Signal Transduction and Targeted Therapy最新文献

The effect of immune‐based therapies on patients with epidermal growth factor receptor (EGFR)-positive advanced non-small cell lung cancer (NSCLC) resistant to EGFR tyrosine kinase inhibitor (TKI) therapy remains unclear. The ALTER-L038 study aimed to evaluate efficacy and safety of a chemotherapy-free combination of benmelstobart, an anti-programmed cell death ligand 1 antibody, and anlotinib, a small-molecule multi-target anti-angiogenic TKI, in EGFR-positive advanced NSCLC patients who progressed after EGFR TKI therapy. Patients were enrolled in a phase I/II study. In phase I (dose-escalation), patients received anlotinib (8, 10, 12 mg) plus benmelstobart (1200 mg). Recommended phase II dose, determined during phase I, was used in phase II dose-expansion cohort. Primary endpoints were maximum tolerable dose in phase I and progression-free survival (PFS) in phase II. At the data cutoff date (March 10, 2024), 55 patients were enrolled in phase II dose-expansion cohort. Median PFS of patients included in phase II cohort was 9.0 months, median overall survival was 28.9 months, objective response rate was 25.5%, disease control rate was 87.3%, and median duration of response was 19.8 months. Incidence of grade ≥3 treatment-related adverse events in study population was 25.5% (14/55), whereas grade ≥3 immune-related adverse events occurred in 10.9% (6/55) of patients. Benmelstobart plus anlotinib showed promising anti-tumor efficacy with tolerable safety profile, supporting the value of further development of this convenient chemotherapy-free regimen for patients with EGFR-positive advanced NSCLC who progressed after EGFR TKI therapy. Trial Registration: ChiCTR1900026273.

Interferon Regulatory Factors (IRFs), a family of transcription factors, profoundly influence the immune system, impacting both physiological and pathological processes. This review explores the diverse functions of nine mammalian IRF members, each featuring conserved domains essential for interactions with other transcription factors and cofactors. These interactions allow IRFs to modulate a broad spectrum of physiological processes, encompassing host defense, immune response, and cell development. Conversely, their pivotal role in immune regulation implicates them in the pathophysiology of various diseases, such as infectious diseases, autoimmune disorders, metabolic diseases, and cancers. In this context, IRFs display a dichotomous nature, functioning as both tumor suppressors and promoters, contingent upon the specific disease milieu. Post-translational modifications of IRFs, including phosphorylation and ubiquitination, play a crucial role in modulating their function, stability, and activation. As prospective biomarkers and therapeutic targets, IRFs present promising opportunities for disease intervention. Further research is needed to elucidate the precise mechanisms governing IRF regulation, potentially pioneering innovative therapeutic strategies, particularly in cancer treatment, where the equilibrium of IRF activities is of paramount importance.

Evidences regarding the feasibility of transcatheter arterial chemoembolization (TACE)-based therapy for unresectable hepatocellular carcinoma (uHCC) remains limited. This study aimed to investigate the efficacy and safety of TACE combined with envafolimab and lenvatinib for uHCC. Eligible patients with uHCC received envafolimab and lenvatinib after TACE until disease progression, conversion to surgery, intolerable toxicities, or death. The primary endpoint was the objective response rate (ORR) assessed according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria. Between March 2022 and July 2022, 38 patients were included for safety analysis, and 36 patients were included for efficacy analysis. As of the data cutoff (13 December 2023), the median follow-up was 16.9 months. The ORR was 50%, and disease control rate (DCR) was 83.3% per RECIST 1.1 (ORR and DCR of both 83.3% per modified RECIST (mRECIST)). The median progression-free survival (PFS) was 7.58 months. Of 36 patients, 17 patients were converted to resectable HCC with a surgical conversion rate of 47.2%, and 16 patients underwent surgery with R0 resection rate of 100%, pathologic complete response (pCR) rate of 31.3%. Overall incidences of treatment-related adverse events (TRAEs) of any grade was 97.4%. Grade ≥ 3 TRAEs were observed in 52.6% patients. No treatment-related deaths occurred. Image mass cytometry (IMC) analysis revealed that combined treatment improved the immune status of the tumor microenvironment, and resident macrophages had the potential to predict efficacy of this treatment. Envafolimab plus lenvatinib and TACE yielded promising survival outcomes and conversion efficiency with a tolerable safety profile. Trial registration Clinical trials: NCT05213221.

Axis inhibition protein 1 (AXIN1), a scaffold protein interacting with various critical molecules, plays a vital role in determining cell fate. However, its impact on the antiviral innate immune response remains largely unknown. Here, we identify that AXIN1 acts as an effective regulator of antiviral innate immunity against both DNA and RNA virus infections. In the resting state, AXIN1 maintains the stability of the transcription factor interferon regulatory factor 3 (IRF3) by preventing p62-mediated autophagic degradation of IRF3. This is achieved by recruiting ubiquitin-specific peptidase 35 (USP35), which removes lysine (K) 48-linked ubiquitination at IRF3 K366. Upon virus infection, AXIN1 undergoes a phase separation triggered by phosphorylated TANK-binding kinase 1 (TBK1). This leads to increased phosphorylation of IRF3 and a boost in IFN-I production. Moreover, KYA1797K, a small molecule that binds to the AXIN1 RGS domain, enhances the AXIN1-IRF3 interaction and promotes the elimination of various highly pathogenic viruses. Clinically, patients with HBV-associated hepatocellular carcinoma (HCC) who show reduced AXIN1 expression in pericarcinoma tissues have low overall and disease-free survival rates, as well as higher HBV levels in their blood. Overall, our findings reveal how AXIN1 regulates IRF3 signaling and phase separation-mediated antiviral immune responses, underscoring the potential of the AXIN1 agonist KYA1797K as an effective antiviral agent.

