Over the past decade, therapeutic messenger RNAs (mRNAs) have emerged as a highly promising new class of drugs for protein replacement therapies. Due to the recent developments, the incorporation of modified nucleotides in synthetic mRNAs can lead to maximizing protein expression and reducing adverse immunogenicity. Despite these stunning improvements, mRNA therapy is limited by the need for the development of safe and efficient carriers to protect the mRNA integrity for in vivo applications. Recently, leading candidates for in vivo drug delivery vehicles are cell-derived exosomes, which have fewer immunogenic responses. In the current study, the key hurdles facing mRNA-based therapeutics, with an emphasis on recent strategies to overcoming its immunogenicity and instability, were highlighted. Then the immunogenicity and toxicity of exosomes derived from various cell sources were mentioned in detail. Finally, an overview of the recent strategies in using exosomes for mRNA delivery in the treatment of multiple diseases was stated.

This meta-analysis aimed to evaluate the prognostic value of tumor-infiltrating lymphocytes (TILs) and programmed death-ligand 1 (PD-L1), their associations with the clinicopathological characteristics, and the association between their levels in patients with triple-negative breast cancer (TNBC). PubMed, EMBASE, Scopus, ProQuest, Web of Science, and Cochrane Library databases were searched to obtain the relevant papers. Seven studies with 1152 patients were included in this study. Like the level of TILs, there were no significant associations between PD-L1 expression and tumor size, tumor stage, lymph node metastasis, histological grade, and Ki67 (All p-values ≥ 0.05). Furthermore, there was no significant association between PD-L1 expression with overall survival (OS) and disease-free survival (DFS). In assessment of TILs and survival relationship, the results showed that a high level of TILs was associated with long-term OS (hazard ratios (HR) = 0.48, 95% CI: 0.30 to 0.77, p-value < 0.001) and DFS (HR = 0.53, 95% CI: 0.35 to 0.78, p-value < 0.001). The results displayed that tumoral PD-L1 expression was strongly associated with high levels of TILs in TNBC patients (OR = 8.34, 95% CI: 2.68 to 25.95, p-value < 0.001). In conclusion, the study has shown the prognostic value of TILs and a strong association between tumoral PD-L1 overexpression with TILs in TNBC patients.

The programmed death-ligand 1 (PD-L1)/programmed cell death protein 1 (PD-1) is a well-established inhibitory immune checkpoint axis in triple-negative breast cancer (TNBC). Growing evidence indicates that tumoral PD-L1 can lead to TNBC development. Although conventional immune checkpoint inhibitors have improved TNBC patients’ prognosis, their effect is mainly focused on improving anti-tumoral immune responses without substantially regulating oncogenic signaling pathways in tumoral cells. Moreover, the conventional immune checkpoint inhibitors cannot impede the de novo expression of oncoproteins, like PD-L1, in tumoral cells. Accumulating evidence has indicated that the restoration of specific microRNAs (miRs) can downregulate tumoral PD-L1 and inhibit TNBC development. Since miRs can target multiple mRNAs, miR-based gene therapy can be an appealing approach to inhibit the de novo expression of oncoproteins, like PD-L1, restore anti-tumoral immune responses, and regulate various intracellular singling pathways in TNBC. Therefore, we conducted the current systematic review based on the preferred reporting items for systematic reviews and meta-analyses (PRISMA) to provide a comprehensive and unbiased synthesis of currently available evidence regarding the effect of PD-L1-inhibiting miRs restoration on TNBC development and tumor microenvironment. For this purpose, we systematically searched the Cochrane Library, Embase, Scopus, PubMed, ProQuest, Web of Science, Ovid, and IranDoc databases to obtain the relevant peer-reviewed studies published before 25 May 2021. Based on the current evidence, the restoration of miR-424-5p, miR-138-5p, miR-570-3p, miR-200c-3p, miR-383-5p, miR-34a-5p, miR-3609, miR-195-5p, and miR-497-5p can inhibit tumoral PD-L1 expression, transform immunosuppressive tumor microenvironment into the pro-inflammatory tumor microenvironment, inhibit tumor proliferation, suppress tumor migration, enhance chemosensitivity of tumoral cells, stimulate tumor apoptosis, arrest cell cycle, repress the clonogenicity of tumoral cells, and regulate various oncogenic signaling pathways in TNBC cells. Concerning the biocompatibility of biomimetic carriers and the valuable insights provided by the single-cell sequencing technologies, single-cell sequencing-guided biomimetic delivery of these PD-L1-inhibiting miRs can decrease the toxicity of traditional approaches, increase the specificity of miR-delivery, enhance the efficacy of miR delivery, and provide the affected patients with personalized cancer therapy.

