Manganese molybdate nanodots with dual amplification of STING activation for“cycle”treatment of metalloimmunotherapy

Certain types of cationic metal ions,such as Mn^(2+)are able to activate immune functions via the stimulator of interferon genes(STING)pathway,showing potential applications in eliciting antitumor immunity.How anionic ions interact with immune cells remains largely unknown.Herein,selecting from a range of cationic and anionic ions,we were excited to discover that MoO_(4)^(2-)could act as a cGAS-STING agonist and further confirmed the capability of Mn^(2+)to activate the cGAS-STING pathway.Inspired by such findings,we synthesized manganese molybdate nanoparticles with polyethylene glycol modification(MMP NDs)for cancer metalloimmunotherapy.Meanwhile,MMP NDs could consume glutathione(GSH)over-expressed in tumors and induce ferroptosis owing to high-valence Mo and Mn to elicit tumor-specific immune responses,which was further amplified by MMP-triggered the cGAS-STING activation.In turn,activated CD8+T cells to secrete high levels of interferonγ(IFN-γ)and reduced GPX4 expression in tumor cells to trigger ferroptosis-specific lipid peroxidation,which constituted a“cycle”of therapy.As a result,the metalloimmunotherapy with systemic administration of MMP NDs offered a remarkable tumor inhibition effect for a variety of tumor models.Our work for the first time discovered the ability of anionic metal ions to activate the immune system and rationally designed bimetallic oxide nanostructures as a multifunctional therapeutic nanoplatform for tumor immunotherapy.

Dendritic cell maturation in the tumor microenvironment

Maturation is essential for dendritic cells(DCs)to function as a bridge between innate and adaptive immunity.The plastic maturation states correspond to the multifaceted roles of DCs in the initiation of protective,tolerogenic and pathogenic immune responses.The formation of a distinct maturation state of DCs involves the complex crosstalk between the intrinsic differences in their ontogeny and the immune environments.Recent studies have defined a universal mature DC population in the tumor microenvironment(TME),but their ontogenesis and functions remain unclear.Here,we summarize recent advances in DC maturation and attempt to dissect the complex functions of mature DCs in the TME.We highlighted that there is a distinct similarity and heterogeneity of mature DCs in the TME,in which the environment and development are both important.These help us revisit the diversity of DC maturation and to better dissect the complex functions of DCs in the TME.

Interferon γ Stimulates Cellular Maturation of Dendritic Cell Line DC2.4 Leading to Induction of Efficient Cytotoxic T Cell Responses and Antitumor Immunity

Dendritic cells （DCs） are the most potent antigen-presenting cells （APCs） for the initiation of antigen （Ag）-specific immune responses. In most studies, mature DCs are generated from bone marrow cells or peripheral monocytes; in either case, the harvested cells are then cultured in medium containing recombinant GM-CSF, IL-4 and TNF-α for 7-10 days and stimulated with lipopolysaccharide （LPS）. However, this approach is time-consuming and expensive. There is another less cost approach of using immobilized DC cell lines, which can easily grow in the medium. A disadvantage with the immobilized DC cell lines, however, is that they are immature DCs and lack expression of MHC class Ⅱ and costimulatory CD40 and CD80 molecules. This, therefore, limits their capacity for inducing efficient antitumor immunity. In the current study, we investigated the possible efficacy of various stimuli （IL-1β, IFN-γ, TNF-α CpG and LPS） in converting the immature dendritic cell line DC2.4 to mature DCs. Our findings were quite interesting since we demonstrated for the first time that IFN-γ was able to stimulate the maturation of DC2.4 cells. The IFN-γ-activated ovalbumin （OVA）-pulsed DC2.4 cells have capacity to upregulate MHC class Ⅱ, CD40, CD80 and CCR7, and to more efficiently stimulate in vitro and in vivo OVA-specific CD8^＋ T cell responses and antitumor immunity. Therefore, IFN-γ-activated immortal DC2.4 ceils may prove to be useful in the study of DC biology and antitumor immunity.

Nanomedicine-mediated ubiquitination inhibition boosts antitumor immune response via activation of dendritic cells

Tumor immunotherapy as a promising method for tumor treatment received tremendous attention. However, the problem of low clinical response rate still needs to be solved, especially in the poorly immunogenic tumors. The enhancement of tumor antigens presentation can effectively activate dendritic cells (DCs) and improve the tumor immunotherapy. In this work, TAK-243 as an inhibitor of the ubiquitin activating enzyme (UAE), was fabricated into cationic lipid-assisted nanoparticle (CLANTAK-243). The obtained CLANTAK-243 could act as an effective tumor immunotherapy enhancer to promote the maturation of DCs as well as antigen presentation, which obviously stimulated the T cells activation and proliferation. Such CLANTAK-243 injected intravenously could well trigger immune response to tumor cells in vivo. Importantly, mice treated with CLANTAK-243 could obtain a long immune memory effect to protect themselves from re-challenged tumor cells. Therefore, this work presented an effective immunotherapy strategy for poorly immunogenic tumor.