Mechanisms, combination therapy, and biomarkers in cancer immunotherapy resistance.

Anti-programmed death 1/programmed death ligand 1 (anti-PD-1/PD-L1) antibodies exert significant antitumor effects by overcoming tumor cell immune evasion and reversing T-cell exhaustion. However, the emergence of drug resistance causes most patients to respond poorly to these immune checkpoint inhibitors (ICIs). Studies have shown that insufficient T-cell infiltration, lack of PD-1 expression, deficient interferon signaling, loss of tumor antigen presentation, and abnormal lipid metabolism are all considered to be closely associated with immunotherapy resistance. To address drug resistance in tumor immunotherapy, a lot of research has concentrated on developing combination therapy strategies. Currently, ICIs such as anti-PD-1 /PD-L1 antibody combined with chemotherapy and targeted therapy have been approved for clinical treatment. In this review, we analyze the mechanisms of resistance to anti-PD-1/PD-L1 therapy in terms of the tumor microenvironment, gut microbiota, epigenetic regulation, and co-inhibitory immune checkpoint receptors. We also discuss various promising combination therapeutic strategies to address resistance to anti-PD-1/PD-L1 drugs, including combining these therapies with traditional Chinese medicine, non-coding RNAs, targeted therapy, other ICIs, and personalized cancer vaccines. Moreover, we focus on biomarkers that predict resistance to anti-PD-1/PD-L1 therapy as well as combination therapy efficacy. Finally, we suggest ways to further expand the application of immunotherapy through personalized combination strategies using biomarker systems.

Connecting the mechanisms of tumor sex differences with cancer therapy.

Sex differences in cancer incidence and survival are constant and pronounced globally, across all races and all age groups of cancer types. In 2016, after the National Institutes of Health proposed a policy of utilizing sex as a biological variable, researchers started paying more attention to the molecular mechanisms behind gender variations in cancer. Historically, most previous studies investigating sex differences have been centered on gonadal sex hormones. Nevertheless, sex differences also involve genetic and molecular pathways that run throughout the entire process of cancer cell proliferation, metastasis, and treatment response, in addition to sex hormones. In particular, there is significant gender dimorphism in the efficacy and toxicity of oncology treatments, including conventional radiotherapy and chemotherapy, as well as the emerging targeted therapies and immunotherapy. To be clear, not all mechanisms will exhibit gender bias, and not all gender bias will affect cancer risk. Our goal in this review is to discuss some of the significant sex-related changes in fundamental cancer pathways. To this purpose, we summarize the differential impact of gender on cancer development in three dimensions: sex hormones, genetics, and epigenetics, and focus on current hot subjects including tumor suppressor function, immunology, stem cell renewal, and non-coding RNAs. Clarifying the essential mechanisms of gender differences will help guide the clinical treatment of both sexes in tumor radiation and chemotherapy, medication therapy with various targets, immunotherapy, and even drug development. We anticipate that sex-differentiated research will help advance sex-based cancer personalized medicine models and encourage future basic scientific and clinical research to take sex into account.

Single-cell analysis technologies for cancer research: from tumor-specific single cell discovery to cancer therapy.

Single-cell sequencing (SCS) technology is changing our understanding of cellular components, functions, and interactions across organisms, because of its inherent advantage of avoiding noise resulting from genotypic and phenotypic heterogeneity across numerous samples. By directly and individually measuring multiple molecular characteristics of thousands to millions of single cells, SCS technology can characterize multiple cell types and uncover the mechanisms of gene regulatory networks, the dynamics of transcription, and the functional state of proteomic profiling. In this context, we conducted systematic research on SCS techniques, including the fundamental concepts, procedural steps, and applications of scDNA, scRNA, scATAC, scCITE, and scSNARE methods, focusing on the unique clinical advantages of SCS, particularly in cancer therapy. We have explored challenging but critical areas such as circulating tumor cells (CTCs), lineage tracing, tumor heterogeneity, drug resistance, and tumor immunotherapy. Despite challenges in managing and analyzing the large amounts of data that result from SCS, this technique is expected to reveal new horizons in cancer research. This review aims to emphasize the key role of SCS in cancer research and promote the application of single-cell technologies to cancer therapy.

