Biomineralized MnO₂ Nanoplatforms Mediated Delivery of Immune Checkpoint Inhibitors with STING Pathway Activation to Potentiate Cancer Radio-Immunotherapy

Abstract

Radiotherapy (RT), as one of the main methods in the clinical treatment of various malignant tumors, would induce systemic immunotherapeutic effects by triggering immunogenic cell death (ICD) of cancer cells. However, the antitumor immune responses produced by RT-induced ICD alone usually are not robust enough to eliminate distant tumors and thus ineffective against cancer metastases. Herein, a biomimetic mineralization method for facile synthesis of MnO 2 nanoparticles with high antiprogrammed death ligand 1 (αPDL1) encapsulation efficiency (αPDL1@MnO 2 ) is proposed to reinforce RT-induced systemic antitumor immune responses. This therapeutic nanoplatformsmediated RT can significantly improve the killing of tumor cells and effectively evoke ICD by overcoming hypoxia-induced radioresistance and reprogramming the immunosuppressive tumor microenvironment (TME). Furthermore, the released Mn 2+ ions from αPDL1@MnO 2 under acidic tumor pH can activate the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway and facilitate the dendritic cells (DCs) maturation. Meanwhile, αPDL1 released from αPDL1@MnO 2 nanoparticles would further promote the intratumoral infiltration of cytotoxic T lymphocytes (CTLs) and trigger systemic antitumor responses, resulting in a strong abscopal effect to effectively inhibit tumor metastases. Overall, the biomineralized MnO 2 -based nanoplatforms offer a simple strategy for TME modulation and immune activation, which are promising for enhanced RT immunotherapy.

Manganese Dioxide-Entrapping Dendrimers Co-Deliver Protein and Nucleotide for Magnetic Resonance Imaging-Guided Chemodynamic/Starvation/Immune Therapy of Tumors

“…Such activation of the cGAS-STING pathway induces the generation of type I interferons (IFNs) to improve antigen presentation by dendritic cells (DCs) for augmented antitumor T cell responses. With these merits, innovative nanoplatforms such as amorphous porous manganese phosphate nanoparticles (NPs), biomineralized manganese dioxide (MnO 2 ), Mn 2+ -coordinated micelles, and metal-phenolic networks , have been developed for successful cGAS-STING-associated combination immunotherapy. Although Mn-based nanosystems have emerged as potent weapons in tumor immunotherapy, because of their multiple functions in immune activation, TME remodeling, and MR imaging monitoring, there are rare reports to integrate all the advantages of Mn in one nanoplatform for enhanced cancer treatment, especially by the combination of natural enzyme-based catalysts, metal-based catalysts, and immune stimulating agents.…”

Metal–Organic Framework-Based Nano-Activators Facilitating Microwave Combined Therapy via a Divide-and-Conquer Tactic for Triple-Negative Breast Cancer

“…Many studies have confirmed that activation of innate immunity has emerged as a hopeful strategy to expedite cancer immunotherapy; , as a key component of innate immunity, the cyclic GMP–AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway also plays a crucial role in activating antitumor immune response and reshaping tumor microenvironment (TME). − Briefly, the activation of the cGAS-STING pathway can promote the production of type I interferon (IFN) and the secretion of pro-inflammatory cytokines, thereby inducing innate immune response, increasing T lymphocyte infiltration, improving tumor immunosuppressive microenvironment, − and is expected to enhance the efficacy of MWTT-ICB combined therapy. According to recent researches, Mn 2+ can comprehensively enhance the activation of cGAS , and initiate the cGAS-STING pathway to obtain synergistic antitumor efficacy. , Some Mn 2+ -based treatment strategies have made conspicuous progress in clinical trials. − Thus, it is highly desirable to design a targeted and responsive delivery system that generates sufficient Mn 2+ to activate the cGAS-STING pathway in tumor cells, while achieving high concentration accumulation and penetration of immune agents.…”

Escherichia coli-Based In Situ Triggerable Probe as an Amplifier for Sensitive Diagnosis and Penetrated Therapy of Cancer

“…Hypoxia in tumor microenvironment (TME) is one of the most important factors that limit the effect of antitumor therapy. − For instance, oxygen plays a pivotal role in stabilizing DNA damages; typically, hypoxia limits radiation-induced DNA damages and thus induces radiotherapy resistance. , Besides, hypoxia suppresses the photosensitizer (PS) to photosensitize oxygen (O 2 ) into reactive oxygen species (ROS), , which further impairs the efficacy of photodynamic therapy (PDT). − Therefore, hypoxia relief is crucial for cancer treatment, and several methods have been performed to relieve hypoxia nowadays, including improving oxygen delivery, in situ oxygen generation, and inhibiting cellular respiration. − Escherichia coli (E. coli), with tumor-targeting ability and catalytic property under TME, can effectively release catalase after entering the tumor cells.…”