T cells become dysfunctional when they encounter self antigens or are exposed to chronic infection or to the tumour microenvironment1. The function of T cells is tightly regulated by a combinational co-stimulatory signal, and dominance of negative co-stimulation results in T cell dysfunction2. However, the molecular mechanisms that underlie this dysfunction remain unclear. Here, using an in vitro T cell tolerance induction system in mice, we characterize genome-wide epigenetic and gene expression features in tolerant T cells, and show that they are distinct from effector and regulatory T cells. Notably, the transcription factor NR4A1 is stably expressed at high levels in tolerant T cells. Overexpression of NR4A1 inhibits effector T cell differentiation, whereas deletion of NR4A1 overcomes T cell tolerance and exaggerates effector function, as well as enhancing immunity against tumour and chronic virus. Mechanistically, NR4A1 is preferentially recruited to binding sites of the transcription factor AP-1, where it represses effector-gene expression by inhibiting AP-1 function. NR4A1 binding also promotes acetylation of histone 3 at lysine 27 (H3K27ac), leading to activation of tolerance-related genes. This study thus identifies NR4A1 as a key general regulator in the induction of T cell dysfunction, and a potential target for tumour immunotherapy.

While immunotherapy holds great promise for combating cancer, the limited efficacy due to an immunosuppressive tumor microenvironment and systemic toxicity hinder the broader application of cancer immunotherapy. Here, we report a combinatorial immunotherapy approach that uses a highly efficient and tumor-selective gene carrier to improve anticancer efficacy and circumvent the systemic toxicity. In this study, we engineered tumor-targeted lipid-dendrimer-calcium-phosphate (TT-LDCP) nanoparticles (NPs) with thymine-functionalized dendrimers that exhibit not only enhanced gene delivery capacity but also immune adjuvant properties by activating the stimulator of interferon genes (STING)–cGAS pathway. TT-LDCP NPs delivered siRNA against immune checkpoint ligand PD-L1 and immunostimulatory IL-2–encoding plasmid DNA to hepatocellular carcinoma (HCC), increased tumoral infiltration and activation of CD8+ T cells, augmented the efficacy of cancer vaccine immunotherapy, and suppressed HCC progression. Our work presents nanotechnology-enabled dual delivery of siRNA and plasmid DNA that selectively targets and reprograms the immunosuppressive tumor microenvironment to improve cancer immunotherapy.

The efficacy of checkpoint immunotherapy to non-small cell lung cancer (NSCLC) largely depends on the tumor microenvironment (TME). Here, we demonstrate that CCL7 facilitates anti-PD-1 therapy for the KrasLSL−G12D/+Tp53fl/fl (KP) and the KrasLSL−G12D/+Lkb1fl/fl (KL) NSCLC mouse models by recruiting conventional DC 1 (cDC1) into the TME to promote T cell expansion. CCL7 exhibits high expression in NSCLC tumor tissues and is positively correlated with the infiltration of cDC1 in the TME and the overall survival of NSCLC patients. CCL7 deficiency impairs the infiltration of cDC1 in the TME and the subsequent expansion of CD8+ and CD4+ T cells in bronchial draining lymph nodes and TME, thereby promoting tumor development in the KP mouse model. Administration of CCL7 into lungs alone or in combination with anti-PD-1 significantly inhibits tumor development and prolongs the survival of KP and KL mice. These findings suggest that CCL7 potentially serves as a biomarker and adjuvant for checkpoint immunotherapy of NSCLC.

Mesoporous silica nanoparticles (MSNs) have received increasing interest due to their tunable particle size, large surface area, stable framework, and easy surface modification. They are increasingly being used in varying applications as delivery vehicles including bio-imaging, drug delivery, biosensors and tissue engineering etc.Precise structure control and the ability to modify surface properties of MSNs are important for their applications. This review summarises the different synthetic methods for the preparation of well-ordered MSNs with tunable pore volume as well as the approaches of drugs loading, especially highlighting the facile surface 2 functionalization for various purposes and versatile biomedical applications in oncology. Finally, the challenges of clinical transformation of MSNs-based nanomedicines are further discussed.

No abstract

Germinal center (GC) responses potentiate the generation of follicular regulatory T (TFR) cells. However, the molecular cues driving TFR cell formation remain unknown. Here, we show that sclerostin domain-containing protein 1 (SOSTDC1), secreted by a subpopulation of follicular helper T (TFH) cells and T–B cell border–enriched fibroblastic reticular cells, is developmentally required for TFR cell generation. Fate tracking and transcriptome assessment in reporter mice establishes SOSTDC1-expressing TFH cells as a distinct T cell population that develops after SOSTDC1– TFH cells and loses the ability to help B cells for antibody production. Notably, Sostdc1 ablation in TFH cells results in substantially reduced TFR cell numbers and consequently elevated GC responses. Mechanistically, SOSTDC1 blocks the WNT–β-catenin axis and facilitates TFR cell differentiation.

Brucine, a weak alkaline indole alkaloid, is one of the main bioactive and toxic constituents of Nux-vomica. Modern pharmacology studies and clinical practice demonstrate that brucine possesses wide pharmacological activities, such as anti-tumor, anti-inflammatory, analgesic, and the effects on cardiovascular system and nervous system, etc. However, its central nervous system toxicity severely limits its clinical application. Herein, the physicochemical properties, pharmacological activities, and toxicity of brucine were reviewed, and the novel strategies to address the toxicity issues were discussed, aiming to bring new insights into further research and application of this active component.

No abstract