Jul 2026· Journal of Controlled Release· pp.
115197
· 0 citations· 43 references
Medicine
TL;DR
Combined with anti-PD-1 antibody (α-PD-1), NPMn/Syro exerts synergistic antitumor efficacy, providing a promising therapeutic strategy for clinical management of tumor.
Abstract
Metabolically deranged tumor microenvironment (TME) with compromised innate immune signaling induces severe immunosuppression and markedly blunts the efficacy of cancer immunotherapy. Activation of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway can boost antitumor immunotherapy, and a manganese complex, called TPE-Mn, was developed in this work. Nevertheless, the excess lactate accumulation and poor tumor-targeted delivery jointly restrict the clinical translation of Mn2+-based immune stimulation. Herein, we designed glutathione (GSH)-sensitive nanoparticles (NPMn/Syro) co-loaded with TPE-Mn and the monocarboxylate transporter 1/4 (MCT1/4) inhibitor syrosingopine (Syro) at an optimized ratio to simultaneously remodel tumor metabolism and activate innate immunity. Upon effective intratumoral accumulation, NPMn/Syro concurrently release two payloads: Syro inhibit lactate efflux and elevates intracellular lactate, while TPE-Mn disrupts mitochondrial dynamics. Collectively, these synergistic effects shift the mitochondrial fusion-fission balance toward excessive fission, leading to mitochondrial fragmentation and cytosolic mitochondrial DNA (mtDNA) leakage. The leaked mtDNA activates cGAS, while Mn2+ further amplifies the activation of the STING pathway to boost innate immune responses. Moreover, metabolic disruption and mitochondrial injury cooperatively trigger immunogenic cell death (ICD) and potentiate systemic antitumor immunity. Furthermore, combined with anti-PD-1 antibody (α-PD-1), NPMn/Syro exerts synergistic antitumor efficacy, providing a promising therapeutic strategy for clinical management of tumor. This work presents a metabolic-metal synergistic strategy to augment the cGAS-STING pathway activation and significantly reverse metabolism-mediated immunosuppressive TME.
Cancer immunotherapy has substantially advanced cancer treatment; however, durable responses remain uncommon in tumors with low immunogenicity and strongly suppressive tumor microenvironments (TME). Among innate immune pathways, cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) signaling has attracted considerable attention because of its ability to initiate broad antitumor immune responses. Despite this promise, the therapeutic use of STING agonists is limited by rapid systemic clearance, insufficient tumor accumulation, and dose-limiting inflammatory toxicity. Simultaneously, metabolic adaptations within tumors, including elevated glycolytic flux, lactate enrichment, and redox imbalance, continue to undermine immune cell function and restrict treatment efficacy. Zn-based nanoplatforms have recently emerged as versatile systems capable of simultaneously addressing both challenges. Controlled intracellular release of Zn2+ can potentiate cGAS activity and strengthen downstream STING signaling, whereas oxidative stress induced by these nanomaterials promotes DNA damage, cytosolic DNA leakage, and immunogenic cell death. These effects are not limited to the activation of innate immunity. Several Zn-containing nanoplatforms reshape the metabolic landscape of the TME by lowering lactate accumulation and partially restoring immune cell activity. Consequently, dendritic cell (DC) maturation and antigen presentation are enhanced, leading to more effective T cell-driven antitumor responses. This review examines the emerging role of Zn2+ in regulating the immune and metabolic pathways relevant to cancer therapy. We discuss current strategies for designing Zn-based nanoplatforms, with particular emphasis on the mechanisms linking metabolic intervention to cGAS-STING activation. Dedicated sections examine Zn-based platforms for drug delivery and photodynamic and sonodynamic therapies, as well as their capacity to promote DC activation and combination immunotherapy. Finally, we consider the major barriers to clinical translation, including biosafety, delivery efficiency, and large-scale manufacturing, and outline the directions for the development of next-generation Zn-based immunotherapeutic systems. STATEMENT OF SIGNIFICANCE: This review provides a comprehensive, mechanistically integrated perspective on Zn-based nanoplatforms as multifunctional immunotherapeutic systems that bridge tumor metabolic reprogramming and cGAS-STING-mediated innate and adaptive immune activation. Unlike previous reviews that primarily focused on STING agonists or Zn-based nanomaterials independently, this study highlights how tumor-responsive Zn²⁺ release, oxidative stress, DNA damage, and metabolic remodeling collectively enhance antitumor immunity. This review critically compares the design principles, therapeutic mechanisms, and translational potential of diverse Zn-based nanoplatforms and discusses the key challenges in biosafety, manufacturing, and clinical translation. This review offers a conceptual framework to guide the rational development of next-generation Zn-based nanomedicines for precision cancer immunotherapy.
