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MicroRNAs (miRNAs) are critical mediators of posttranscriptional regulation via their targeting of the imperfect antisense complementary regions of coding and non-coding transcripts. Recently, researchers have shown that miRNAs play roles in many aspects of regulation of immune cell function by targeting of inflammation-associated genes, including Toll-like receptors (TLRs). Besides this indirect regulatory role of miRNAs, they can also act as physiological ligands of specific TLRs and initiate the signaling cascade of immune response. In this review, we summarize the potential roles of miRNAs in regulation of TLR gene expression and TLR signaling, with a focus on the ability of miRNAs bind to TLRs.

Toll-like receptors (TLRs) are pattern recognition receptors (PRRs) expressed in various immune cell types and perform multiple purposes and duties involved in the induction of innate and adaptive immunity. Their capability to propagate immunity makes them attractive targets for the expansion of numerous immunotherapeutic approaches targeting cancer. These immunotherapeutic strategies include using TLR ligands/agonists as monotherapy or combined therapeutic strategies. Several TLR agonists have demonstrated significant efficacy in advanced clinical trials. In recent years, multiple reports established the applicability of TLR agonists as adjuvants to chemotherapeutic drugs, radiation, and immunotherapies, including cancer vaccines. Cancer vaccines are a relatively novel approach in the field of cancer immunotherapy and are currently under extensive evaluation for treating different cancers. In the present review, we tried to deliver an inclusive discussion of the significant TLR agonists and discussed their application and challenges to their incorporation into cancer immunotherapy approaches, particularly highlighting the usage of TLR agonists as functional adjuvants to cancer vaccines. Finally, we present the translational potential of rWTC-MBTA vaccination [irradiated whole tumor cells (rWTC) pulsed with phagocytic agonists Mannan-BAM, TLR ligands, and anti-CD40 agonisticAntibody], an autologous cancer vaccine leveraging membrane-bound Mannan-BAM, and the immune-inducing prowess of TLR agonists as a probable immunotherapy in multiple cancer types.

Adjuvants have been used in vaccines for over a century, however, the search for safe and effective vaccine adjuvants continues. In recent decades toll-like-receptor (TLR) agonists have been investigated as potential vaccine adjuvants. In this regard, the majority of the currently investigated TLR agonists are non-protein microbial components such as lipopolysaccharides, oligonucleotides, and lipopeptides. On the other hand, a growing number of studies reveal that TLR signaling and immune responses can be activated by numerous bacterial proteins. However, their potential roles as adjuvants have been somewhat overlooked. Herein, we discuss several such bacterial proteins which exhibit adjuvant properties, including the activation of TLR signaling, antigen presenting cell maturation, pro-inflammatory cytokine production and adaptive immune response. The protein nature of these TLR agonists presents several unique features not shared by non-protein TLR agonists. These properties include the amenability for modifying the structure and function as necessary for optimal immunogenicity and minimal toxicity. Protein adjuvants can be genetically fused to protein antigens which ensure the co-delivery of adjuvant-antigen not only into the same cell but also in the same endocytic cargo, leading to more effective activation of innate and adaptive immune response.

