents against SPP1⁺ cells, providing a strategy to target resistant subpopulations. Conclusion This study establishes SPP1 as both a key driver of immunotherapy resistance in heterogeneous ESCC tumors and a promising therapeutic target for overcoming treatment failure.

Alcoholic liver disease (ALD) poses a growing therapeutic challenge due to the scarcity of effective pharmacotherapies. Here, BRP2, a novel polysaccharide from Butyriboletus roseoflavus, was isolated and structurally characterized, featuring a complex backbone comprising →6)-α-Galp-(1→, →2,6)-α-Galp-(1→, and →2,6)-β-Manp-(1 → 3)-β-Fucp-(1→. This unique polysaccharide significantly ameliorated hepatic steatosis and DNA damage in both acute and chronic ALD models. Mechanistically, BRP2 reshaped the gut microbiota by enriching Akkermansia and suppressing Desulfovibrio, leading to a marked reduction in the microbial metabolite trimethylamine N-oxide (TMAO). Reduced TMAO levels alleviated inhibition of AMPK phosphorylation and enhanced Sirt1 deacetylase activity, which subsequently suppressed mTORC1 signaling. This cascade potently activated hepatoprotective autophagy, as evidenced by decreased p62/SQSTM1 and increased LC3-II levels. Collectively, this study reveals a BRP2-driven, microbiota-TMAO-dependent pathway that alleviates ALD through the AMPK/Sirt1/mTORC1-mediated autophagy axis, offering new insights into polysaccharide-based interventions for liver diseases.

ObjectiveAmid acknowledged sex-based disparities in immune system response, the effect of patients’ sex on the efficacy of immune checkpoint inhibitors (ICIs) treatment remains inconsistent across cancers, and even inconclusive in esophageal squamous-cell carcinoma (ESCC). We conducted a systematic review and meta-analysis to assess the sex-based heterogeneity in response to first-line immunotherapy in advanced ESCC.MethodsPubMed, Web of Science, Cochrane Library and Embase were searched from inception to December 1st, 2025 to retrieve randomized controlled trials (RCTs) investigating the efficacy of first-line immunotherapy plus chemotherapy versus chemotherapy alone for advanced ESCC. The studies reporting sex-stratified outcomes for overall survival (OS) with or without progression-free survival (PFS), were eligible for inclusion. Pooled hazard ratios (HRs) and 95%CI were calculated separately in men and women using a random-effects model, and the heterogeneity between the two estimates was assessed using an interaction test.ResultsNine phase 3 RCTs, reporting on 4591 men (85.6%) and 773 women (14.4%), were included. An OS benefit of immunotherapy was found for both men (HR, 0.70; 95%CI, 0.65-0.75) and women (HR, 0.71; 95%CI, 0.58-0.87) in the overall population and in the PD-L1-positive subgroup (HR for men: 0.66, 95%CI, 0.55-0.80; HR for women: 0.48, 95%CI, 0.30-0.78). Similarly, the PFS benefit was found for both men (HR, 0.59; 95%CI, 0.54-0.63) and women (HR, 0.58; 95%CI, 0.46-0.74) in the overall population. Random-effects meta-analysis demonstrated no statistically significant study-level differences in response to immunotherapy between the sexes in the overall population (OS, I2 = 14%; P = 0.94; PFS, I2 = 18%; P = 0.95) as well as in the PD-L1-positive subgroup (PFS, I2 = 0%; P = 0.24).ConclusionFirst-line immunotherapy plus chemotherapy can improve OS and PFS in advanced ESCC for both men and women. No evidence was found to support an association of sex with the efficacy of immunotherapy plus chemotherapy.

