Well-/dedifferentiated liposarcoma is characterized by frequent local recurrence and limited responsiveness to immune checkpoint blockade (ICB), highlighting the need for pathology-feasible immune stratification and rational combination strategies. We integrated bulk transcriptomics, single-cell RNA sequencing, proteomics, and spatial immunofluorescence to characterize the tumor immune microenvironment in WD/DD LPS. Unsupervised analyses identified two reproducible states: an immune-high (Hi) subtype enriched for type I interferon programs and an immune-low (Lo) subtype enriched for extracellular matrix (ECM)-associated features. Based on these signatures, we derived a five-marker immunohistochemistry (IHC) panel (CD8A, CD27, AOAH, NCF1, and LST1) to enable pathology-based immune subtyping. In a small, independent exploratory cohort of ICB-treated WD/DD LPS patients (n = 10), the locked classifier showed a directionally consistent trend in outcomes, but was underpowered and should be considered hypothesis-generating, warranting validation in larger, prospectively collected cohorts. IFN-α downregulated tumor-cell-derived COL6A1 in vitro and was associated with reduced ECM-linked exclusion features. In a PBMC-humanized xenograft model, IFN-α plus anti-PD-1 therapy enhanced tumor control, accompanied by increased CD8+ T-cell infiltration, providing preclinical proof-of-concept support for IFN-α as a combination partner for PD-1 blockade. Mechanistically, the proposed COL6 axis is a hypothesis supported by in vitro IFN-α-dependent suppression of tumor cell COL6A1 and correlative multi-omic/spatial observations; the in vivo model used here does not establish COL6 causality, and definitive testing will require genetic loss-of-function studies. Together, these findings define an immune-ECM axis, present a pathology-ready IHC framework for hypothesis-generating immune stratification, and support further investigation of IFN-α-based combination strategies under rigorous clinical validation.

Fibrosarcoma is an infiltrative malignant soft tissue sarcoma primarily managed with extensive surgical resection. However, securing adequate margins often compromises organ function, while postoperative recurrence and distant metastasis remain formidable clinical challenges, underscoring the urgent need for effective neoadjuvant therapeutic strategies. Neoadjuvant mild photo-immunotherapy represents a promising strategy for coupling preoperative tumor shrinkage with systemic immune priming. Notably, integrated analyses revealed relatively high expression of stimulator of interferon genes (STING) in fibrosarcoma, highlighting STING as a rational target for immunomodulation. Herein, we developed a biomimetic dual-driven STING nanoagonist for neoadjuvant mild photo-immunotherapy against fibrosarcoma. This nanoagonist comprises poly(lactic-co-glycolic acid) (PLGA) nanoparticles co-encapsulating the STING agonist 2',3'-cyclic GMP-AMP (cGAMP) and the photosensitizer indocyanine green (ICG) (cGAMP/ICG@PLGA, GIP), which are further camouflaged with calreticulin (CRT)-enriched fibrosarcoma cell membranes (CRTM) to form GIP@CRTM. The biomimetic CRTM cloak retains tumor cell membrane antigens and CRT "eat-me" signals, promoting homotypic tumor accumulation and uptake by dendritic cells (DCs), thereby facilitating cGAMP delivery and dual-driven STING activation in both tumor cells and DCs. Upon near-infrared irradiation, ICG-mediated mild phototherapy induces moderate photothermal heating and reactive oxygen species (ROS) generation, triggering immunogenic cell death and further amplifying tumor-intrinsic STING signaling through ROS-induced DNA damage. This synergistic therapeutic effect enabled effective preoperative tumor shrinkage while eliciting systemic antitumor immunity to suppress postoperative contralateral rechallenge tumor outgrowth and limit distant tumor progression. Thus, this study establishes a STING-amplified mild photo-immunotherapeutic strategy, providing a potential neoadjuvant treatment option for fibrosarcoma.

