Immune checkpoint inhibitors can improve the prognosis of patients with advanced malignancy; however, only a small subset of advanced colorectal cancer patients in microsatellite-instability-high or mismatch-repair-deficient colorectal cancer can benefit from immunotherapy. Unfortunately, the mechanism behind this ineffectiveness is unclear. The tumor microenvironment plays a critical role in cancer immunity, and may contribute to the inhibition of immune checkpoint inhibitors and other novel immunotherapies in patients with advanced cancer. Herein, we demonstrate that the DNase I enzyme plays a pivotal role in the degradation of NETs, significantly dampening the resistance to anti-PD-1 blockade in a mouse colorectal cancer model by attenuating tumor growth. Remarkably, DNase I decreases tumor-associated neutrophils and the formation of MC38 tumor cell-induced neutrophil extracellular trap formation in vivo. Mechanistically, the inhibition of neutrophil extracellular traps with DNase I results in the reversal of anti-PD-1 blockade resistance through increasing CD8+ T cell infiltration and cytotoxicity. These findings signify a novel approach to targeting the tumor microenvironment using DNase I alone or in combination with immune checkpoint inhibitors.

Metabolic-dysfunction-associated steatotic liver disease (MASLD) is becoming a leading cause of end-stage liver disease globally. Metabolic-dysfunction-associated steatohepatitis (MASH) represents a progressive inflammatory manifestation of MASLD. MASH underlies a versatile and dynamic inflammatory microenvironment, accompanied by aberrant metabolism and ongoing liver regeneration, establishing itself as a significant risk factor for hepatocellular carcinoma (HCC). The mechanisms underlying the escape and survival of malignant cells within the extensive inflammatory microenvironment of MASH remain elusive. Regulatory T cells (Tregs) play a crucial role in maintaining homeostasis and preventing excessive immune responses in the liver. Paradoxically, Tregs have been implicated in inhibiting tumour-promoting inflammation and facilitating the evasion of cancer cells. Recent studies have unveiled distinct behaviours of Tregs at different stages of MASLD, suggesting a dual role in the pathogenesis. In this review, we explore the fate of Tregs from MASLD to HCC, offering recent insights into potential targets for clinical intervention.

Novel treatments for autoimmune hepatitis (AIH) are highly demanded due to the limitations of existing therapeutic agents. Costunolide is a promising candidate due to its anti-inflammatory and hepatoprotective function, but its effect in AIH remains obscure. In this study, we integrated network pharmacology and experimental validation to reveal the effect and mechanism of costunolide in AIH. A total of 73 common targets of costunolide and AIH were obtained from databases. Pathway enrichment analysis indicated that PI3K-AKT pathway was the core pathway of costunolide in AIH. Protein–protein interaction network analysis and molecular docking revealed that SRC and IGF1R might play critical roles. In two murine AIH models, costunolide significantly attenuated liver injury, inflammation, and fibrosis reflected by the liver gross appearance, serum transaminases, necrosis area, spleen index, immune cell infiltration, and collagen deposition. Western blot and immunohistochemistry confirmed that phosphorylated AKT, SRC, and IGF1R were upregulated in AIH models, and costunolide administration could inhibit the phosphorylation of these proteins. In summary, costunolide significantly ameliorates murine AIH. The therapeutic effect might work by suppressing the activation of PI3K-AKT pathway and inhibiting the phosphorylation of SRC and IGF1R. Our research reveals the potent therapeutic effect of costunolide in AIH and the potential role of SRC and IGF1R in AIH for the first time, which may further contribute to the novel drug development for AIH and other autoimmune diseases.