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.
The clinical efficacy of melanoma immunotherapy is frequently compromised by an immunosuppressive, "cold" tumor microenvironment (TME) driven by redox dysregulation and the metabolic polarization of tumor-associated macrophages (TAMs). To overcome these intertwined barriers, a macrophage-targeted, biomimetic nanoplatform (MOF-808-Ro-G/N) is developed. This system integrates a catalytic metal-organic framework (MOF-808) core loaded with a PERK inhibitor and a CD47 blocking agent, encapsulated within a Rhizopus oryzae (Ro)-derived fungal shell. The biomimetic shell leverages Dectin-1 interactions to enable precise TAM targeting and accumulation. Upon endocytosis, the acidic endosomal microenvironment activates the MOF core to deplete glutathione and trigger a surge of reactive oxygen species, thereby inducing immunogenic cell death. Synergistically, the released payloads disrupt the PERK-ATF4 metabolic stress axis, reprogramming pro-tumorigenic M2 TAMs toward an anti-tumor M1 phenotype, while concurrently blocking the CD47-SIRPα checkpoint to restore macrophage phagocytosis. Through this orchestrated modulation, MOF-808-Ro-G/N effectively remodels the TME into an immunologically "hot" niche, promoting robust cytotoxic T lymphocyte infiltration and achieving substantial tumor growth suppression. Overall, this "metabolic-immune dual-reprogramming" strategy provides a promising materials-driven paradigm to overcome immunotherapy resistance in solid tumors.
The results indicate that calcium overload, FTY720-mediated TRPM7 inhibition, and MnO2-induced redox imbalance can drive PANoptosis, offering a new concept for enhancing cancer immunotherapy.
Aiyang Tong, Yang Zhou, Yang Ding et al.· Materials Today Bio· 0 citations
A TME-responsive nanoplatform composed of MPDA core shielded by manganese dioxide (MnO2) shell, enabling sequential co-delivery of doxorubicin and resveratrol for chemo-/chemodynamic/photothermal therapy, offering a promising paradigm for overcoming chemoresistance in bladder cancer.
Zhihua Zeng, Chao Hu, Yihe Li et al.· Colloids and Surfaces B: Bio...· 0 citations
Renal cell carcinoma (RCC) remains highly resistant to conventional therapies, highlighting the need for innovative treatments. Tumor-associated macrophages (TAMs) play a critical role in RCC progression by promoting immune evasion and supporting tumor growth. Manganese ions have been shown to activate the cGAS-STING pathway, enhancing anti-tumor immunity. However, precise targeting and controlled release of manganese in the tumor microenvironment remain major challenges.
We developed manganese-polydopamine nano-immunomodulators (PDA-Mn-HA NPs), coated with hyaluronic acid (HA), to selectively target CD44 receptors on TAMs and RCC cells. These nanoparticles were characterized for their size, surface charge, and manganese release profile. In vitro, we assessed their ability to induce M1 macrophage polarization, stimulate cytokine production, and generate reactive oxygen species (ROS). We also evaluated their potential to induce pyroptosis in RCC cells and tested their therapeutic effects in a preclinical RCC mouse model.
PDA-Mn-HA NPs effectively induced M1 macrophage polarization, promoting the release of pro-inflammatory cytokines and chemokines crucial for immune activation. Transcriptomic analysis showed significant changes in gene expression related to immune response in macrophages, confirming the nanoparticles’ immunomodulatory role. In RCC cells, PDA-Mn-HA NPs induced ROS-mediated pyroptosis through the caspase-3/GSDME pathway, further enhancing immune system activation. In vivo, PDA-Mn-HA NPs not only inhibited RCC tumor growth but also increased immune cell infiltration, particularly cytotoxic T cells, reshaping the tumor microenvironment to promote anti-tumor immunity.
PDA-Mn-HA NPs offer a promising strategy for RCC treatment by synergistically targeting both TAMs and RCC cells. This dual action enhances anti-tumor immunity and addresses the challenges of manganese ion delivery, presenting a novel approach to RCC immunotherapy.
This work was funded by the National Natural Science Foundation of China (Grant No. 81801913) and the Guangdong Basic and Applied Basic Research Foundation (Grant No. 2020B1515020036).
Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)
