Key Takeaways & Executive Findings
- •• • Combination of COD/MTO@PLGA@FA and αPD-L1 reduced tumor-infiltrating CD8+PD-1+ T cells to 5.93%, compared to 35.9% in PBS controls (p < 0.01), demonstrating reversal of T cell exhaustion. This 6-fold reduction directly addresses a primary mechanism of immunotherapy resistance, potentially improving clinical response rates in checkpoint inhibitor-refractory patients. • • MDSC infiltration in tumor tissues decreased from 16.3% to 2.25% with the combination therapy and to 6.14% with COD/MTO@PLGA@FA alone, indicating effective inhibition of immunosuppressive cell populations. This 7.2-fold reduction in MDSCs could overcome a major barrier to chemo-immunotherapy efficacy, as MDSCs are known to suppress antitumor immunity. • • Splenic CD4+ and CD8+ T cell percentages increased from 63.4% to 72.3% and 25.7% to 32.5%, respectively, after combination treatment, reflecting robust systemic immune activation. This 8.9% and 6.8% absolute increase in helper and cytotoxic T cells suggests potential for durable antitumor memory responses, critical for preventing recurrence. • • DC maturation in tumor-draining lymph nodes reached 35.3% with COD/MTO@PLGA@FA plus αPD-L1, compared to 31.0% for MTO@PLGA, enhancing antigen presentation. This 4.3 percentage point improvement over MTO@PLGA alone underscores the added benefit of cholesterol depletion in promoting adaptive immunity, which is essential for effective chemo-immunotherapy.
China Clean Energy & Battery Radar
Get verified English translations, SEM micrographs & open-access PDF alerts from China's leading state key laboratories delivered to your inbox every Monday at 08:00 EST.
Abstract
Chemotherapy induces immunogenic cell death (ICD) but is compromised by elevated cholesterol in the tumor microenvironment (TME), which activates myeloid-derived suppressor cells (MDSCs) and exhausts CD8+ T cells. A poly(lactide-co-glycolide) (PLGA)-based nanoplatform (COD/MTO@PLGA@FA) co-loading mitoxantrone (MTO) and cholesterol oxidase (COD) was engineered to respond to acidic TME, releasing MTO and COD. MTO kills tumor cells and triggers ICD; COD consumes cholesterol, downregulating PD-1 on tumor-infiltrating CD8+ T cells and inhibiting MDSC activation. In 4T1 tumor-bearing mice, COD/MTO@PLGA@FA plus αPD-L1 increased splenic CD4+ and CD8+ T cells from 63.4% to 72.3% and 25.7% to 32.5%, respectively. CD8+PD-1+ T cells decreased to 5.93% versus 35.9% (PBS), 31.4% (αPD-L1), 29.0% (MTO@PLGA), 23.0% (COD/MTO@PLGA), and 12.2% (COD/MTO@PLGA@FA). MDSC infiltration dropped from 16.3% to 2.25% (combination) and 6.14% (COD/MTO@PLGA@FA alone). DC maturation in tumor-draining lymph nodes reached 35.3% with the combination. The platform reverses CD8+ T cell exhaustion and remodels the immunosuppressive TME, significantly inhibiting tumor growth. This strategy offers a practical approach to enhance chemo-immunotherapy by targeting cholesterol metabolism.
1. Introduction
Chemotherapeutic agents such as mitoxantrone (MTO) and doxorubicin induce immunogenic cell death (ICD), releasing tumor antigens and damage-associated molecular patterns (DAMPs) that activate antitumor immune responses. However, the tumor microenvironment (TME) imposes immunosuppressive barriers: elevated cholesterol levels, a byproduct of rapid tumor proliferation, drive the activation and proliferation of myeloid-derived suppressor cells (MDSCs) and promote exhaustion of tumor-infiltrating CD8+ T cells. This exhaustion, characterized by upregulated PD-1 expression, severely limits the efficacy of chemo-immunotherapy, leading to poor clinical outcomes and resistance to immune checkpoint blockade.