Background: Today, treating cancer patients with monoclonal antibodies (mAbs), by targeting immune checkpoints, is one of the most outstanding immunotherapeutic methods. Immune checkpoints are special molecules having regulatory role in immune system responses. Once these molecules are presented on cancer cells, these cells will be capable of evading the immune system through their own specific pathways. This Evasion can be prevented by counterbalancing immune system responses with immune checkpoints related antibodies.Aims: The current study aimed to highlight immunotherapy and its methods, describe the immune checkpoints pathways, outline the immune checkpoint inhibitors (ICIs), and recent advances in this field, and sketch an outlook on the best treatment options for the most prevalent cancers.Materials & Methods: This research implemented a narrative review method. A comprehensive literature review on the history, molecular and cellular biology, and the clinical aspects of immune checkpoint molecules was performed to illustrate the pathways involved in various cancers. Also, currently‐available and future potential immunotherapies targeting these pathways were extracted from the searched studies.Results: The immune checkpoint family consists of many molecules, including CTLA‐4, PD‐1, PD‐L1, LAG‐3, TIM‐3, and TIGIT. Attempts to modify these molecules in cancer treatment led to the development of therapeutic monoclonal antibodies. Most of these antibodies have entered clinical studies and some of them have been approved by the Food and Drug Administration (FDA) to be used in cancer patients' treatment plans.Discussion: With these novel treatments and the combination therapies they offer, there is also hope for better treatment outcomes for the previously untreatable metastatic cancers. In spite of the beneficial aspects of immune checkpoint therapy, similar to other treatments, they may cause side effects in some patients. Therefore, more studies are needed to reduce the probable side effects and uncover their underlying mechanism.Conclusion: Based on the data shown in this review, there is still a lack of knowledge about the complete properties of ICIs and the possible combination therapies that we may be able to implement to achieve a better treatment response in cancer patients.

Gynecologic cancers account for approximately 11% of the newly diagnosed cancers in women in the United States and for 18% globally. The presence of tumor-infiltrating lymphocytes (TILs) influences the clinical outcome of cancer patients and immune checkpoint inhibitors (ICIs), including anti programmed cell death protein-1 (anti-PD-1), anti-programmed death-ligand 1 (anti-PD-L1), and anticytotoxic T-lymphocyte antigen 4 (anti-CTLA-4), which have been approved for treating different types of malignancies. Antibodies targeting the PD-1/PD-L1 checkpoint have shown dynamic and durable tumor regressions, suggesting a rebalancing of the host–tumor interaction. There are several the US food and drug administration (FDA)-approved ICIs targeting PD-1, including pembrolizumab and nivolumab, as well as those targeting PD-L1, including avelumab, atezolizumab, and durvalumab for melanoma, renal cell cancer, colorectal cancer, head and neck cancer, cervix cancer, urothelial cancer, and lung cancer. Current pre-clinical and clinical studies assessing PD-1/PD-L1 inhibitors in several gynecologic cancers have reported significant antitumor activity. In this review, we investigate pre-clinical and clinical studies that describe the safety and efficacy of anti-PD-1/PD-L1 antibodies, with a particular focus on ongoing clinical trials, analyzing the oncological outcome and adverse effects of ICIs in gynecologic cancers.