Combining this CuZnS@BSA nanoregulator with PD-L1 blockade led to potent suppression of both subcutaneous tumor growth and lung metastasis, thus providing a direct, elegant link between metabolic reprogramming and systemic immune activation for TNBC therapy.
Abstract
Rationale Since the therapeutic resistance of triple-negative breast cancer (TNBC) is mainly attributable to excessive glutathione (GSH) accumulation and its ‘cold’ immune landscape, we designed biomimetic CuZnS@BSA nanoregulators that exploit a pH-triggered ‘disarm-and-attack’ cascade, thereby initiating a well-defined, sequential therapeutic process in the acidic tumor microenvironment. Methods Biomimetic CuZnS@BSA nanoclusters were synthesized via a self-assembly method. Their pH-responsive release kinetics and synergistic therapeutic mechanisms (GSH depletion, ROS generation, and cuproptosis) were systematically evaluated in vitro using 4T1 cells. In vivo anti-tumor efficacy, immune microenvironment remodeling, and anti-metastatic effects were investigated in subcutaneous and lung metastasis TNBC mouse models, both alone and in combination with PD-L1 blockade. Results The platform first releases H2S to deplete intracellular GSH, thus removing the major antioxidant defenses of the tumor, then follows with the release of Cu2+ to induce cuproptosis, which effectively bypasses the apoptosis resistance commonly seen in TNBC. In addition, the released Zn2+ acts as an immune modulator by promoting the recognition of leaked mitochondrial DNA. This activates the cGAS-STING signaling pathway, and in vivo experiments clearly showed that it remodels the tumor microenvironment in a highly favorable manner, characterized by increased CD8+ T cell infiltration and enhanced dendritic cell maturation. Conclusion Combining this nanoregulator with PD-L1 blockade led to potent suppression of both subcutaneous tumor growth and lung metastasis, thus providing a direct, elegant link between metabolic reprogramming and systemic immune activation for TNBC therapy.
Although strategic combination of cuproptosis and chemotherapy is emerging as a promising strategy against triple-negative breast cancer (TNBC), current drug delivery systems remain considerable challenges in achieving co-delivery of different formulas, such as complex nanocarrier design, limited drug loading capacity, and insufficient tumor targeting. Herein, cancer cell membrane-camouflaged, self-assembled nanoparticles (DCM@CCM) were fabricated for precision combination therapy against TNBC. In the strategy, the carrier-free self-assembled nanoparticles were one-pot fabricated by co-assembling copper ions (Cu2+), doxorubicin (DOX), and methotrexate (MTX) via hydrogen bonds, π-π stacking and metal-ligand coordination effect, followed by in situ camouflaging with cancer cell membranes. Benefiting from the homologous targeting effect, the developed DCM@CCM could specifically target tumor cells, promoting their cellular uptake. Following internalization into tumor cells, the DCM@CCM disassembled in response to a weakly acidic tumor microenvironment, releasing Cu2+, DOX, and MTX. Importantly, the Cu2+ was reduced to Cu+ by depleting intracellular glutathione, which not only activated cuproptosis but also catalyzed the endogenous hydrogen peroxide into highly toxic hydroxyl radicals via a Fenton-like reaction, resulting in mitochondrial dysfunction. Simultaneously, both DOX and MTX disrupted DNA synthesis to trigger cell apoptosis. Both in vitro and in vivo experiments indicated that DCM@CCM exhibited potent cytotoxicity against TNBC cells and effectively suppressed tumor growth in heterotopic tumor models with minimal side effects. Overall, our study not only provides a promising strategy for precision combination therapy against TNBC but also expands insight for developing nanoscale self-assembly-enabled nanomedicine.
