Adenosine (Ado), mainly produced by the hydrolysis of ATP, exhibits significantly elevated levels in the tumor microenvironment (TME) compared to normal tissues. Upon binding to adenosine receptors (AdoRs), Ado initiates downstream signaling pathways that suppress tumor antigen presentation and immune cell activation, thereby inhibiting tumor adaptive immunity. Ado downregulates major histocompatibility complex II (MHC II) and co-stimulatory factors expression on DCs and macrophages, thereby inhibiting antigen presentation to T cells. Ado inhibits the binding of the T cell receptor (TCR) to its ligand and transmembrane signal transduction on T cells, thus suppressing anti-tumor cytokines secretion and inhibiting T cell activation. Ado also inhibits the secretion of chemokines and the KCa3.1 channel, thereby suppressing the trafficking and infiltration of effector T cells into the tumor site. Moreover, Ado inhibits the cytotoxicity of T cells against tumor cells by promoting the secretion of immune-suppressive cytokines, increasing the expression of immune checkpoint proteins, and enhancing the activity of immune-suppressive cells. Due to the inhibitory effects of Ado on tumor adaptive immunity, reducing Ado production in the TME can exert significant anti-tumor immune effects and enhance the efficacy of other immunotherapies. Various inhibitors blocking Ado generation or AdoRs are now under preclinical or clinical development. Therefore, this article will summarize and analyze the inhibitory effects and molecular mechanisms of Ado on tumor adaptive immunity, as well as provide an overview of the latest advancements in targeting Ado pathways in anti-tumor immune responses.

Acute respiratory distress syndrome (ARDS) is an acute respiratory disease which is characterized by non-cardiogenic pulmonary oedema. It has a high mortality rate and lacks effective pharmacotherapy. As the outbreak of COVID worldwide, the mortality of ARDS has increased correspondingly, which makes it urgent to find effective targets and strategies for the treatment of ARDS. Recent clinical trials of Janus kinase (JAK) inhibitors in treating COVID induced ARDS have shown a positive outcome, which makes the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway a potential therapeutic target for treating ARDS. Here, we review the complex cause of ARDS, the molecular pathway of JAK/STAT involved in ARDS pathology, and the progress that has been made in strategies of targeting JAK/STAT to treat ARDS Specially, JAK/STAT signaling directly participates in the progression of ARDS or collude with other pathways to aggravate ARDS. We summarize JAK and STAT inhibitors with ARDS treatment benefits, including inhibitors in clinical trials and pre-clinical studies and natural products, and discuss the side effects of the current JAK inhibitors to reveal the future trends in designing of JAK inhibitors, which will help to develop effective treatment strategies for ARDS in the future.

Background and Purpose Lapatinib, a widely-used dual inhibitor of EGFR/ERBB1 and HER2/ERBB2 effectively targeting HER2 positive breast cancer, has been seriously limited due to cutaneous toxicity. However, the specific mechanism of lapatinib-induced cutaneous toxicity has not been clarified, leading to a lack of effective strategy targets to improve clinical safety. Here, we aimed to identify molecular mechanism occurs in this process and strive for effective intervention strategies against lapatinib-induced cutaneous side effects. Experimental and Approach C57BL/6 mice were subjected to lapatinib via intragastric administration, serum was used for ELISA assay, skin tissue was collected and performed with histopathological analysis. Apoptotic assay was analyzed in HaCaT and NHEK cell lines, comet assay was conducted to measure the damage of DNA, real-time PCR was used to assess the level of HMGB and inflammatory factors. Key Results We found that lapatinib could induce mitochondrial dysfunction, lead to DNA damage and finally cause apoptosis of keratinocytes. In addition, we found that lapatinib could induce aberrant immune response and promote the release of inflammatory factors in vitro and in vivo. Mechanistically, downregulated expression of HMGB1 played a critical role in these toxic reaction processes. Delightfully, we found that saikosaponin A could significantly rescue the reduced HMGB1 transcription, which could alleviate lapatinib-induced DNA damage, inhibit keratinocyte apoptosis and further prevent toxicity of lapatinib in mice. Conclusion and Implications Our study provided molecular mechanism of lapatinib-induced cutaneous toxicity, and shed new light on the prevention of cutaneous adverse drug reactions induced by EGFR inhibitors.

A document by Yueping Qiu. Click on the document to view its contents.