Severe COVID-19 is characterized by a “cytokine storm”, the mechanism of which is not yet understood. I propose that cytokine storms result from synergistic interactions among Toll-like receptors (TLR) and nucleotide-binding oligomerization domain-like receptors (NLR) due to combined infections of SARS-CoV-2 with other microbes, mainly bacterial and fungal. This proposition is based on eight linked types of evidence and their logical connections. (1) Severe cases of COVID-19 differ from healthy controls and mild COVID-19 patients in exhibiting increased TLR4, TLR7, TLR9 and NLRP3 activity. (2) SARS-CoV-2 and related coronaviruses activate TLR3, TLR7, RIG1 and NLRP3. (3) SARS-CoV-2 cannot, therefore, account for the innate receptor activation pattern (IRAP) found in severe COVID-19 patients. (4) Severe COVID-19 also differs from its mild form in being characterized by bacterial and fungal infections. (5) Respiratory bacterial and fungal infections activate TLR2, TLR4, TLR9 and NLRP3. (6) A combination of SARS-CoV-2 with bacterial/fungal coinfections accounts for the IRAP found in severe COVID-19 and why it differs from mild cases. (7) Notably, TLR7 (viral) and TLR4 (bacterial/fungal) synergize, TLR9 and TLR4 (both bacterial/fungal) synergize and TLR2 and TLR4 (both bacterial/fungal) synergize with NLRP3 (viral and bacterial). (8) Thus, a SARS-CoV-2-bacterium/fungus coinfection produces synergistic innate activation, resulting in the hyperinflammation characteristic of a cytokine storm. Unique clinical, experimental and therapeutic predictions (such as why melatonin is effective in treating COVID-19) are discussed, and broader implications are outlined for understanding why other syndromes such as acute lung injury, acute respiratory distress syndrome and sepsis display varied cytokine storm symptoms.

In the dark path of tumorigenesis, the more carefully the cancer biology is studied, the more brilliant answers could be given to the countless questions about its orchestrating derivers. The identification of the correlation between Toll‐like receptors (TLRs) and different processes involved in carcinogenesis was one of the single points of blinding light highlighting the interconnection between the immune system and cancer. TLRs are a wide family of single‐pass membrane‐spanning receptors that have developed through the evolution to recognize the structurally conserved molecules derived from microorganisms or damaged cells. But this is not everything about these receptors as they could orchestrate several downstream signalling pathways leading to the formation or suppression of cancer cells. The present review is tempted to provide a concise schematic about the biology and the characters of TLRs and also summarize the major findings of the regulatory role of TLRs and their associated signalling in the pathogenesis of human cancers.

Despite advances in critical care medicine, infection remains a significant problem that continues to be complicated with the challenge of antibiotic resistance. Immunocompromised patients are highly susceptible to development of severe infection which often progresses to the life-threatening condition of sepsis. Thus, immunotherapies aimed at boosting host immune defenses are highly attractive strategies to ward off infection and protect patients. Recently there has been mounting evidence that activation of the innate immune system can confer long-term functional reprogramming whereby innate leukocytes mount more robust responses upon secondary exposure to a pathogen for more efficient clearance and host protection, termed trained immunity. Toll-like receptor (TLR) agonists are a class of agents which have been shown to trigger the phenomenon of trained immunity through metabolic reprogramming and epigenetic modifications which drive profound augmentation of antimicrobial functions. Immunomodulatory TLR agonists are also highly beneficial as vaccine adjuvants. This review provides an overview on TLR signaling and our current understanding of TLR agonists which show promise as immunotherapeutic agents for combating infection. A brief discussion on our current understanding of underlying mechanisms is also provided. Although an evolving field, TLR agonists hold strong therapeutic potential as immunomodulators and merit further investigation for clinical translation.