Existing strategies to modulate the TME have focused on metabolic interventions, such as lactate consumption, but cholesterol metabolism remains underexploited. The designed nanoplatform, COD/MTO@PLGA@FA, co-loads MTO and cholesterol oxidase (COD) in a PLGA matrix functionalized with folic acid for tumor targeting. Upon accumulation in the acidic TME, the platform rapidly releases MTO and COD. MTO directly kills tumor cells and induces ICD, while COD enzymatically oxidizes cholesterol to hydrogen peroxide, depleting a critical immunosuppressive metabolite. This dual action reverses CD8+ T cell exhaustion, inhibits MDSC activation, and synergizes with anti-PD-L1 antibody to amplify antitumor immunity. The platform addresses the bottleneck of TME-mediated immunosuppression by targeting a previously overlooked metabolic pathway, offering a translatable approach to enhance chemo-immunotherapy.
Loading authentic research manuscript (Pages 1–5)...
ZHOU Hao, HE Hao-Ze, LI Qian-Ru, ZHANG Xiao-Yang, LIU Chang-Jiang, HU Xu-Qi, CHEN Zhu, CHEN Wei-Hai, ZHANG Xian-Zheng (2025). Nanotherapeutic Platform-Mediated Cholesterol Metabolism Regulation for Boosting Antitumor Chemo-Immunotherapy. SCIENCE CHINA Materials. https://doi.org/10.1007/s40843-025-3348-1
Research & Educational Purpose Only: The translations, structured abstracts, analytical annotations, and data reports provided by SinoGreenTechare intended exclusively for academic research, internal corporate R&D, and educational benchmarking. They do not constitute formal engineering, chemical safety, legal, or professional advice.
Copyright & Intellectual Property Notice: Original copyright of the underlying source articles and experimental data remains with the respective authors, institutions, and original publishing journals. SinoGreenTech claims intellectual property only over its proprietary translations, analytical syntheses, and AEO structured enhancements in accordance with international fair use and academic citation principles.
Frequently Asked Questions
What is the mechanism by which COD/MTO@PLGA@FA reverses CD8+ T cell exhaustion, and what quantitative evidence supports it?
COD consumes cholesterol in the TME, downregulating PD-1 expression on tumor-infiltrating CD8+ T cells. In 4T1 tumor-bearing mice, the percentage of CD8+PD-1+ T cells decreased to 5.93% with COD/MTO@PLGA@FA plus αPD-L1, compared to 35.9% in PBS controls (p < 0.01). This 6-fold reduction directly correlates with restored T cell effector function, as evidenced by increased splenic CD8+ T cells (25.7% to 32.5%).
How does the platform inhibit MDSC activation, and what are the industrial implications for overcoming immunosuppression?
Cholesterol depletion by COD inhibits MDSC activation and proliferation. MDSC infiltration in tumor tissues dropped from 16.3% to 2.25% with combination therapy and to 6.14% with COD/MTO@PLGA@FA alone. This 7.2-fold reduction addresses a major clinical hurdle: MDSCs suppress antitumor immunity and correlate with poor prognosis. The platform's ability to remodel the TME could enhance responsiveness to checkpoint inhibitors in patients with high MDSC burden.
What are the scalability and manufacturing challenges for COD/MTO@PLGA@FA, and how might they impact cost parity with existing nanomedicines?
The PLGA-based platform utilizes established nanoprecipitation methods, but co-loading COD (a protein) and MTO requires careful optimization to maintain enzymatic activity and drug ratio. Scalability may be limited by COD stability and the need for cold-chain storage. However, PLGA is FDA-approved and cost-effective; with process optimization, the platform could achieve cost parity with liposomal doxorubicin (e.g., Doxil) at scale, though final pricing depends on COD sourcing and purification costs.
What is the translational potential of targeting cholesterol metabolism in chemo-immunotherapy, and what are the key failure risks?
Targeting cholesterol metabolism is promising because it addresses a fundamental immunosuppressive mechanism. In vivo, the combination achieved 35.3% DC maturation and significant tumor inhibition. However, risks include potential systemic cholesterol depletion affecting normal cells, immunogenicity of COD, and heterogeneity in TME cholesterol levels across tumor types. Long-term safety and efficacy in human trials remain to be established, but the preclinical data warrant further investigation.
How does the acidic TME-responsive release profile of COD/MTO@PLGA@FA compare to passive targeting, and what are the pharmacokinetic advantages?