Qian Liu, Xinyi Tao, Yawen Luo et al.· ACS Applied Bio Materials· 0 citations
Hepatocellular carcinoma (HCC) remains highly lethal due to a complex tumor microenvironment (TME) that limits therapeutic efficacy. Herein, a dual-targeted nanotherapeutic platform (SC@GRT-COF-366) based on a covalent organic framework (COF-366) is reported for synergistic HCC treatment. This multifunctional system integrates chemotherapy, photodynamic therapy, autophagy regulation, and TME remodeling to synergistically inhibit tumor metastasis. Gal-D5HT-modified nanoparticles achieve enhanced HCC targeting via myeloperoxidase (MPO)-responsive aggregation in the inflammatory microenvironment and ASGPR-mediated uptake. Upon light irradiation, COF-366 generates singlet oxygen to induce tumor cell apoptosis and simultaneously enhances MPO expression and neutrophil infiltration, further amplifying MPO-triggered nanoparticle aggregation and establishing a self-amplifying retention-therapy cascade. Meanwhile, co-loaded sorafenib and chloroquine enable combined chemotherapy and autophagy inhibition, effectively overcoming drug resistance. In vivo results demonstrate significantly enhanced and prolonged tumor accumulation compared with single-targeted systems, resulting in a tumor growth inhibition rate of 93.5 ± 1.02% in subcutaneous models and effective suppression of lung metastasis in orthotopic HCC models. Notably, treatment markedly reduces neutrophil extracellular traps (NETs) formation, indicating favorable remodeling of the tumor immune microenvironment. Collectively, this multifunctional COF-based nanoplatform integrates dual-targeted delivery, amplified tumor retention, and synergistic multimodal therapy, offering a promising strategy for advanced HCC treatment.
Le Wang, Xiang Wang, Hengrui Li et al.· Small· 0 citations
Resistance to cyclin-dependent kinase (CDK) 4/6 inhibitors, such as ribociclib (RB), limits breast cancer therapy. Although PEG10 siRNA (siPEG10) can counteract this resistance, achieving targeted, synchronized co-delivery to reshape the immunosuppressive tumor microenvironment (TME) remains a formidable challenge. By loading RB and siPEG10 into PEG-β-CD-modified mesoporous silica nanoparticles (PMSNs) and coating them with breast cancer cell membranes (CM), the nanocomposite RB/siPEG10@PMSNs-CM was synthesized. The nanomaterials were characterized for size, charge, drug loading, and pH-responsive release. Therapeutic efficacy, immunotherapy-related potentials, and underlying mechanisms were evaluated using in vitro functional assays, an anoikis resistance model, and in vivo breast cancer models. Toxicity was assessed in liver and kidney tissue. The nanodrug RB/siPEG10@PMSNs-CM (<200 nm) exhibited enhanced cellular uptake and pH-dependent drug release. The zeta potential of the RB/siPEG10@PMSNs-CM was negative. The nanodrug significantly inhibited tumor cell growth, migration, invasion, and metastasis, while inducing apoptosis. Crucially, the nanodrug overcame anoikis resistance, upregulated cleaved caspase-3 and cleaved PARP, reversed epithelial-mesenchymal transition (EMT) markers (increased E-cadherin and decreased Vimentin), and inhibited p-STAT3 and p-ERK signaling. Furthermore, the nanodrug exhibited lower toxicity to liver and kidney than RB. In Conclusion, the developed biomimetic nano-delivery system RB/siPEG10@PMSNs-CM successfully co-delivers RB and siPEG10 and exhibits a favorable safety profile. This platform exhibits anti-primary tumor and anti-metastatic efficacy and effectively overcomes anoikis resistance in breast cancer, which correlated with the suppression of the MEK/ERK and STAT3 signaling pathways, offering a promising combination strategy for advanced breast cancer immunotherapy and targeted treatment.
Yifan Yu, Lidan Liu, Ying Cai et al.· Cancer Letters· 0 citations
Incomplete microwave ablation (iMWA) remains a major challenge in the clinical management of hepatocellular carcinoma (HCC), as residual tumors often foster an immunosuppressive microenvironment and upregulate PD-L1 expression, thereby promoting immune evasion and recurrence. This study systematically elucidates the mechanisms underlying HCC progression and metastasis following iMWA and describes the design of a dual-ion/immune checkpoint nanoplatform (aP@Mn/Ca) based on a metal-organic framework (MOF). Leveraging the excellent biocompatibility and tumor microenvironment-responsive degradability of MOFs, this platform enables efficient co-delivery of Ca2+, Mn2+, and an anti-PD-L1 (aPD-L1) antibody specifically to residual tumor tissues to overcome post-ablation immune barriers. Specifically, upon tumor accumulation, controlled Ca2+ release induces mitochondrial stress and inflammasome activation, triggering gasdermin-mediated pyroptosis and immunogenic cell death (ICD). Concurrently, Mn2+ activates innate immunity by potentiating the cGAS-STING signaling pathway. This synergistic induction of pyroptosis and STING activation promotes inflammatory cytokine production, antigen presentation, and cytotoxic T cell priming. Meanwhile, the local delivery of aPD-L1 mitigates adaptive immunosuppression and reduces systemic toxicity. Consequently, aP@Mn/Ca transforms iMWA into a systemic immunotherapeutic strategy, effectively suppressing HCC recurrence and metastasis both in vitro and in vivo. In summary, this work establishes an ion-based immunomodulatory paradigm integrating ICD, innate immune activation, and immune checkpoint blockade, offering a promising nanotherapeutic framework for preventing post-ablation HCC recurrence and enhancing immunotherapy in solid tumors.