Cuproptosis, an emerging copper-dependent regulated cell death pathway, demonstrates significant potential for overcoming therapeutic resistance in oncology. However, its clinical translation remains constrained by the poor bioavailability of copper ionophores and intrinsic resistance mechanisms in tumor cells. Here, we developed a tumor microenvironment-responsive nanoparticle platform (PEMA) co-loading an MPC1 (mitochondrial pyruvate carrier 1) overexpression plasmid and the copper ionophore Elesclomol to establish a synergistic "metabolic reprogramming-oxidative stress amplification" strategy. The PEMA nanoparticle design incorporated disulfide bonds to deplete intracellular glutathione (GSH), while Elesclomol-mediated copper transport induced mitochondrial dysfunction and reactive oxygen species (ROS) generation. In vitro, PEMA achieved >99% tumor cell eradication in ACHN renal carcinoma models, accompanied by characteristic DLAT oligomerization, FDX1 downregulation, and disruption of mitochondrial ultrastructure. In vivo, PEMA treatment induced substantial tumor regression in xenograft models without detectable systemic toxicity. This study establishes a novel therapeutic paradigm that integrates metabolic targeting with oxidative stress potentiation to overcome therapeutic resistance in solid tumors.

Well-differentiated liposarcoma (WDLPS) and dedifferentiated liposarcoma (DDLPS) are characterized by recurrent MDM2-centered amplification of chromosome 12q13–15, yet this diagnostic label reduces a complex structural lesion to a binary result. An architecture-resolved 12q amplicon platform requires an MDM2-centered dosage anchor plus direct evidence of nontrivial topology or carrier state; cargo, regulatory, and functional data define progressively higher-resolution features. When only MDM2 amplification is documented, the lesion is best described as diagnostic 12q amplification rather than a fully resolved platform. This review presents an evidence-graded architecture-to-function framework that separates direct WDLPS/DDLPS observations from mechanisms inferred from broader amplification biology. Disease-specific evidence supports heterogeneous 12q carriers, including ring, giant marker, rod-shaped, discontinuous, and neochromosome-like structures, as well as enhancer coamplification or altered 3D contacts. In contrast, chromothripsis, telomere crisis/BFB remodeling, ecDNA-like dynamics, and enhancer hubs are treated as extrapolated or testable mechanisms unless directly validated in liposarcoma. Conclusions are weighted by methodological resolution: cytogenetics/FISH define diagnostic amplification and visible carrier classes; MLPA or array-based assays define dosage and discontinuity; WGS with long-read or optical mapping is needed for junction-level architecture; and single-cell/spatial assays mainly resolve cellular-state or ecosystem context unless paired with structural readouts. MDM2–p53 and CDK4–RB remain central outputs, whereas selected cargo, lineage state, metabolism, and tumor–microenvironment programs are interpreted as evidence-ranked cooperating or downstream modules. Clinically, architecture-aware interpretation is proposed as a prospective framework for sampling, model design, biomarker development, and trial stratification, not as an established basis for routine management.

Chemotherapy resistance remains a critical bottleneck limiting its clinical efficacy in small cell lung cancer (SCLC), with its core mechanisms and targeted intervention strategies urgently requiring breakthroughs. Our study revealed that the BMX (bone marrow tyrosine kinase on chromosome X)-E2F1 (E2F transcription factor 1) axis is a pivotal regulator of chemoresistance in SCLC. Synchronous upregulation of phosphorylated BMX (Tyr566) and E2F1 was observed in SCLC tissues and cells. Mechanistically, BMX stabilized E2F1 via the ERK1/2 (extracellular signal-regulated kinase 1/2)-Cyclin D1/CDK4/6 (cyclin-dependent kinase 4/6) signaling axis, phosphorylating E2F1 at Ser332/337 and inhibiting its degradation via the ubiquitin-proteasome pathway. Inhibition or knockdown of BMX reduced E2F1 stability, promoting its degradation and reversing chemoresistance. E2F1 knockdown decreased the expression of genes associated with cell cycle regulation, migration, invasion, and DNA repair, further sensitizing chemoresistant SCLC cells to cisplatin. We also discovered IHMT-15137, a potent and selective BMX inhibitor. In vitro studies using SCLC patient-derived cells (PDCs)/patient-derived organoids (PDOs) and chemoresistant cell lines revealed that IHMT-15137, combined with cisplatin, synergistically induced cell cycle arrest, apoptosis, and DNA damage while suppressing cell migration and invasion. In vivo xenograft models demonstrated that the combination significantly inhibited tumor growth without causing significant toxicity. Our findings reveal the molecular mechanisms of SCLC chemoresistance and suggest potential therapeutic strategies targeting the BMX-E2F1 axis to overcome this challenge.