Metabolism, including glycolysis, oxidative phosphorylation, fatty acid oxidation, and other metabolic pathways, impacts the phenotypes and functions of immune cells. The metabolic regulation of the immune system is important in the pathogenesis and progression of numerous diseases, such as cancers, autoimmune diseases and metabolic diseases. The concept of immunometabolism was introduced over a decade ago to elucidate the intricate interplay between metabolism and immunity. The definition of immunometabolism has expanded from chronic low-grade inflammation in metabolic diseases to metabolic reprogramming of immune cells in various diseases. With immunometabolism being proposed and developed, the metabolic regulation of the immune system can be gradually summarized and becomes more and more clearer. In the context of many diseases including cancer, autoimmune diseases, metabolic diseases, and many other disease, metabolic reprogramming occurs in immune cells inducing proinflammatory or anti-inflammatory effects. The phenotypic and functional changes of immune cells caused by metabolic regulation further affect and development of diseases. Based on experimental results, targeting cellular metabolism of immune cells becomes a promising therapy. In this review, we focus on immune cells to introduce their metabolic pathways and metabolic reprogramming, and summarize how these metabolic pathways affect immune effects in the context of diseases. We thoroughly explore targets and treatments based on immunometabolism in existing studies. The challenges of translating experimental results into clinical applications in the field of immunometabolism are also summarized. We believe that a better understanding of immune regulation in health and diseases will improve the management of most diseases.

In a recent study published in Cell, Odendaal et al. characterized the human upper respiratory tract (URT) microbiota by using samples from 3160 Dutch individuals.¹ They presented an atlas of the URT microbiota and were able to define associations with host and environmental factors that shape the respective ecological niches (saliva, oropharynx and nasopharynx).

A recent study by Tang et al. ¹ in Science reveals the cross-kingdom widespread occurrence of functional nucleotide-diphosphate (NDP)-heptose biosynthetic enzymes (HBEs) that accounts for the synthesis of NDP-heptoses to activate the alpha-protein kinase 1 (ALPK1)-dependent innate immune response. This study not only highlights the importance of the metabolite β-D-manno-heptose as pathogen-associated molecular patterns (PAMPs) but also raises the question of possibly other biological roles, especially in the different kingdoms (Fig. 1).

New findings on NDP-heptoses as agonists for the immune response. Small molecule metabolites such as ADP-heptose are synthesized by HBEs exhibiting isomerase, kinase, phosphatase, and nucleotidyltransferase activities. Of note, three subgroups of HBEs with nucleotidyltransferase activity (HENases) exist, exhibiting solely this activity or combined with kinase, or isomerase/kinase activities. In bacteria, where HBEs were first reported, they catalyzed the four-step biosynthesis of ADP-heptose starting from D-sedoheptulose 7-phosphate. Functional HBEs are prevalent in bacteria, archaea, viruses, and some eukaryotes. The authors discovered the presence of a widely conserved arginine residue at the fifth N-terminal position of the (F/L)XXGXSTT motif (STT_R5) in HENases that enable them to synthesize also CDP- and UDP-heptoses. A striking feature of the NDP-heptoses is their ability to act as immunostimulants. Pathogenic organisms deliver NDP-heptoses into mammalian cells, where they are detected by ALPK1, triggering its kinase activity. The ensuing TIFA phosphorylation initiates a signaling cascade to activate NF-κB, leading to the release of cytokines and chemokines that result in the recruitment of immune cells. In addition, NDP-heptoses could also serve as building blocks for protein glycosylation, or the production of LPS or antibiotics. The figure is created with BioRender.com

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In their paper published in Cell,¹ Xu et al. leveraged single-cell sequencing and cell lineage tracing tools combined with two-photon live imaging to characterise the spatiotemporal immune recruitment and infiltration to the choroid plexus (ChP). They provide seminal insights into the communication between specialised ChP epithelial and macrophage populations, which coordinate the stepwise response to inflammation and its resolution.

In a recent study published in Cell, Wang X et al.¹ reported the first use of allogeneic anti-CD19 CAR T cells in patients with therapy-resistant autoimmune diseases, demonstrating their effectiveness in reducing disease activity, with good tolerability and persistence. These findings suggest that allogeneic CAR T cells could offer a scalable, off-the-shelf treatment option for autoimmune disorders.

A recent study published in Cell revealed that in the aging brain, the microglia-derived complement component C1q is internalized into neurons through endocytosis, integrates into ribonucleoprotein (RNP) complexes where it inhibits neuronal protein synthesis and alters the protein content. These findings demonstrate an unexpected intracellular function of C1q in neurons with significant implications for understanding age-related changes in brain function and potentially neurodegenerative diseases.¹