Anti-PD-1 monoclonal antibodies, nivolumab and pembrolizumab, and anti-CTLA-4 antibody ipilimumab are being in clinic trials to treat melanoma. Here, we performed a meta-analysis to evaluate the efficacy and toxicity of them against advanced melanoma. Eleven reports from 6 randomized control trials on treating metastatic melanoma, which were divided into 3 subgroups, nivolumab/pembrolizumab versus chemotherapy, nivolumab versus ipilimumab, and nivolumab-plus-ipilimumab versus ipilimumab, were included and the meta-analysis was performed for each subgroup. The outcome measures were objective response rates (ORR), median progression free survival (PFS), 1-year overall survival rates (OS), and toxicity estimated by grade 3 to 4 adverse events. For nivolumab/pembrolizumab versus chemotherapy, nivolumab versus ipilimumab, and nivolumab-plus-ipilimumab versus ipilimumab, the pooled risk ratios (RR) of the ORR were 3.43 (95% CI: 2.57–4.58), 2.51 (95% CI: 2.03–3.09), and 3.28 (95% CI: 2.58–4.17), respectively. The pooled HR of PFS were 0.42 (95% CI: 0.36–0.49), 0.58 (95% CI: 0.50–0.66), and 0.41 (95% CI: 0.30–0.52), respectively. The pooled RR of 1-year OS was 1.37 (95% CI: 1.08–1.74) and 1.54 (95% CI: 0.90–2.63) for nivolumab versus ipilimumab and nivolumab-plus-ipilimumab versus ipilimumab. These results suggested that anti-PD-1 monotherapy and nivolumab-plus-ipilimumab therapy had ORR and PFS benefit compared with the control group. Anti-PD-1 treatment increased 1-year OS for patients compared with ipililumab treatment. But there is no significantly difference on 1-year OS between the nivolumab-plus-ipilimumab treatment and the ipilimumab treatment group. The toxicity analysis showed that there is less risk of adverse events in the anti-PD-1 treatment group compared with the chemotherapy and ipilimumab group. Combining nivolumab with ipilimumab increased the risk for high-grade adverse events compared with ipilimumab alone but the adverse events were generally manageable. Anti-PD-1 monotherapy and nivolumab-plus-ipilimumab therapy improved ORR and prolonged PFS of patients with advanced melanoma and the adverse events are generally manageable. The therapy is indeed a promising approach for treatment of advanced melanoma.

Although therapeutic proteins have achieved recognized clinical success, they are inherently membrane impermeable, which limits them to acting only on extracellular or membrane‐associated targets. Developing an efficient protein delivery method will provide a unique opportunity for intracellular target‐related therapeutic proteins. In this review article, we summarize the different pathways by which cells take up proteins. These pathways fall into two main categories: One in which proteins are transported directly across the cell membrane and the other through endocytosis. At the same time, important features to ensure successful delivery through these pathways are highlighted. We then provide a comprehensive overview of the latest developments in the transduction of covalent protein modifications, such as coupling cell‐penetrating motifs and supercharging, as well as the use of nanocarriers to mediate protein transport, such as liposomes, polymers, and inorganic nanoparticles. Finally, we emphasize the existing challenges of cytoplasmic protein delivery and provide an outlook for future progress.

Background: B-cell lymphoma 10 (BCL10) is a key signaling molecule that plays a pivotal role in activating the NF-κB signaling pathway. However, it is unclear whether prolonged activation of BCL10 within tumors lead to T cell exhaustion and suppress immune responses against cancer.Methods: In this study, through multi-layered bioinformatics analysis and experimental verification, the role of BCL10 on immune cells in the tumor immune microenvironment was systematically investigated. The correlation between BCL10 expression and infiltrated immune cells was analyzed by immune algorithms such as xCELL, CIBERSORT, QUANTISEQ and MCPcounter using TCGA and GTEx databases. Furthermore, single-cell RNA sequencing data of the cervical squamous cell carcinoma(CESC)microenvironment were analyzed using the GEO database. Moreover, an implanted CESC mice model was established, in which the expression and correlation of BCL10, NF-κB, and PD-1 in CD8+ T cells, as well as the proliferation and apoptosis of CD8+ T cells, were analyzed.Results: In silico analysis revealed that the upregulation of BCL10 in tumor immune microenvironment (TIME) was correlation with decreased infiltration of CD8+T cells, CD4+Th1 cells and NK T cells, and increased infiltration of Treg cells and CD4+Th2 cells in most tumors including CESC. In implanted CESC mice model, BCL10 expression was found upregulated in CD8+T cells, consequently activating the NF-κB signaling, and leading to upregulation of PD-1 expression, inhibiting proliferation of CD8+T cells, and promoting apoptosis of CD8+T cells.Conclusions: BCL10 is closely associated with immunosuppression across various tumor types. In CESC, chronic stimulation and over-activation by tumor antigens result in exhaustion of CD8+ T cells through the over-activation of the NF-κB signaling pathway and upregulation of PD-1 expression.