Abstract Having a hypoxic microenvironment is a common and salient feature of most solid tumors. Hypoxia has a profound effect on the biological behavior and malignant phenotype of cancer cells, mediates the effects of cancer chemotherapy, radiotherapy, and immunotherapy through complex mechanisms, and is closely associated with poor prognosis in various cancer patients. Accumulating studies have demonstrated that through normalization of the tumor vasculature, nanoparticle carriers and biocarriers can effectively increase the oxygen concentration in the tumor microenvironment, improve drug delivery and the efficacy of radiotherapy. They also increase infiltration of innate and adaptive anti-tumor immune cells to enhance the efficacy of immunotherapy. Furthermore, drugs targeting key genes associated with hypoxia, including hypoxia tracers, hypoxia-activated prodrugs, and drugs targeting hypoxia-inducible factors and downstream targets, can be used for visualization and quantitative analysis of tumor hypoxia and antitumor activity. However, the relationship between hypoxia and cancer is an area of research that requires further exploration. Here, we investigated the potential factors in the development of hypoxia in cancer, changes in signaling pathways that occur in cancer cells to adapt to hypoxic environments, the mechanisms of hypoxia-induced cancer immune tolerance, chemotherapeutic tolerance, and enhanced radiation tolerance, as well as the insights and applications of hypoxia in cancer therapy. 

/pdf/hypoxic-microenvironment-in-cancer-molecular-mechanisms-and-2xbbj46h.pdf

Hypoxic microenvironment in cancer: molecular mechanisms and therapeutic interventions

Hypoxia-inducible factors (HIFs) are master regulators of oxygen homeostasis that match O2 supply and demand for each of the 50 trillion cells in the adult human body. Cancer cells co-opt this homeostatic system to drive cancer progression. HIFs activate the transcription of thousands of genes that mediate angiogenesis, cancer stem cell specification, cell motility, epithelial-mesenchymal transition, extracellular matrix remodeling, glucose and lipid metabolism, immune evasion, invasion, and metastasis. In this Review, the mechanisms and consequences of HIF activation in cancer cells are presented. The current status and future prospects of small-molecule HIF inhibitors for use as cancer therapeutics are discussed.

Hypoxia-inducible factors: cancer progression and clinical translation

Hepatocellular carcinoma (HCC) has a high prevalence and mortality rate worldwide. Sorafenib monotherapy has been the standard of first-line treatment for advanced HCC for a long time, but there are still many shortcomings. In recent years, with the deepening of research on tumor immune microenvironment, researchers have begun to explore new approaches in immunotherapy, and the introduction of immune checkpoint inhibitors has brought fundamental changes to the treatment of HCC. Programmed cell death protein 1 (PD-1) is an immune checkpoint molecule that plays an important role in down-regulating immune system function and promoting tolerance. Programmed cell death ligand 1 (PDL-1) is involved in tumor immune evasion by binding to PD-1, resulting in failure of treatment. Currently, immunotherapy targeting the PD-1/PD-L1 axis has achieved unprecedented success in HCC, but it also faces great challenges, with its low remission rate still to be solved. For most patients with HCC, the PD-1/PD-L1 pathway is not the only rate limiting factor of antitumor immunity, and blocking only the PD-1/PD-L1 axis is not enough to stimulate an effective antitumor immune response; thus, combination therapy may be a better option. In this study, changes in the immune microenvironment of HCC patients were reviewed to clarify the feasibility of anti-PD-1/PD-L1 therapy, and a series of monotherapy and combination therapy clinical trials were summarized to verify the safety and efficacy of this newly developed treatment in patients with advanced HCC. Furthermore, we focused on hyperprogressive disease and drug resistance to gain a better understanding of PD-1/PD-L1 blockade as a promising treatment.

/pdf/pd-1-pd-l1-checkpoint-inhibitors-in-advanced-hepatocellular-139dm3g6.pdf

PD-1/PD-L1 checkpoint inhibitors in advanced hepatocellular carcinoma immunotherapy

Metabolic reprogramming is one of the most important hallmarks of malignant tumors. Specifically, lipid metabolic reprogramming has marked impacts on cancer progression and therapeutic response by remodeling the tumor microenvironment (TME). In the past few decades, immunotherapy has revolutionized the treatment landscape for advanced cancers. Lipid metabolic reprogramming plays pivotal role in regulating the immune microenvironment and response to cancer immunotherapy. Here, we systematically reviewed the characteristics, mechanism, and role of lipid metabolic reprogramming in tumor and immune cells in the TME, appraised the effects of various cell death modes (specifically ferroptosis) on lipid metabolism, and summarized the antitumor therapies targeting lipid metabolism. Overall, lipid metabolic reprogramming has profound effects on cancer immunotherapy by regulating the immune microenvironment; therefore, targeting lipid metabolic reprogramming may lead to the development of innovative clinical applications including sensitizing immunotherapy.

