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Hedgehog (Hh) pathway controls complex developmental processes in vertebrates. Abnormal activation of Hh pathway is responsible for tumorigenesis and maintenance of multiple cancers, and thus addressing this represents promising therapeutic opportunities. In recent years, two Hh inhibitors have been approved for basal cell carcinoma (BCC) treatment and show extraordinary clinical outcomes. Meanwhile, a series of novel agents are being developed for the treatment of several cancers, including lung cancer, leukemia, and pancreatic cancer. Unfortunately, Hh inhibition fails to show satisfactory benefits in these cancer types compared with the success stories in BCC, highlighting the need for better understanding of Hh signaling in cancer. Autophagy, a conserved biological process for cellular component elimination, plays critical roles in the initiation, progression, and drug resistance of cancer, and therefore, implied potential to be targeted. Recent evidence demonstrated that Hh signaling interplays with autophagy in multiple cancers. Importantly, modulating this crosstalk exhibited noteworthy capability to sensitize primary and drug-resistant cancer cells to Hh inhibitors, representing an emerging opportunity to reboot the efficacy of Hh inhibition in those insensitive tumors, and to tackle drug resistance challenges. This review will highlight recent advances of Hh pathway and autophagy in cancers, and focus on their crosstalk and the implied therapeutic opportunities.

Inflammasomes have emerged as critical innate sensors of host immune that defense against pathogen infection, metabolism syndrome, cellular stress and cancer metastasis in the liver. The assembly of inflammasome activates caspase-1, which promotes the maturation of interleukin-1β (IL-1β) and interleukin-18 (IL-18), and initiates pyroptotic cell death (pyroptosis). IL-18 exerts pleiotropic effects on hepatic NK cells, priming FasL-mediated cytotoxicity, and interferon-γ (IFN-γ)-dependent responses to prevent the development of liver diseases. However, considerable attention has been attracted to the pathogenic role of inflammasomes in various acute and chronic liver diseases, including viral hepatitis, nanoparticle-induced liver injury, alcoholic and non-alcoholic steatohepatitis. In this review, we summarize the latest advances on the physiological and pathological roles of inflammasomes for further development of inflammasome-based therapeutic strategies for human liver diseases.

Although numerous clinical trials have been implemented, an absolutely effective treatment against coronavirus disease 2019 (COVID-19) is still elusive. Interleukin-22 (IL-22) has attracted great interest over recent years, making it one of the best-studied cytokines of the interleukin-10 (IL-10) family. Unlike most interleukins, the major impact of IL-22 is exclusively on fibroblasts and epithelial cells due to the restricted expression of receptor. Numerous studies have suggested that IL-22 plays a crucial role in anti-viral infections through significantly ameliorating the immune cell-mediated inflammatory responses, and reducing tissue injury as well as further promoting epithelial repair and regeneration. Herein, we pay special attention to the role of IL-22 in the lungs. We summarize the latest progress in our understanding of IL-22 in lung health and disease and further discuss maneuvering this cytokine as potential immunotherapeutic strategy for the effective manage of COVID-19.

The miRNA-based therapeutics held great promise for the treatment of diseases associated with aberrant gene expression. However, the development of miRNA-based drugs still faces many obstacles, including stability, targetability, tissue penetration, and induction of immune responses. To overcome these challenges, researchers developed various miRNA modification methods and miRNA-based delivery systems, which can protect miRNA from degradation and facilitate their transport across biological barriers. Here, we give an overview of the latest advancements in a variety of delivery systems, including virus, lipid, polymer, inorganic, and exosome-based nanosystems, which have been proved as versatile and valuable carriers for miRNA. Moreover, the use of stimuli-responsive materials allows for the controlled release of oligonucleotides in response to specific triggers. Importantly, the current miRNA-based therapeutics in clinical trials are summarized in this review. The combination of these advancements has the potential to promote more effective and safer treatment designs for a wide range of diseases. This review will contribute to developing more precise targeted delivery systems of miRNA, ultimately facilitating its clinical development. Graphical Abstract

Interleukin-15 (IL-15) is a cytokine that belongs to the interleukin-2 (IL-2) family and is essential for the development, proliferation, and activation of immune cells, including natural killer (NK) cells, T cells and B cells. Recent studies have revealed that interleukin-15 also plays a critical role in cancer immunotherapy. Interleukin-15 agonist molecules have shown that interleukin-15 agonists are effective in inhibiting tumor growth and preventing metastasis, and some are undergoing clinical trials. In this review, we will summarize the recent progress in interleukin-15 research over the past 5 years, highlighting its potential applications in cancer immunotherapy and the progress of interleukin-15 agonist development.

As nano-sized materials prepared by isolating, disrupting and extruding cell membranes, cellular vesicles are emerging as a novel vehicle for immunotherapeutic drugs to activate antitumor immunity. Cell membrane-derived vesicles inherit the surface characteristics and functional properties of parental cells, thus having superior biocompatibility, low immunogenicity and long circulation. Moreover, the potent antitumor effect of cellular vesicles can be achieved through surface modification, genetic engineering, hybridization, drug encapsulation, and exogenous stimulation. The capacity of cellular vesicles to combine drugs of different compositions and functions in physical space provides a promising vehicle for combinational immunotherapy of cancer. In this review, the latest advances in cellular vesicles as vehicles for combinational cancer immunotherapy are systematically summarized with focuses on manufacturing processes, cell sources, therapeutic strategies and applications, providing an insight into the potential and existing challenges of using cellular vesicles for cancer immunotherapy.