Gabriela Barbosa,1,2 Maria Carolina Ximenes De Godoy,1 Caroline Cavalli Bighetto,1 Emily Macedo Skakum,1 Lívia Bitencourt Pascoal,1,2 Alessandra Gambero,1,2 Leonardo O Reis1– 3 1ImmunOOncology, Pontifical Catholic University of Campinas, Campinas, São Paulo, Brazil; 2UroGen, National Institute of Science, Technology and Innovation in Genitourinary Cancer (INCT), Campinas, São Paulo, Brazil; 3UroScience, State University of Campinas, Campinas, São Paulo, BrazilCorrespondence: Leonardo O Reis, Email reisleo.l@gmail.comBackground: Programmed death-ligand 1 (PD-L1) is a key immune checkpoint molecule involved in tumor immune evasion. Its expression is highly heterogeneous across cancer types and subtypes, influencing therapeutic response. Understanding how different immunomodulatory agents influence PD-L1 expression in breast cancer cells could inform novel therapeutic strategies. This study aimed to investigate the temporal and dose-dependent effects of Bacillus Calmette-Guérin (BCG) and Toll-like receptor (TLR) agonists on PD-L1 expression in two breast cancer cell lines: MCF7 (luminal) and MDA-MB-231 (triple-negative).Methods: MTT (thiazolyl blue tetrazolium bromide) assays were conducted to determine non-cytotoxic concentrations of the immunomodulatory agents: 25 μM IMQ (imiquimod), 10 μg PPG (peptidoglycan), 1 mg LPS (lipopolysaccharide), and two BCG doses (200 μg/mL and 800 μg/mL). Flow cytometry assessed anti-PD-L1 (CD274) antibody expression at 24- and 48 hours post-treatment.Results: In MCF7 cells, BCG induced a dose-dependent upregulation of PD-L1 at 24 hours, which was not sustained at 48 hours, while TLR agonists had minimal or slightly suppressive effects. In contrast, MDA-MB-231 cells exhibited a time-dependent modulation of PD-L1, with an increase at 24 hours followed by a reduction at 48 hours in response to BCG, while TLR agonists consistently decreased PD-L1 levels compared to controls.Conclusion: These findings suggest distinct immunomodulatory responses between cancer subtypes, emphasizing the need for tailored approaches targeting the PD-1/PD-L1 axis. Further studies should explore the molecular mechanisms underlying these differential effects and assess the potential for combinatorial immunotherapeutic strategies in cancer.Keywords: PD-L1, immunomodulation, TLR, BCG, breast cancer

Cell death is central to development, organismal homeostasis, and immune responses. The cell death field has experienced tremendous progress by delineating the molecular programs specific to each of the apoptotic and inflammatory cell death pathways. Moreover, the discovery of the inflammasomes and pyroptosis and necroptosis pathway regulators have provided the genetic basis for the programmed inflammatory cell death pathways. Earlier research highlighted the unique regulation of each of these pathways, but emerging studies discovered co-regulation and crosstalk between these seemingly different cell death complexes. The progress in this area has led to an idea that master regulators play central roles in orchestrating multiple cell death pathways. Here, we provide a brief review of the master regulators, the innate immune sensor ZBP1 and the essential cell survival kinase TAK1, that play vital roles in the regulation of RIPK1/RIPK3-FADD-caspase-8 cell death complex assembly and its versatility in executing Pyroptosis, Apoptosis, and Necroptosis, which we dubbed here as PAN-optosis. Furthermore, we discuss the implications and therapeutic potential of targeting these master regulators in health and disease. ZBP1 and TAK1 regulate PAN-optosis.

Infection with human papillomavirus (HPV) typically leads to cervical cancer, skin related cancers and many other tumors. HPV is mainly responsible for evading immune tumor monitoring in HPV related cancers. Toll like receptors (TLRs) are particular pattern recognition molecules. When the body is facing immune danger, it can lead to innate and direct adaptive immunity. TLR plays an important role in initiating antiviral immune responses. HPV can affect the expression level of TLR and interfere with TLR related signaling pathways, resulting in sustained viral infection and even carcinogenesis. This paper introduces the HPV virus and HPV related cancers. We discussed the present comprehension of TLR, its expression and signaling, as well as its role in HPV infection. We also provided a detailed introduction to immunotherapy methods for HPV related diseases based on TLR agonists. This will provide insights into methods that support the therapeutic method of HPV related conditions with TLR agonists

Innate immunity is maintained in part by antigen presenting cells (APCs) including dendritic cells, macrophages, and B cells. APCs interact with T cells to link innate and adaptive immune responses. By displaying bacterial and tumorigenic antigens on their surface via major histocompatibility complexes, APCs can directly influence the differentiation of T cells. Likewise, T cell activation, differentiation, and effector functions are modulated by APCs utilizing multiple mechanisms. The objective of this review is to describe how APCs interact with and influence the activation of T cells to maintain innate immunity during exposure to microbial infection and malignant cells. How bacteria and cancer cells take advantage of some of these interactions for their own benefit will also be discussed. While this review will cover a broad range of topics, a general focus will be held around pathogens, cancers, and interactions that typically occur within the gastrointestinal tract.