ABSTRACT Therapeutic barriers and resistance limit the efficacy of immunotherapy in metastatic breast cancer. Here, we report a dual‐nanobody autophagy‐targeting chimera (AUTAC), hereafter referred to as Nb, that selectively degrades heat shock protein 90 (HSP90) via p62‐dependent autophagy, restoring tumor sensitivity to immunogenic cell death (ICD). To construct the delivery nanoplatform, Nb was preassembled into protein‐polymer nanoparticles (Nb‐PC), coated with cholesterol‐depleted 4T1 tumor cell membranes (Nb‐PC@M), and further decorated with citrate‐stabilized Pd nanoparticles (Pd NPs) to obtain Nb‐PC@MPd. This hierarchical design integrates reversible protein‐polymer assembly, biomimetic membrane coating, and asymmetric Pd anchoring. In vivo, Nb‐PC@MPd achieves EPR‐ and membrane‐assisted tumor accumulation, followed by NIR‐assisted intratumoral Nb delivery and intracellular Nb release, promotes p62‐dependent HSP90 autophagic degradation, and potentiates mild photothermal therapy (mPTT)‐induced ICD. Consequently, Nb‐PC@MPd elicits systemic antitumor immunity and effectively suppresses both tumor growth and pulmonary metastasis. This platform integrates programmable protein degradation, biomimetic thermophoretic delivery, and tumor‐directed immunomodulation, providing a versatile strategy for precision macromolecular therapeutics.

Biodegradable hydrogels are promising for bone regeneration but are limited by a significant mechanical mismatch with bone tissue in modulus, strength, and toughness. To address the weakness, this work reported a mesh-like hydrogel woven from calcium-alginate gel fibers. The fibers, manufactured via wet-spinning, possessed tensile strengths (36-285 MPa) and moduli (200 MPa-9.1 GPa) comparable to those of bone tissue. This feature made the woven hydrogel withstand complex physiological loads while maintaining its biodegradable properties. In vitro, the degraded hydrogel promoted the osteogenic differentiation of rat bone mesenchymal stem cells, achieving 155% increment of alkaline phosphatase (ALP) activity and 294% increment of mineralized calcium nodules. After implantation into cranial bone defects in vivo, complete biodegradation resulted in continuous release of bioactive calcium, significantly accelerating bone regeneration and achieving a regenerated bone volume to tissue volume (BV/TV) ratio of 67.2%. This study demonstrates a paradigm of degradation-mediated nutrient release, highlighting the pivotal role of bioactive calcium delivery for effective bone regeneration.

The Al-Sb co-doped SnO2 composite thin films were prepared by the sol–gel spin-coating method. The structure, morphology, optical and electrical properties of the samples were investigated using XRD, XPS, SEM, UV-Vis spectroscopy, and Hall effect tester, respectively. It was found that when the aluminum doping amount was 15 at%, the resistivity of the sample was the lowest, and the overall optoelectronic performance was the best. Moreover, the Al-SnO2 composite thin film transformed from an n-type semiconductor to a p-type semiconductor. When Al and Sb were co-doped, the carrier concentration increased significantly from 4.234 × 1019 to 6.455 × 1020. Finally, the conduction type of the Al-Sb-SnO2 composite thin film changed from p-type to n-type. In terms of optical performance, the transmittance of the Al-Sb co-doped SnO2 composite thin films in the visible light region was significantly improved, reaching up to 80% on average, which is favorable for applications in transparent optoelectronic devices. Additionally, the absorption edge of the thin films exhibited a blue-shift after co-doping, indicating an increase in the bandgap energy, which can be exploited to tune the light-absorption properties of the thin films for specific photonic applications.

Colorectal cancer recurrence remains a major challenge after curative resection, and accurate tools for early risk assessment are essential to stratify patients and guide personalized therapeutic planning. We developed MPMRecNet, a dual-stream deep learning model for predicting recurrence using multiphoton microscopy imaging of formalin-fixed paraffin-embedded tissue sections from 1071 patients across two hospitals. MPMRecNet employs MaxViT-based encoders, cross-modal attention fusion, and classification under focal loss with mixed-precision optimization. It achieved strong external validation performance (ROC-AUC = 0.849, PR-AUC = 0.664), outperforming traditional clinical predictors. Multivariable analysis confirmed MPMRecNet as the most powerful independent predictor of recurrence (OR = 5.66, p < 0.001), and a combined nomogram incorporating clinical variables further improved stratification (ROC-AUC = 0.872). MPMRecNet offers a non-destructive tool for recurrence prediction from routine pathology slides, supporting precise risk assessment and postoperative surveillance.

