Targeting metabolic sensing switch GPR84 on macrophages for cancer immunotherapy.

INTRODUCTION: As one of the major components of the tumor microenvironment, tumor-associated macrophages (TAMs) possess profound inhibitory activity against T cells and facilitate tumor escape from immune checkpoint blockade therapy. Converting this pro-tumorigenic toward the anti-tumorigenic phenotype thus is an important strategy for enhancing adaptive immunity against cancer. However, a plethora of mechanisms have been described for pro-tumorigenic differentiation in cancer, metabolic switches to program the anti-tumorigenic property of TAMs are elusive. MATERIALS AND METHODS: From an unbiased analysis of single-cell transcriptome data from multiple tumor models, we discovered that anti-tumorigenic TAMs uniquely express elevated levels of a specific fatty acid receptor, G-protein-coupled receptor 84 (GPR84). Genetic ablation of GPR84 in mice leads to impaired pro-inflammatory polarization of macrophages, while enhancing their anti-inflammatory phenotype. By contrast, GPR84 activation by its agonist, 6-n-octylaminouracil (6-OAU), potentiates pro-inflammatory phenotype via the enhanced STAT1 pathway. Moreover, 6-OAU treatment significantly retards tumor growth and increases the anti-tumor efficacy of anti-PD-1 therapy. CONCLUSION: Overall, we report a previously unappreciated fatty acid receptor, GPR84, that serves as an important metabolic sensing switch for orchestrating anti-tumorigenic macrophage polarization. Pharmacological agonists of GPR84 hold promise to reshape and reverse the immunosuppressive TME, and thereby restore responsiveness of cancer to overcome resistance to immune checkpoint blockade.

A self-activating electron transfer antibacterial strategy: Co3O4/TiO2 P-N heterojunctions combined with photothermal therapy.

Implant-associated infections are significant impediments to successful surgical outcomes, often resulting from persistent bacterial contamination. It has been hypothesized that bacteria can transfer electrons to semiconductors with comparable potential to the biological redox potential (BRP). Building on this concept, we developed an antibiotic-free bactericidal system, Co3O4/TiO2-Ti, capable of achieving real-time and sustainable bactericidal effects. Our study demonstrated that Co3O4/TiO2-Ti, possessing an appropriately set valence band, initiated charge transfer, reactive oxygen species (ROS) production, and membrane damage in adherent Staphylococcus aureus (S. aureus). Notably, in vivo experiments illustrated the remarkable antibacterial activity of Co3O4/TiO2-Ti, while promoting soft-tissue reconstruction and demonstrating excellent cytocompatibility. Transcriptomic analysis further revealed a down-regulation of aerobic respiration-associated genes and an up-regulation of ROS-associated genes in S. aureus in the presence of Co3O4/TiO2-Ti compared to Ti. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis and gene set enrichment analysis (GSEA) identified alterations in respiratory metabolism, oxidative phosphorylation, and the synthesis of amino acid in S. aureus cultured on Co3O4/TiO2-Ti. Furthermore, when combined with near-infrared (NIR) irradiation and photothermal therapy (PTT), Co3O4/TiO2-Ti eliminated 95.71% of floating and adherent S. aureus in vitro. The findings suggest that this antibiotic-free strategy holds substantial promise in enhancing implant sterilization capabilities, thereby contributing to the prevention and treatment of bacterial infections through bandgap engineering of implants and NIR irradiation.

A Biomimetic Nanogenerator to Enhance Bone Regeneration by Restoring Electric Microenvironments.

Piezoelectric materials have received increasing attention in bone regeneration due to their prominent role in bioelectricity in bone homeostasis. This study aimed to develop bioactive barium titanate-chitosan-graphene oxide piezoelectric nanoparticles (BCG-NPs) to improve biocompatibility and stimulate bone repair. Butterfly loops, hysteresis loops, and in vitro microcurrent studies on BCG-NPs confirmed their good piezoelectric properties. BCG-NPs exhibited enhanced alkaline phosphatase activity, mineralized nodule formation, and expression of osteogenic-associated proteins and genes in human umbilical cord Wharton's jelly-derived mesenchymal stem cells by creating microelectric environments in response to noninvasive ultrasound stimulation. Further, BCG-NPs upregulated intracellular calcium ions via electrical stimulation. They acted synergistically with piezo-type mechanosensitive ion channel component 1 and calcium-permeable cation channel transient receptor potential vanilloid 4 to activate osteogenic differentiation. In conclusion, ultrasound-assisted BCG-NPs created a microelectric environment that putatively promoted bone repair in a noninvasive manner.