Retroperitoneal liposarcoma (RPL) presents a distinct "high-risk" disease spectrum, in which the phenotypic transition from well-differentiated liposarcoma (WDLPS) to dedifferentiated liposarcoma (DDLPS) constitutes a critical biological event leading to treatment failure and patient mortality. This review provides a systematic summary of the clinical features and multi-omics mechanisms underlying this transition. Clinically, this process is characterized by time-dependent malignant progression over approximately 7-8 years. Biologically, it reflects a layered evolutionary process involving a shared genomic trunk defined by MDM2 proto-oncogene (MDM2) and cyclin-dependent kinase 4 (CDK4), secondary driver events such as JUN proto-oncogene, AP-1 transcription factor subunit (JUN), and GLI family zinc finger 1 (GLI1), as well as progressive epigenetic locking. Recent single-cell multi-omics studies have further revealed that hypoxia and immunosuppressive pressure within the tumor microenvironment (TME) play pivotal roles in phenotypic plasticity through the selection of tumor adipocyte stem cells (tumor ASCs) with stem-like features. On the basis of this genome-epigenome-microenvironment coupling model, we discuss novel therapeutic strategies including induced redifferentiation, metabolic targeting, and microenvironment remodeling, thereby providing a theoretical foundation for interrupting the malignant progression of RPL.

Immune checkpoint blockade (ICB) has shown clinical promise in cancer immunotherapy, but colorectal cancer (CRC) remains difficult to treat due to a complex immunosuppressive tumor microenvironment (TME). This TME features dysregulated CD47/SIRPα and PD-1/PD-L1 pathways, T cell exhaustion, and infiltration of immunosuppressive cells. Therefore, novel strategies to reshape TME are critically needed. Here we developed bioinspired nanodevices (SPCM@DMgTi-ADM) for CRC immunotherapy. These nanodevices consist of dendritic titanium-magnesium nanoparticles (DMgTi) that serve as both a sonosensitizer and a carrier for aldometanib (ADM). The nanoparticles are coated with genetically engineered membranes displaying SIRPα and PD-1 decoy receptors (SPCM). This design achieves cascade reinforcement between AMP-activated protein kinase (AMPK) activation and cGAS-STING activation. The SPCM coating simultaneously blocks SIRPα/CD47 and PD-1/PD-L1 axes, preliminarily reshaping the TME. Released Mg2+ induces conformational changes in LFA-1 on CD8+ T cells, promoting their tumor infiltration and cytotoxic function. ADM together with sonodynamic therapy (SDT) induces AMPK activation, which drives autophagy-dependent ferroptosis. This synergistic process triggers strong Immunogenic cell death (ICD). The released dsDNA potently activates the cGAS-STING, which in turn inhibits GPX4 and sustains ferroptotic stress. This creates a self-amplifying loop: ferroptosis promotes dsDNA release, which activates cGAS-STING; STING then suppresses GPX4, worsens ferroptosis and further boosting anti-tumor immunity. Both in vitro and in vivo studies confirm that our nanodevice effectively evaluates tumors and activates systemic anti-tumor immunity, offering a clinically translatable strategy for precision CRC therapy.

Design of effective methanol oxidation reaction (MOR) electrocatalysts with fast reaction kinetics and exceptional CO resistance remains a grand challenge. Herein, we report an electron-restructuring strategy based on an inverse interfacial structure, by decorating the vanadium carbide nanoclusters (VC NCs) on hexagonal Pd nanosheets (NSs) for efficient MOR. The VC-decorated Pd NSs evolve into unique mulberry leaf-like structures (NMLs) with the jagged edges, enhancing active sites exposure and interfacial charge transfer. The VC0.01/Pd NMLs exhibit high mass activity (1768.44 A g(Pd)(-1)), 23.6 and 6.4 times higher than Pd NSs and commercial Pd/C catalyst, respectively. The VC0.01/Pd NMLs also show high tolerance to CO poisoning. Theoretical calculations further reveal a strong VC-Pd interfacial interaction, modulating the Pd's d-band center, reducing CO* adsorption, and enhancing OH* generation. The work shows that the construction of inverse VC-Pd interfaces is an effective approach to improve electrocatalytic performance of Pd catalysts for MOR.