Kaempferol liposome hydrogel is a novel drug carrier designed to solve the problems of the poor water solubility and low bioavailability of kaempferol. By combining kaempferol with liposomes and further forming a hydrogel, this composite formulation not only improves the stability of the drug but also enhances its penetration and therapeutic effect on the skin. It was demonstrated that the liposomal hydrogel of kaempferol had ex vivo and in vivo antioxidant activities, which could effectively inhibit the inflammatory response and oxidative stress and, thus, showed significant efficacy in the treatment of acute eczema. In the acute eczema model, kaempferol liposome hydrogel significantly improved the skin condition of mice by reducing the symptoms of skin redness, swelling, and itching. The experimental results showed that the hydrogel was rapidly absorbed into the skin after application and continued to release the drug to maintain its efficacy for a longer period of time. In addition, the kaempferol liposome hydrogel also showed good physicochemical stability and was not easily discolored or separated, making it suitable for long-term use. As an innovative drug carrier for the treatment of acute eczema, the kaempferol liposome hydrogel shows good application prospects and provides a new treatment option for eczema patients.

Psoriasis is a chronic skin disease caused by the interaction of multiple factors that leads to the abnormal growth of stratum corneum cells and has been called an immortal cancer. Docetaxel has been trialed for the treatment of psoriasis due to its superior ability to induce apoptosis, but its insolubility and low bioavailability have hampered its development. Here, docetaxel (DTX)-loaded liposomes-in-gel (DTX-LP-G) as the transdermal delivery was investigated to the treatment of psoriasis via modulating the IL6-HIF-1α-VEGF axis. The results demonstrated that DTX-LP-G cumulatively released a much higher amount of drug into the skin than that from DTX-loaded liposomes (DTX-LPs) and DTX-loaded gel (DTX-G). DTX-LP-G was also the most efficient in scavenging hydrogen peroxide free radicals in vitro. In a mouse model of psoriasis, DTX-LP-G acted as a preliminary therapeutic agent for psoriasis in terms of apparent evaluation, splenomegaly, suppression of MDA content in skin tissue, and down-regulated the expression of IL6, HIF-1α, and VEGF to control the proliferation of vessels, except for a less pronounced effect on the stratum corneum. In addition, enrichment analysis can speculate that DTX also treated psoriasis by resisting the production of keratin-forming cells.

Psoriasis is a common immune-mediated squamous skin disease, primarily characterized by the over proliferation of keratinocytes and a significant thickening of the stratum corneum. Traditional systemic drug delivery therapies often fall short due to low drug bioavailability and significant toxic side effects. Topical medications, while capable of achieving local or systemic treatment via transdermal routes, face limitations in psoriasis patients due to the abnormal thickening of the epidermis, which reduces skin permeability and hampers drug penetration efficiency. Hydrogel microneedles, as an emerging transdermal drug delivery technology, offer significant advantages such as high permeability, ease of use, low toxicity and side effects, and controlled release. Therefore, this study developed a liposome-hydrogel microneedle delivery system for the administration of berberine hydrochloride. We successfully prepared berberine hydrochloride-loaded liposomes (Ber-LPs) with high encapsulation efficiency and good stability, and integrated them into hydrogel microneedles crosslinked with PVA and PEGDA (Ber-LPs-PEGDA&PVA MNs) through a photocuring method. These microneedles exhibit an intact structure, high mechanical strength, and effective skin penetration. In vivo studies on anti-psoriatic effects showed that, compared to the model group, Ber-LPs-PEGDA&PVA MNs significantly alleviated imiquimod-induced psoriasis-like symptoms in mice, reduced skin epidermal thickness, decreased the expression levels of inflammatory cytokines, and lowered the expression of CD31 and VEGF, demonstrating excellent therapeutic efficacy. Additionally, the microneedles exhibited good drug release properties, antioxidant capacity, and biocompatibility. The novel hydrogel microneedle drug delivery system developed in this study offers a safe and effective solution for the treatment of psoriasis, with significant potential for clinical application.

Neutrophils are integral to the frontline defense against pathogenic bacterial and fungal invasions. Beyond their traditional roles, these cells are increasingly recognized for their dualistic contributions to the pathology of autoimmune and inflammatory diseases, as well as their complex involvement in cancer progression. Neutrophils interact with different disease states, highlighting their potential as therapeutic targets. Within tumor microenvironment (TME), tumor-associated neutrophils (TANs) exhibit a functional dichotomy, capable of either fostering or impeding tumor growth and metastasis. This binary functional potential of TANs, under certain conditions, suggests a reversible state that could transition from tumor-promoting to tumor-eradicating phenotypes. Despite the critical implications of such functional plasticity, systematic studies of TAN behavioral shifts in the context of cancer immunotherapy remain scarce. Herein, we review recent advancements in the understanding of TANs within the TME, highlighting their binary regulatory effects on solid tumors. Leveraging the latest insights from experimental and clinical research, this review elucidates the complex roles of TANs in tumor development and explores their molecular interactions as potential therapeutic targets. The elucidation of these mechanisms holds promise for novel cancer treatment strategies, aiming to improve patient outcomes by manipulating the tumor-promoting or -suppressing functions of TANs.