The platform exploits the weakly acidic TME (pH ~6.5) to rapidly release MTO and COD, enhancing local drug availability. This active release mechanism contrasts with passive accumulation, potentially reducing systemic toxicity. While pharmacokinetic data are not detailed in the provided text, the targeted delivery via folate functionalization likely improves tumor accumulation. The rapid release ensures high intratumoral concentrations of both agents, which is critical for inducing ICD and cholesterol depletion, as evidenced by the significant immune cell modulation observed.
Related Chinese Research & Cross-Citations
Ammonium Vanadate Cathodes in Aqueous Zinc-Ion Batteries: Design Strategies and Research Progress
Aqueous zinc-ion batteries (AZIBs) offer a compelling combination of high safety, environmental compatibility, and abundant zinc resources, positioning them as viable candidates for grid-scale energy storage. Their practical deployment, however, is constrained by cathode materials that suffer from structural degradation, sluggish Zn2+ diffusion, and inadequate electronic conductivity. Ammonium vanadates (AVOs) have emerged as high-performance cathodes owing to their layered or tunneled frameworks, which accommodate reversible Zn2+ (de)intercalation with diffusion coefficients superior to conventional vanadium oxides. This review systematically examines recent advances in AVO cathodes for AZIBs, correlating morphological variations—including nanowires, nanobelts, and microflowers—with electrochemical characteristics. The analysis establishes structure–performance relationships that govern capacity retention, rate capability, and cycling stability. Key optimization strategies are critically assessed: defect engineering to enhance electronic conductivity and active site density, interlayer spacing modulation via pre-intercalated cations or structural water to facilitate Zn2+ transport, and composite construction with conductive carbonaceous or polymeric matrices to mitigate dissolution and improve mechanical integrity. Despite these advances, challenges persist in achieving long-term cycling stability (>10,000 cycles) and high areal mass loading (>10 mg cm-2) required for commercial viability. The review concludes by outlining future research directions, including operando characterization of degradation mechanisms and scalable synthesis routes for AVO cathodes in practical AZIB configurations.
Microenvironment-responsive therapeutic platforms: Innovations for spinal cord injury repair
Spinal cord injury (SCI) remains a formidable clinical challenge due to the complex, dynamic lesion microenvironment that impedes axonal regeneration and functional recovery. This highlight examines a microenvironment-responsive therapeutic platform integrating microneedle delivery, ferroptosis modulation, and hydrogen therapy. The platform leverages the pathological hallmarks of SCI—oxidative stress, iron dyshomeostasis, and lipid peroxidation—to achieve spatiotemporally controlled cargo release. By combining microneedle arrays for minimally invasive intraparenchymal administration with hydrogen-releasing biomaterials, the system addresses the dual bottlenecks of poor drug penetration across the blood-spinal cord barrier and insufficient neutralization of reactive oxygen species. Ferroptosis inhibition is achieved through iron chelation and glutathione peroxidase 4 (GPX4) stabilization, while hydrogen gas scavenges hydroxyl radicals and peroxynitrite. This multimodal strategy attenuates secondary injury cascades, reduces glial scar formation, and promotes neural stem cell differentiation. The work is supported by the National Natural Science Foundation of China (82574518) and the Talent Cultivation Project of Paring Academicians with Young Talents in higher education institutions in Zhejiang. The authors declare no conflict of interest. This highlight underscores the translational potential of microenvironment-responsive platforms for SCI repair, emphasizing the need for rigorous preclinical validation and scalable manufacturing.
Dual-Site Adsorption over Phosphorus-Doped Copper Oxide for Efficient CO2 Electroreduction to Ethylene
Electroreduction of CO2 to ethylene offers a promising route for renewable electricity storage, yet achieving high ethylene selectivity at industrial current densities remains challenging due to the large energy barrier for C–C coupling. Here, we report a “MOF-assisted in situ doping” strategy to introduce the oxophilic nonmetal phosphorus (P) into the copper oxide (CuO) lattice, constructing a localized Cu–P dual-site adsorption configuration for the key *OCCHO intermediate. The optimized catalyst delivers an impressive Faradaic efficiency of 64.6% for ethylene with a partial current density of 646 mA cm-2. Comprehensive structural characterizations demonstrate that P mainly occupies Cu sites, generating abundant lattice defects and oxygen vacancies. In situ synchrotron infrared spectroscopy and theoretical calculations reveal that P doping modulates the electronic structure of Cu, optimizes the binding energies of *CO and *CHO, and stabilizes *OCCHO via P–O/Cu–C dual-site adsorption, thereby significantly lowering the asymmetric C-C coupling energy barrier to 0.74 eV. This work highlights a dual-site microenvironment regulation strategy for CO2-to-ethylene electroreduction.