Oridonin attenuates LPS-induced early pulmonary fibrosis by regulating impaired autophagy, oxidative stress, inflammation and EMT.

CONTEXT: Oridonin (Ori) possesses anti-inflammatory, antioxidant and antitumor properties. However, the effects of Ori on Lipopolysaccharide (LPS)-induced early pulmonary fibrosis remain unclear. OBJECTIVE: We evaluated the protective effects of Ori on the mice model of pulmonary fibrosis. MATERIALS AND METHODS: The BALB/C mice were given LPS (1 mg/kg) or Ori (20 mg/kg) according to experimental grouping. Then the left lung tissues were used for HE, immunohistochemical and Masson staining, and the right lung tissues were used for hydroxyproline measurement and western blot experiments. Bronchoalveolar lavage fluid was collected for Giemsa staining. RESULTS: The high levels of hydroxyproline induced by LPS were reduced by Ori treatment. Immunohistochemical staining and western blot analysis showed that Ori inhibited the increased levels of fibrosis-related proteins (α-smooth muscle actin, transforming growth factor-ß, Collagen Ⅰ and phosphorylated-smad). Additionally, Ori treatment increased E-cadherin levels and decreased in Snail and Slug levels. Besides, Ori could suppress LPS-induced the infiltration of neutrophils and activation of the NLRP3 inflammasome. In addition, LPS caused the upregulation of NADPH oxidase 4 and exacerbated lung fibrosis. As the activator of NF-E2 related factor-2, Ori exerted protective effects in this animal model. Moreover, Ori reversed the LPS-triggered increases in Beclin-1, P62/sequestosome 1, autophagy related 3 and LC3. CONCLUSIONS: These findings suggested that Ori protected against LPS-induced early pulmonary fibrosis by inhibiting NLRP3-dependent inflammation, NADPH oxidase 4-dependent oxidative stress, the impaired autophagy and epithelial mesenchymal transformation.

Amentoflavone Ameliorates Carrageenan-Induced Pleurisy and Lung Injury by Inhibiting the NF-κB/STAT3 Pathways via Nrf2 Activation.

Many natural flavonoids can activate nuclear factor erythroid 2-related factor 2 (Nrf2), which is pivotal for alleviating various diseases related to inflammation and oxidative stress, including pleurisy. Amentoflavone (AMF), a biflavonoid extracted from many plants, has some beneficial bioactivities, especially anti-inflammatory and antioxidative activities. We aimed to investigate whether AMF protects against pleurisy and lung injury induced by carrageenan (Car) by activating Nrf2. Pleurisy was induced in wild-type (WT) and Nrf2-deficient (Nrf2-/-) mice. Then, pleural exudate and lung tissue were collected for biochemical analysis, H&E staining, immunocytochemistry and western blotting. Our results indicated that AMF protected against Car-induced pleurisy and lung injury. The Wright-Giemsa and H&E staining results showed that AMF alleviated inflammatory effusion and pathological injury. In addition, AMF decreased SOD and GSH depletion and MDA and MPO generation in the lung tissue of mice. AMF activated Nrf2 through keap-1 dissociation and subsequently increased heme oxygenase-1 (HO-1), NAD(P)H-quinone oxidoreductase 1 (NQO1), and γ-glutamylcysteine ligase (GCL) levels. Furthermore, AMF suppressed IL-1ß and TNF-α levels and increased IL-10 levels in pleural exudate by blocking the proinflammatory NF-κB, signal transducer and activator of transcription 3 (STAT3) and extracellular signal-regulated kinase (ERK) pathways induced by Car. However, these antioxidative and anti-inflammatory effects were weakened in Nrf2-/- mice. Moreover, AMF failed to suppress the NF-κB and STAT3 pathways in Nrf2-/- mice. Our results demonstrated that AMF exerted anti-inflammatory and antioxidative effects in Car-induced lung injury and pleurisy in a Nrf2-dependent manner.