Metastatic BRAFV600E colorectal cancer (CRC) confers poor prognosis and represents a therapeutic bottleneck. To identify resistance mechanisms of the mitogen-activated protein kinase (MAPK) pathway in BRAFV600E CRC, we perform genome-wide CRISPR-Cas9 screening and discover that targeting glutathione peroxidase 4 (GPX4) overcomes resistance to BRAF inhibitor (BRAFi) combined with or without epidermal growth factor receptor inhibitor (EGFRi) in BRAFV600E CRC. Specifically, BRAFi ± EGFRi upregulates GPX4 expression, which antagonizes therapy-induced ferroptosis. Moreover, polo-like kinase 1 (PLK1) substrate activation promotes PLK1 translocation to the nucleus, activating chromobox protein homolog 8 (CBX8) phosphorylation at Ser265 to drives GPX4 expression. Targeting PLK1 enhances BRAFi ± EGFRi inhibition and triggers ferroptosis in vitro, vivo, organoid, and patient-derived xenograft model. Collectively, we demonstrate a PLK1-CBX8-GPX4 signaling axis that relays the ferroptosis mechanism of therapeutic resistance and propose a clinically actionable strategy to overcome BRAFi ± EGFRi resistance in BRAFV600E CRC.

Background: Gastrointestinal stromal tumors (GISTs) are a type of tumor that originates from gastrointestinal mesenchymal tissue. Although several somatic or germline mutation GIST mice were established, however, there is still a lack of an authentic mice GIST cell lines for further experimental study. Methods: We developed a chemically induced C57BL/6 J GIST model using 3- methylcholanthrene. Tumor characteristics were confirmed through histology and IHC. Primary cells were isolated to establish the mGSTc01 cell line, and molecular profiling was conducted. Additionally, we established GIST model in immunocompetent mice to evaluate their sensitivity to imatinib. Results: Our study successfully developed a chemically induced murine GIST model, characterized by positive staining of c-kit and DOG-1. The mGSTc01 monoclonal cell line exhibited slender morphology and expressed the c-kit marker, Whole exome sequencing uncovered mutations of Lamb1, MMP9, and c-kit in GIST cells and provided a detailed picture of the entire genome's copy number variations. RNA sequencing indicated genes associated with cell adhesion and focal adhesion were enriched in mGSTc01 cells. The mGSTc01 cells demonstrated obvious malignant behaviors, notably elevated migration, adhesion, and proliferation. In immunocompetent mice, subcutaneous xenografts not only reserved the aggressive phenotype but also displayed a response to imatinib, underscoring the model's applicability for advancing therapeutic research. Conclusion: We firstly established a mGSTc01 cell line derived from C57BL/6 J mice GIST tumor offers, which closely mimicking human disease characteristics. It is a potent platform for investigating tumor microenvironment of GIST in mice model, and provides a novel way for new therapeutic discoveries in GIST.

By the coordination between dimethylimidazole and ZnNO36H2O, the dodecahedral ZIF-8 were prepared first. Using ZIF-8 as template and dopamine hydrochloride as raw material, polydopamine nanoparticles(PDA NPs) with hollow structure were then prepared by chelation competition induced polymerization(CCIP) method. Further & hybull; more, by using PDA NPs as drug carrier, azithromycin loaded PDA NPs(AZM@PDA NPs) were finally prepared. The hollow structure of PDA NPs contributed to high azithromycin loading with a drug loading rate of up to 20.2%. AZM@PDA NPs have high biocompatibility and low cytotoxicity, and can promote the expression of antiinflammatory cytokines in cells. The sustained release of azithromycin achieved by AZM@PDA NPs can effectively treat periodontitis and resist alveolar ridge resorption, with good biosafety in vivo and broad application prospects.