The human gut microbiota, comprising trillions of microorganisms residing in the gastrointestinal tract, has emerged as a pivotal player in modulating various aspects of human health and disease. Recent research has shed light on the intricate relationship between the gut microbiota and pharmaceuticals, uncovering profound implications for drug metabolism, efficacy, and safety. This review depicted the landscape of molecular mechanisms and clinical implications of dynamic human gut Microbiota-Drug Interactions (MDI), with an emphasis on the impact of MDI on drug responses and individual variations. This review also discussed the therapeutic potential of modulating the gut microbiota or harnessing its metabolic capabilities to optimize clinical treatments and advance personalized medicine, as well as the challenges and future directions in this emerging field.

Background Pancreatic cancer is a highly aggressive malignancy with limited treatment options and a poor prognosis. Trophoblast cell surface antigen 2 (TROP2), a cell surface antigen overexpressed in the tumors of more than half of pancreatic cancer patients, has been identified as a potential target for antibody–drug conjugates (ADCs). Almost all reported TROP2-targeted ADCs are of the IgG type and have been poorly studied in pancreatic cancer. Here, we aimed to develop a novel nanobody-drug conjugate (NDC) targeting TROP2 for the treatment of pancreatic cancer. Results In this study, we developed a novel TROP2-targeted NDC, HuNb TROP2-HSA -MMAE, for the treatment of TROP2-positive pancreatic cancer. HuNb TROP2-HSA -MMAE is characterized by the use of nanobodies against TROP2 and human serum albumin (HSA) and has a drug-antibody ratio of 1. HuNb TROP2-HSA -MMAE exhibited specific binding to TROP2 and was internalized into tumor cells with high endocytosis efficiency within 5 h, followed by intracellular translocation to lysosomes and release of MMAE to induce cell apoptosis in TROP2-positive pancreatic cancer cells through the caspase-3/9 pathway. In a xenograft model of pancreatic cancer, doses of 0.2 mg/kg and 1 mg/kg HuNb TROP2-HSA -MMAE demonstrated significant antitumor effects, and a dose of 5 mg/kg even eradicated the tumor. Conclusion HuNb TROP2-HSA -MMAE has desirable affinity, internalization efficiency and antitumor activity. It holds significant promise as a potential therapeutic option for the treatment of TROP2-positive pancreatic cancer. Graphical Abstract

Natural killer cell engagers (NKCEs) are a specialised subset of antibodies capable of simultaneously targeting endogenous NK cells and tumour cells, generating precise and effective cytolytic responses against cancer. This review systematically explores NK engagers as a rising star in NK‐mediated immunotherapy, specifically focusing on multi‐specific engagers. It examines the diverse configuration of NKCEs and how certain biologics could be employed to boost NK activity, including activating receptor engagement and cytokine incorporation. Some challenges and future perspectives of current NKCEs therapy are also discussed, including optimising pharmacokinetics, addressing the immunosuppressive tumour microenvironment and exploring potential combinatorial approaches. By offering an in‐depth analysis of the current landscape and future trajectories of multi‐specific NKCEs in cancer treatment, this review serves as a valuable resource for understanding this promising field of immunotherapy. Highlights Innovative NKCEs: NK cell engagers (NKCEs) represent a promising new class of immunotherapeutics targeting tumours by activating NK cells. Multi‐specific formats: The transition from bi‐specific to multi‐specific NKCEs enhances their versatility and therapeutic efficacy. Mechanisms of action: NKCEs have the potential to improve NK cell activation by engaging activating receptors and incorporating cytokines. Clinical potential: Current clinical trials demonstrate the safety and efficacy of various NKCEs across different cancer types. Future research directions: Optimising NKCE designs and exploring combination therapies are essential for overcoming challenges in cancer treatment. Multi‐specific NKCEs: Multi‐specific NK cell engagers (NKCEs) enhance the immune system's ability to target and destroy tumor cells. Diverse targeting: These NKCEs can engage multiple antigens on NK cells and tumor cells, providing a more robust cytotoxic response. Enhanced cancer immunotherapy: The multi‐specific design of these NKCEs offers improved effectiveness in cancer immunotherapy, potentially leading to better clinical outcomes.

The determination of RNA secondary structure (RSS) could help understand RNA’s functional mechanisms, guiding the design of RNA-based therapeutics, and advancing synthetic biology applications. However, traditional methods such as NMR for determining RSS are typically time-consuming and labor-intensive. As a result, the accurate prediction of RSS remains a fundamental yet unmet need in RNA research. Various deep learning (DL)-based methods achieved improved accuracy over thermodynamic-based methods. However, the over-parameterization nature of DL makes these methods prone to overfitting and thus limits their generalizability. Meanwhile, the inconsistency of RSS predictions between these methods further aggravated the crisis of generalizability. Here, we propose TrioFold to achieve enhanced generalizability of RSS prediction by integrating base-pairing clues learned from both thermodynamic- and DL-based methods by ensemble learning and convolutional block attention mechanism. TrioFold achieves higher accuracy in intra-family predictions and enhanced generalizability in inter-family and cross-RNA-types predictions. Additionally, we have developed an online webserver equipped with widely used RSS prediction algorithms and analysis tools, providing an accessible platform for the RNA research community. This study demonstrated new opportunities to improve generalizability for RSS predictions by efficient ensemble learning of base-pairing clues learned from both thermodynamic- and DL-based algorithms.