Abstract Background Retroperitoneal sarcoma (RPS) is a type of malignant tumour arising from mesenchymal tissues within the retroperitoneal space. RPSs tend to develop covertly and are often undiscovered when they have already grown significantly and invaded surrounding tissues and organs. These malignancies demonstrate high recurrence rates, present surgical challenges and exhibit limited responsiveness to radiotherapy and chemotherapy. Serum‐derived molecules are known to play critical roles in tumourigenesis and tumour progression. However, the serum molecular profile of RPS patients remains unclear. Methods We performed multi‐omics analysis of serum samples from patients with retroperitoneal dedifferentiated liposarcoma. Prolactin concentrations were quantified using Enzyme‐Linked Immunosorbent Assay (ELISA). RNA‐seq facilitated the identification of candidate signalling pathways, while gene expression was validated through quantitative polymerase chain reaction, immunohistochemistry and western blot analyses. Molecular mechanisms underlying transcriptional regulation were investigated through Chromatin Immunoprecipitation‐qPCR (ChIP‐qPCR) and dual‐luciferase reporter gene assays. Results Integrative multi‐omics profiling identified significant perturbations in galactose metabolism coupled with marked elevation of prolactin (PRL) levels in Retroperitoneal Liposarcoma (RLPS) patients. Further screening of serum prolactin levels in 100 patients with retroperitoneal tumours revealed that 90% of the cases exhibited hyperprolactinaemia in our research cohort, encompassing both malignant sarcomas and benign tumours. Studies at the clinical sample, cellular and animal levels have found that abnormally elevated prolactin in the serum can originate from sarcoma tissues. Mechanistic investigations identified SRY‐box transcription factor 4 (SOX4) as a previously unrecognised transcriptional regulator of PRL. Functionally, PRL not only enhanced liposarcoma cell and fibrosarcoma cell proliferation but also conferred resistance to MDM2 inhibitors. Signalling pathway analysis revealed that PRL activates the Janus Kinase–Signal Transducer and Activator of Transcription Pathway (JAK–STAT) signalling pathway and up‐regulates c‐MYC expression. Conclusions This study indicates that PRL can serve as an oncogenic driver and therapeutic target. The identification of SOX4–PRL–c‐MYC signalling axis provides actionable insights for developing novel therapeutic strategies against this malignancy. Key points Retroperitoneal sarcoma cells can secrete prolactin into the bloodstream, inducing hyperprolactinaemia, which subsequently triggers metabolic reprogramming, such as glucose metabolism. SOX4 can function as a transcription factor that facilitates PRL transcription. PRL can activate the JAK–STAT signalling pathway by binding to PRLR on sarcoma cells, leading to the up‐regulation of c‐MYC.

Previous studies have demonstrated that induction of reactive oxygen species (ROS) significantly enhances the cytotoxicity of paclitaxel (Ptx). Tetrandrine (Tet), a potent ROS inducer, synergistically enhances the antitumor effects of Ptx. To codeliver Ptx and Tet, which have low solubility, high systemic toxicity, and poor tumor selectivity, we designed a tumor microenvironment-activatable prodrug-based delivery system. A ROS-responsive prodrug was developed by the conjugation of Ptx to a biocompatible polymer (1,2-distearoyl-sn-glycero-3-phosphoethanolamine-poly(ethylene glycol), DSPE-PEG) via the ROS-cleavable thioketal (TK) linker, which could self-assemble into core-shell nanoparticles with Tet in the inner core to form redox-responsive Ptx/Tet-coloaded nanoparticles (P/T-NPs). The synergistic anticancer mechanism of Ptx and Tet was systematically investigated by cytotoxicity assays, ROS detection, mitochondrial tracing, transmission electron microscopy, and both in vitro and in vivo experiments. Cell uptake of P/T-NPs increased in a time-dependent manner, with partial accumulation observed in the mitochondria. The targeted release of Tet in tumor sites with high ROS levels could further elevate intracellular ROS, which in turn accelerated the cleavage of the TK linker and promoted the release of Ptx, thereby enhancing its antitumor effect. P/T-NPs showed superior cytotoxicity, which is strongly correlated to the superior autophagy-inducing ability of P/T-NPs. Moreover, P/T-NPs effectively inhibit the tumor growth compared to either the free drug or their combination therapy. This study integrates tumor microenvironment activation, self-amplified drug release, and ROS-enhanced chemotherapy into a single nanoplatform, offering a promising strategy for targeted cancer therapy.