Hydrophilic Single-Atom Interface Unlocks Low-Potential CO Removal on Pt in PEMFCs
Proton exchange membrane fuel cells (PEMFCs) fed with reformate hydrogen suffer severe anode poisoning by trace CO, necessitating high CO electrooxidation potentials that degrade performance and durability. This work introduces a Pt@CrSA-N-C anode catalyst featuring a hydrophilic Cr single-atom interface that simultaneously weakens CO adsorption on Pt via electronic regulation and promotes water activation, thereby lowering the CO oxidation onset potential to approximately 0.13 V vs. RHE. The onset potential was determined by two independent methods: the first potential at which the background-corrected current exceeds 0 mA cm-2 during CO oxidation reaction tests in a three-electrode system, and the potential at which the forward scan current exceeds the N2 background current in CO-stripping voltammetry. The catalyst achieves a maximum power density under 100 ppm CO that surpasses reported advanced catalysts, as compiled in Table S5. Structural, spectroscopic, and electrochemical characterizations collectively establish a coherent rationale for the hydrophilic single-atom interface strategy. This approach addresses the longstanding trade-off between CO tolerance and Pt utilization, offering a viable route for low-potential CO removal in practical PEMFC anodes.
An Ionoelastomer-Based Bioinspired Wearable Electronics with Tele-Perception and Tactile Sensation for Machine Learning-Assisted Rehabilitation Management
Comprehensive assessment of rehabilitation efficiency is essential for designing appropriate training programs for better musculoskeletal functional recovery. Existing contact-receptor-dependent rehabilitation assessment systems mostly focus on assessing the restoration of muscle function by evaluating grip strength or joint flexion angle; however, parameters reflecting neuromuscular synergistic function are always overlooked. Herein, we develop an ionoelastomer-based soft artificial electroreceptor (SAER) that integrates tele-perception and tactile sensation to track the rehabilitation process, collecting signals related to approaching speed and grip strength sequentially. The SAER uses polyurethane ionoelastomer incorporated with quasi-solid conductive salt as the electric field receptor, and is integrated on a rehabilitation-training ball after assembly to establish an untethered detection device; this enables the remote capture of hand approaching parameter within a 9 cm range, followed by the quantification of grip strength when contacting and grasping. Furthermore, a data-driven assessment system is established by integrating machine learning, which accurately classifies rehabilitation efficiency into six levels; it supports for rehabilitation evaluation and training programs adjustment. Overall, the SAER-based rehabilitation management system establishes a paradigm that synergistically evaluating parameters corresponding to neuromuscular functional restoration and holds strong potential for home-based active rehabilitation for minimizing dependence on frequent clinical supervision.
Microwave-Absorbing Materials with Strong Environmental Adaptability for Corrosion Protection, Anti-Icing, and Thermal Management
Microwave-absorbing materials (MAMs) deployed on naval vessels, aerospace vehicles, and critical electronic systems face coupled electromagnetic, marine salt-spray corrosion, and extreme-temperature loads that legacy single-function absorbers cannot withstand. This review consolidates progress on three environmentally adaptive MAM classes: corrosion-protective, anti-icing, and thermal-management absorbers. The electromagnetic loss and impedance-matching fundamentals are first established, then the synergistic mechanisms, design strategies, and characterization protocols for each class are examined against representative material systems and their measured performance. The analysis identifies a shared design logic—multiscale hierarchical architecture, interfacial polarization engineering, and multifunctional phase integration—while distinguishing the divergent protection mechanisms: barrier and passivation effects for corrosion, surface-energy and latent-heat regulation for anti-icing, and phonon–electron transport decoupling for thermal management. Persistent bottlenecks include the trade-off between impedance matching and protective-layer density, the absence of standardized coupled-field test protocols, and the scarcity of long-term salt-spray and thermal-cycling durability data. Future directions are delineated: intelligent self-adaptive absorbers, multiphysics-coupled simulation frameworks, and environmentally benign multifunctional integration. The review provides a theoretical and technical basis for the design, construction, and engineering scale-up of next-generation high-performance absorbers for aerospace, electronic, and marine equipment.