/pdf/the-role-of-lipid-metabolic-reprogramming-in-tumor-3u6tjdt7.pdf

The role of lipid metabolic reprogramming in tumor microenvironment

Targeting hypoxia-inducible factors: therapeutic opportunities and challenges.

The immune response to ischemic stroke is an area of study that is at the forefront of stroke research and presents promising new avenues for treatment development. Upon cerebral vessel occlusion, the innate immune system is activated by danger-associated molecular signals from stressed and dying neurons. Microglia, an immune cell population within the central nervous system which phagocytose cell debris and modulate the immune response via cytokine signaling, are the first cell population to become activated. Soon after, monocytes arrive from the peripheral immune system, differentiate into macrophages, and further aid in the immune response. Upon activation, both microglia and monocyte-derived macrophages are capable of polarizing into phenotypes which can either promote or attenuate the inflammatory response. Phenotypes which promote the inflammatory response are hypothesized to increase neuronal damage and impair recovery of neuronal function during the later phases of ischemic stroke. Therefore, modulating neuroimmune cells to adopt an anti-inflammatory response post ischemic stroke is an area of current research interest and potential treatment development. In this review, we outline the biology of microglia and monocyte-derived macrophages, further explain their roles in the acute, subacute, and chronic stages of ischemic stroke, and highlight current treatment development efforts which target these cells in the context of ischemic stroke.

/pdf/the-translational-potential-of-microglia-and-monocyte-2gino6dg.pdf

The Translational Potential of Microglia and Monocyte-Derived Macrophages in Ischemic Stroke

Translation of novel therapies for brain cancer into clinical practice is of the utmost importance as primary brain tumors are responsible for more than 200,000 deaths worldwide each year. While many research efforts have been aimed at improving survival rates over the years, prognosis for patients with glioblastoma and other primary brain tumors remains poor. Safely delivering chemotherapeutic drugs and other anti-cancer compounds across the blood–brain barrier and directly to tumor cells is perhaps the greatest challenge in treating brain cancer. Polymeric nanoparticles (NPs) are powerful, highly tunable carrier systems that may be able to overcome those obstacles. Several studies have shown appropriately-constructed polymeric NPs cross the blood–brain barrier, increase drug bioavailability, reduce systemic toxicity, and selectively target central nervous system cancer cells. While no studies relating to their use in treating brain cancer are in clinical trials, there is mounting preclinical evidence that polymeric NPs could be beneficial for brain tumor therapy. This review includes a variety of polymeric NPs and how their associated composition, surface modifications, and method of delivery impact their capacity to improve brain tumor therapy.

/pdf/polymeric-nanoparticles-in-brain-cancer-therapy-a-review-of-2hjilh5h.pdf

Polymeric Nanoparticles in Brain Cancer Therapy: A Review of Current Approaches

BACKGROUND: Interest in machine learning (ML)–based predictive modeling has led to the development of models predicting outcomes after aneurysmal subarachnoid hemorrhage (aSAH), including the Nijmegen acute subarachnoid hemorrhage calculator (Nutshell). Generalizability of such models to external data remains unclear. OBJECTIVE: To externally validate the performance of the Nutshell tool while comparing it with the conventional Subarachnoid Hemorrhage International Trialists (SAHIT) models and to review the ML literature on outcome prediction after aSAH and aneurysm treatment. METHODS: A prospectively maintained database of patients with aSAH presenting consecutively to our institution in the 2013 to 2018 period was used. The web-based Nutshell and SAHIT calculators were used to derive the risks of poor long-term (12-18 months) outcomes and 30-day mortality. Discrimination was evaluated using the area under the curve (AUC), and calibration was investigated using calibration plots. The literature on relevant ML models was surveyed for a synopsis. RESULTS: In 269 patients with aSAH, the SAHIT models outperformed the Nutshell tool (AUC: 0.786 vs 0.689, P = .025) in predicting long-term functional outcomes. A logistic regression model of the Nutshell variables derived from our data achieved adequate discrimination (AUC = 0.759) of poor outcomes. The SAHIT models outperformed the Nutshell tool in predicting 30-day mortality (AUC: 0.810 vs 0.636, P < .001). Calibration properties were more favorable for the SAHIT models. Most published aneurysm-related ML-based outcome models lack external validation and usable testing platforms. CONCLUSION: The Nutshell tool demonstrated limited performance on external validation in comparison with the SAHIT models. External validation and the dissemination of testing platforms for ML models must be emphasized.

External Validation of a Neural Network Model in Aneurysmal Subarachnoid Hemorrhage: A Comparison With Conventional Logistic Regression Models

Plexin-B3 expression stimulates MET signaling, breast cancer stem cell specification, and lung metastasis.

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