Triple-negative breast cancer (TNBC) frequently exhibits profound chemoresistance and a highly immunosuppressive tumor microenvironment (TME), leading to suboptimal clinical outcomes with high risks of early recurrence and distant metastasis. Existing monotherapies remain inadequate in disrupting these therapeutic barriers. To overcome the aforementioned obstacles, we developed a spatiotemporally regulated organelle-targeted nanoplatform, IR820-GEM@MIL101 (IGM), Its design aims to achieve precise mitochondrial intervention and coordinate cGAS–STING-mediated immune activation. This design relies on EPR-mediated passive targeting to achieve preferential tumor accumulation, allowing IGM to accumulate specifically in tumor tissues and trigger a series of reactions in response to endogenous stimuli (acidic pH and elevated glutathione) in synergy with exogenous near-infrared laser activation, enabling controlled drug release. The platform efficiently eliminates tumor cells by inducing multiple modes of cell death, including pyroptosis, ferroptosis, and apoptosis, while simultaneously triggering immunogenic cell death (ICD) and activating the cGAS–STING pathway. This dual immunostimulatory strategy effectively converts “cold” tumors into “hot” tumors. In a bilateral tumor model, IGM treatment increased CD8+ T-cell infiltration in distal tumors by 94% and achieved a tumor inhibition rate of 92.7% in distant lesions. This work shifts the therapeutic focus from superficial multi-drug packaging to precise organelle-targeted intervention, providing a promising strategy for light-regulated combinatorial immunotherapy against aggressive malignancies.
Pan Zhang, Ming-Lun Liu, Lei Huang et al.· Materials Today Bio· 0 citations
The clinical benefits of cancer immunotherapy are primarily limited by low response rates and an immunosuppressive tumor microenvironment (TME). Metal elements such as iron, manganese, copper, and zinc, as essential micronutrients for the body, play a key regulatory role in the development and effector functions of immune cells, giving rise to the interdisciplinary field of metalloimmunology. However, the poor tumor-targeting ability of free metal ions, their high systemic toxicity, and rapid in vivo metabolism severely hinder their clinical translation. This review systematically summarizes research progress on metal nanomedicines as smart delivery systems in tumor immunotherapy, outlining design paradigms for nanoplatforms from an engineering perspective, covering microenvironment-responsive release, active targeting strategies, and multifunctional integration concepts. It elucidates the molecular mechanisms by which metal ions regulate antitumor immunity by inducing immunogenic cell death (ICD), activating the stimulator of interferon genes (STING) signaling pathway, and reshaping the metabolic microenvironment, and explores synergistic strategies combining metal nanomedicines with immune checkpoint blockade (ICB), photothermal therapy (PTT), or photodynamic therapy (PDT). Unlike previous reviews that often focus on either the immunological functions of metal ions or the engineering of nanocarriers in isolation, this review provides an integrated framework that explicitly links metal ion identity, immune pathway engagement, nanoplatform design parameters, and translational barriers. Central to this framework is a mechanism-design matching principle that connects the specific temporal and intensity requirements of each immune activation pathway with tailored material selection and release kinetics. These immune effects are context-dependent and may vary in selected preclinical models. This paper integrates metallobiology, nanomedicine, and tumor immunology to provide a theoretical framework for the precise design of smart metal immunotherapeutics, while identifying key challenges for clinical translation, such as the therapeutic safety window and metal homeostasis compensation mechanisms.
Shuyong Yan, Fei Zhou· Frontiers in Chemistry· 0 citations
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