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2024

Wang Hai, Chinese Academy of Sciences, and other teams have collaborated to reveal the potential role of metal ion chelating L-phenylalanine nanostructures in activating immune responses!

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In patients receiving immune checkpoint blockade-based cancer immunotherapies, such as programmed death -1 (PD-1) and programmed death-ligand 1 (PD-L1), the immunosuppressive tumor microenvironment strongly influences the response rate.

On August 26, 2024, Wang Hai, Nie Guangjun and Ran Haitao of Chongqing Medical University, the Center for Excellence in Nanoscience of the Chinese Academy of Sciences, jointly communicatedNature Nanotechnology（IF=38）Published online entitled“Metal-ion-chelating phenylalanine nanostructures reverse immune dysfunction and sensitize breast tumour to immune checkpoint blockade”The research paper,The studyIt was demonstrated that metal ion-chelating L-phenylalanine nanostructures act synergistically with short-term starvation (STS) to remodel the immunosuppressive microenvironment of breast and colorectal tumors.

These nanostructures modulate the electrophysiological behavior of dendritic cells and activate them through the NLRP3 inflammasome and calcium-mediated nuclear factor-κB pathway. STS promotes cellular uptake of nanostructures through amino acid transporters and plays a key role in dendritic cell maturation and tumor-specific cytotoxic T lymphocyte responses.This study demonstrates the potential role of metal ion-chelated L-phenylalanine nanostructures in activating immune responses, and the role of STS therapy in improving nanomaterial-mediated cancer immunotherapy.

Immune checkpoint blockade (ICB)-based cancer immunotherapy has shown promising clinical efficacy in a variety of cancer patients. However, clinical observations suggest that only a small percentage of patients derive lasting clinical benefit from ICB immunotherapy. The mechanism that mediates immune tolerance may be due to the establishment of an immunosuppressive tumor microenvironment (TME), which limits the infiltration and depletion of cytotoxic T lymphocytes (CTLs), including tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), tumor-associated neutrophils (TANs), immature dendritic cells (DCs), and regulatory T cells (Tregs). Therefore, reversal of the immunosuppressive barrier has been extensively studied to improve the efficacy of ICB immunotherapy, especially in the treatment of solid tumors.

Despite the low number of DCs in tumors and lymphoid organs, studies have shown that the maturation of DCs is essential for the activation of tumor-specific immunity. In order to induce mature dendritic cells to trigger an initial immune response, pathogen-associated molecular patterns (pathogen-associated molecular patterns, PAMPs) and danger-associated molecular patterns (associated-molecular patterns, DAMPs) have been discovered in recent decades. In addition to these danger signals, DC functions, including maturation, cytokine production, and migration, are also regulated by electrophysiological responses.DC has a variety of functional ion channels, which can flow into or out of metal ions. Importantly, cytoplasmic K in DC⁺and Ca²The concentration of is closely related to DC maturation.

This study describes a strategy that utilizes metal ion-chelated L-phenylalanine (L-Phe) nanostructures to modulate the electrophysiological behavior of DCs to enhance ICB immunotherapy. Magnesium ion (Mg ²), ferrous ion (Fe ²) and zinc ions (Zn ²) Combined with L-phenylalanine to form nanospheres (Ph-Mg), nanoneedles (Ph-Fe) and nanosheets (Ph-Zn). These nanostructures are unstable and break down in the acidic environment of lysosomes. The simulation results show that the metal ion chelate l-Phe dimer is the most stable conformation and can open the potassium ion channel Kv1.3.

With K ⁺efflux, depolarization-induced Ca ²Inflow into DC activates the calmodulin (CaM)-regulated nuclear factor-κB (NF-κB) pathway, promotes DC maturation and triggers the secretion of pro-inflammatory cytokines. In addition, the uptake of nanostructures in DC may induce the release of cathepsin B, which is associated with K ⁺Together, the efflux activates the inflammasome pathway and promotes DC maturation. In particular, malnutrition limits the maturation of DCs to further strengthen. The study suggests that triggering DC maturation with metal ion-chelated nanostructures may be beneficial for programmed death -1 (PD1) or programmed death-ligand 1 (PD-L1)-based immunotherapy.

Huang He and others have shown that oral Shensong Yangxin capsule after radiofrequency ablation can reduce the recurrence of atrial fibrillation in patients with persistent atrial fibrillation!

China Agricultural University Wang Yang/Wu Congming/Shen Jianzhong and other cooperation latest PNAS

Huang He and others have shown that oral Shensong Yangxin capsule after radiofrequency ablation can reduce the recurrence of atrial fibrillation in patients with persistent atrial fibrillation!

China Agricultural University Wang Yang/Wu Congming/Shen Jianzhong and other cooperation latest PNAS