Background:Tracheal adenoid cystic carcinoma (TACC) is a rare malignant tumor with limited treatment options for unresectable cases. Although case reports have indicated the value of photodynamic therapy (PDT), its efficacy, survival outcomes, and prognostic factors remain poorly characterized. This two-center retrospective study aimed to evaluate the long-term outcomes of patients with TACC treated with PDT and to identify predictors of treatment response. Methods:A retrospective analysis was conducted on 39 patients with TACC who received continuous PDT treatment in two hospitals from August 2011 to September 2023. All patients were intravenously injected with hematoporphyrin derivative (HpD) at a dose of 2 mg/kg and treated 48 hours later. The therapeutic effect was evaluated according the 2019 efficacy evaluation standard for PDT for respiratory tumors. The primary endpoints were overall survival (OS) and progression-free survival (PFS), while the secondary endpoints included objective response rate (ORR) and safety. The prognostic factors were analyzed via a Cox regression model. Results:The study included 39 patients, with a mean age of 47.51±14 years (range, 19-79 years). The most recent efficacy evaluation of 39 patients, conducted 1 month after PDT treatment, showed complete response (CR) in 5 patients, partial response (PR) in 25 patients, and progressive disease (PD) in 9 patients. Both OS and PFS were significantly longer in the PR group than in the PD group (OS: P=0.008; PFS: P=0.005). The 5-, 10-, and 15-year survival rates for patients were 73.2%, 64.1%, and 42.7%, respectively. Only 7 patients experienced complications. Univariate Cox regression analysis indicated that the age and treatment interval were significant risk factors for the emergence of TACC (P=0.03). Conclusions:We found that PDT for patients with TACC achieved satisfactory clinical efficacy and safety, resulting in longer survival and fewer complications. Moreover, treatment interval and age were risk factors for the development of TACC.

Exogenous iron delivery using iron-containing nanomaterials is an alternative strategy for enhancing the efficacy in ferroptosis tumor therapy but limited by the problems of low iron content, low tumor enrichment, low cellular uptake, and uncontrolled release of iron ions. To solve the problems, an FeOOH-assisted approach is demonstrated to produce iron hybrid polymer nanospindles (IHPNSs) for efficient iron delivery and ferroptosis tumor therapy. The IHPNSs are prepared through the cohydrolysis of FeCl3·6H2O with aniline, pyrrole, or amino-pyrrole. On the one hand, the hydrolysis of Fe3+ generates FeOOH particles, which further act as the templates to form fusiform architectures. On the other hand, Fe3+ triggers the oxidative polymerization of aniline, pyrrole, or amino-pyrrole. The as-prepared polymers are capable of coordinating with excessive Fe3+ and locate on the FeOOH templates, thus producing Fe3+/polymer composite-coated FeOOH nanospindles. Systematic studies indicate that the one-dimension-like morphology facilitates tumor enrichment and cellular uptake of IHPNSs. Besides the high iron content of IHPNSs, the controlled release of Fe3+ stimulated by the overexpressed glutathione (GSH) in the tumor microenvironment is achieved. The released Fe3+ is further transformed to Fe2+ by scavenging GSH, which leads to excessive accumulation of reactive oxygen species and lipid peroxides and finally induces ferroptosis of tumor cells. As a proof of concept, the IHPNSs show good efficacy in the treatment of a rat model of bladder tumors in situ.

The limitations of existing monotherapies underscore the necessity of exploring innovative synergistic anticancer interventions. Ferroptosis, an iron-dependent form of cell death, is increasingly recognized for its pivotal role in tumor biology and therapeutic strategies. Photothermal therapy (PTT) utilizes near-infrared (NIR) light to induce tumor ablation through heat generation and is a burgeoning area in cancer treatment. Ferroptosis induction generates reactive oxygen species (ROS) and lipid peroxidation (LPO) to enhance the efficacy of mild-temperature PTT. In contrast, photothermal effects can accelerate the rate of the Fenton reaction. Utilizing nanoplatforms such as polymers, metal-phenolic networks (MPNs), metal-based materials, hollow mesoporous Prussian blue (HMPB), biocompatible materials and metal–organic frameworks (MOFs) can effectively modulate the synergistic effects of ferroptosis and PTT. This review delved into the most recent progress regarding the synergistic interactions between collaborative mechanisms involved in ferroptosis and PTT, as well as the potential integration of these strategies with other treatment modalities. Finally, we have offered insights into the perspectives and challenges associated with the clinical translation of this innovative and promising emerging paradigm.