Combination chemotherapy is considered more effective than monotherapy in enhancing clinical outcomes. Ferroptosis, a unique form of regulated cell death, has been demonstrated to inhibit tumor growth and progression. Consequently, combining ferroptosis with chemotherapy represents a promising and innovative approach to antitumor therapy. In this study, we developed a novel TMTP1-modified biomimetic nanocrystal (TRNC@P + L) for the co-delivery of PTX and LF3, aiming to achieve ferroptosis-combined chemotherapy in gastric cancer. TRNC@P + L, which incorporates a tumor-homing peptide-modified red blood cell membrane, demonstrated efficient tumor targeting, prolonged circulation, enhanced drug bioavailability, and reduced non-specific toxicities of free PTX and LF3. By utilizing the synergistic effects of PTX and LF3, TRNC@P + L combination therapy significantly inhibited tumor growth, as demonstrated by both in vitro and in vivo studies. Mechanistically, TRNC@P + L triggers ferroptosis in tumor cells by downregulating GPX4 expression, the promotion of ROS accumulation, and the enhancement of lipid peroxidation. These processes synergistically enhance the anticancer efficacy of PTX.

Rationale: Immunogenic cell death (ICD) offers a promising avenue for the treatment of triple-negative breast cancer (TNBC). However, optimizing immune responses remains a formidable challenge. This study presents the design of RBCm@Pt-CoNi layered double hydroxide (RmPLH), an innovative sonosensitizer for sonodynamic therapy (SDT), aimed at enhancing the efficacy of programmed cell death protein 1 (PD-1) inhibitors by inducing robust ICD responses. Methods: Pt-CoNi layered double hydroxide (LDH) nanocages were synthesized using a two-step method, followed by functionalization with red blood cell membranes to prepare RmPLH. The in vitro assessments included evaluations of cell toxicity, cellular uptake, and sonodynamic effects of RmPLH. Key mechanisms-such as oxidative stress, DNA damage, pyroptosis, cGAS/STING pathway activation, and inhibition of cellular migration and invasion-were explored under varying treatment conditions in 4T1 cells. Tumor-bearing mice were employed to evaluate tumor-targeting capabilities and the synergistic tumor-suppressive effects of RmPLH combined with PD-1 inhibitors. Comprehensive safety evaluations, including blood tests, biochemical analyses, and histopathological examinations, were also conducted. Results: The synthesized Pt-CoNi LDH exhibited a uniform rhombic dodecahedral nanocage morphology with an average particle size of approximately 231 nm. Encapsulation with red blood cell membranes conferred prolonged systemic circulation, enhanced tumor targeting, and reduced immune clearance for RmPLH. Upon ultrasound (US) stimulation, the LDH released substantial levels of reactive oxygen species (ROS) and platinum ions. The ROS effectively induced endoplasmic reticulum stress and ferroptosis, while platinum ions facilitated DNA crosslinking, triggering significant DNA damage. ROS-induced pyroptosis released inflammatory mediators and damage-associated molecular patterns (DAMPs), which activated the cGAS/STING pathway and reinforced ICD. Combining RmPLH with PD-1 inhibitors significantly enhanced therapeutic efficacy against TNBC. Furthermore, safety assessments confirmed the excellent biocompatibility and biosafety of RmPLH. Conclusion: The integration of RmPLH with PD-1 inhibitors substantially amplifies ICD, fostering robust antigen-specific T cell immunity and offering a promising therapeutic strategy for TNBC. This study represents a pioneering application of Pt (II)-based LDH nanocages in oncology, laying a foundation for future innovations in tumor immunotherapy.

Ulcerative colitis (UC) is a diffuse chronic inflammation in the superficial intestine. Excessive accumulation of reactive oxygen species (ROS) leads to the of the colorectal damage. As the anti-inflammation therapy needs to be last for at least 3-5 years, the drugs demand less toxicity. However, current treatments in the clinic are often accompanied by unavoidable adverse side effects. Hydrogen is a nontoxic antioxidant reagent with excellent permeability of biomembranes, which shows the potential in treating UC. A novel simply designed hydrogen storage particle, Magnesium Hydride (MgH2) particle with an outer shell of passivated Magnesium oxide (MgO), was constructed in the current study to enable the safe and controlled release of hydrogen. This studies demonstrated that magnesium hydride particle (MgH2@MgO) was effective in scavenging excessive ROS, relieving the inflammation, and reversing the progression of UC through inhibiting the NF-κB signaling pathway, which provided the experimental evidence for the clinical prevention and therapy of UC.

Transient receptor potential (TRP) channels are not only multimodal ion sensors but also couplers between metabolic states and immune responses. TRP gating is controlled by lipid signaling (PIP2, DAG, cholesterol), redox/energy cues (NAD+/ADPR/ROS, ATP/AMP), and metabolite-derived signals (pH/lactate, bile acids, endocannabinoids, eicosanoids, SCFAs). In turn, TRP-driven Ca2+ signaling reprograms AMPK-mTORC1, glycolysis/OXPHOS, FAO, and glutaminolysis, thereby reshaping the metabolic programs and effector functions of T/B cells, macrophages, NK/DCs. In gut, skin, and arthritis, microbiota-metabolite-TRP axes dictate inflammatory phenotypes; within tumors, lactate, adenosine, and kynurenine modulate TRPs in cancer and immune infiltrates. In this study, we synthesize TRP metabolic sensing mechanisms, immunometabolic reprogramming, and pharmacological opportunities, highlighting synergistic strategies combining metabolic interventions with TRP modulation for precision management of inflammation-related diseases.

INTRODUCTION:5-Aminolevulinic acid (5-ALA)-based photodynamic therapy (PDT) has demonstrated considerable potential in breast cancer treatment. However, its efficacy is limited by low tissue selectivity and the rapid conversion of 5-ALA to non-photosensitive heme in tumor tissues, reducing its therapeutic effectiveness. OBJECTIVES:This study aims to develop a multifunctional nanomedicine to enhance 5-ALA's PDT efficacy while introducing chemodynamic therapy (CDT) for synergistic tumor inhibition. By designing a zinc-ion-doped cuprous metal-organic framework (MOF) nanocarrier loaded with 5-ALA (5-ALA@Zn-CuTz), we seek to improve tumor targeting, prolong photosensitizer retention, and enhance therapeutic outcomes. METHODS:To enhance biocompatibility and active tumor targeting, the surface of 5-ALA@Zn-CuTz nanoparticles (NPs) was modified with a platelet membrane (PM), forming 5-ALA@Zn-CuTz@PM NPs. The therapeutic efficacy was evaluated in vitro and in vivo using mice breast cancer models. Cellular uptake, reactive oxygen species (ROS) generation, and tumor inhibition efficiency were analyzed through fluorescence imaging, biochemical assays, and histological analysis. RESULTS:Upon intravenous administration, 5-ALA@Zn-CuTz@PM NPs selectively accumulated in breast cancer cells. Within the tumor, Zn2+ bound to intracellular protoporphyrin IX (PpIX) to form PpIX-Zn, inhibiting heme oxygenase-1 (HO-1) activity and preventing the conversion of PpIX into heme. This increased the effective intracellular concentration of the photosensitizer, thereby enhancing PDT. Additionally, Cu+ catalyzed the decomposition of excess H2O2 in the tumor microenvironment, generating oxygen and hydroxyl radicals, which alleviated hypoxia and activated CDT. The synergistic PDT/CDT effect significantly enhanced tumor growth inhibition in vitro and in vivo. CONCLUSION:5-ALA@Zn-CuTz@PM NPs effectively enhance PDT efficacy through selective tumor targeting and HO-1 inhibition while simultaneously leveraging CDT for additional tumor suppression. The combined PDT/CDT strategy demonstrated superior therapeutic outcomes, highlighting the potential of this nanoplatform as a promising approach for breast cancer treatment.