Directing hypoxic tumor microenvironment and HIF to illuminate cancer immunotherapy's existing prospects and challenges in drug targets

Cancer is now also reflected as a disease of the tumor microenvironment, primarily supposed to be a decontrolled genetic and cellular expression disease. Over the past two decades, significant and rapid progress has been made in recognizing the dynamics of the tumor's microenvironment and its contribution to influencing the response to various anti-cancer therapies and drugs. Modulations in the tumor microenvironment and immune checkpoint blockade are interesting in cancer immunotherapy and drug targets. Simultaneously, the immunotherapeutic strategy can be done by modulating the immune regulatory pathway; however, the tumor microenvironment plays an essential role in suppressing the antitumor's immunity by its substantial heterogeneity. Hypoxia inducible factor (HIF) is a significant contributor to solid tumor heterogeneity and a key stressor in the tumor microenvironment to drive adaptations to prevent immune surveillance. Checkpoint inhibitors here halt the ability of cancer cells to stop the immune system from activating, and in turn, amplify your body's immune system to help destroy cancer cells. Common checkpoints that these inhibitors affect are the PD-1/PD-L1 and CTLA-4 pathways and important drugs involved are Ipilimumab and Nivolumab, mainly along with other drugs in this group. Targeting the hypoxic tumor microenvironment may provide a novel immunotherapy strategy, break down traditional cancer therapy resistance, and build the framework for personalized precision medicine and cancer drug targets. We hope that this knowledge can provide insight into the therapeutic potential of targeting Hypoxia and help to develop novel combination approaches of cancer drugs to increase the effectiveness of existing cancer therapies, including immunotherapy.

Activatable UCL/CT/MR-Enhanced in vivo Imaging-Guided Radiotherapy and Photothermal Therapy

Although sophisticated radiotherapy (RT) technology has been widely applied in clinical oncotherapy, unsatisfactory therapeutic effect resulted by hypoxic tumor microenvironment and complications are still prevalent. Herein, copper sulphide nanoparticles (CuS...

A GdW10@PDA-CAT Sensitizer with High-Z Effect and Self-Supplied Oxygen for Hypoxic-Tumor Radiotherapy

Anticancer treatment is largely affected by the hypoxic tumor microenvironment (TME), which causes the resistance of the tumor to radiotherapy. Combining radiosensitizer compounds and O2 self-enriched moieties is an emerging strategy in hypoxic-tumor treatments. Herein, we engineered GdW10@PDA-CAT (K3Na4H2GdW10O36·2H2O, GdW10, polydopamine, PDA, catalase, CAT) composites as a radiosensitizer for the TME-manipulated enhancement of radiotherapy. In the composites, Gd (Z = 64) and W (Z = 74), as the high Z elements, make X-ray gather in tumor cells, thereby enhancing DNA damage induced by radiation. CAT can convert H2O2 to O2 and H2O to enhance the X-ray effect under hypoxic TME. CAT and PDA modification enhances the biocompatibility of the composites. Our results showed that GdW10@PDA-CAT composites increased the efficiency of radiotherapy in HT29 cells in culture. This polyoxometalates and O2 self-supplement composites provide a promising radiosensitizer for the radiotherapy field.

A Comprehensive Evaluation of ZrC Nanoparticle in Combined Photothermal and Radiation Therapy for Treatment of Triple-Negative Breast Cancer

Because of the difficulty in treating triple-negative breast cancer (TNBC), the search for treatments has never stopped. Treatment opinions remain limited for triple-negative breast cancer (TNBC). The current treatment approach of using photothermal therapy (PTT) is often imprecise and has limited penetration below the surface of the skin. On the other hand, radiation therapy (RT) has its unavoidable disadvantages, such as side effects or ineffectiveness against hypoxic tumor microenvironment (TME). In this study, we proposed the use of ZrC nanoparticles in conjunction with RT/PTT to enhance antitumor and antimetastatic effect. We modified the ZrC nanoparticle with bovine serum albumin (BSA) and folic acid (FA), sizing desirable about 100nm. The photothermal conversion efficiency was calculated to be 40.51% and sensitizer enhancement ration (SER) was 1.8. With addition of ZrC NPs, more DNA were damaged in γ-H2AX and more ROS were detected with immunofluorescence. In vitro and vivo, the combined therapy with ZrC NPS showed the best effect of tumor cell inhibition and safety. Our results provide evidence that the combination of ZrC NPs, PT, and RT is effective in of TNBC, making it a great potential application for cancer therapy in clinic.

Immunophenotyping of an Unusual Mixed-Type Extraskeletal Osteosarcoma in a Dog

A 6-year-old female Maltese dog presented with a cervical mass without pain. The tumor was surrounded by a thick fibrous tissue and consisted of an osteoid matrix with osteoblasts and two distinct areas: a mesenchymal cell-rich lesion with numerous multinucleated giant cells and a chondroid matrix-rich lesion. The tumor cells exhibited heterogeneous protein expression, including a positive expression of vimentin, cytokeratin, RANKL, CRLR, SOX9, and collagen 2, and was diagnosed as extraskeletal osteosarcoma. Despite its malignancy, the dog showed no sign of recurrence or metastasis three months after the resection. Further analysis of the tumor cells revealed a high expression of proliferation- and metastasis-related biomarkers in the absence of angiogenesis-related biomarkers, suggesting that the lack of angiogenesis and the elevated tumor-associated fibrosis resulted in a hypoxic tumor microenvironment and prevented metastasis.

Biodegradable reduce expenditure bioreactor for augmented sonodynamic therapy via regulating tumor hypoxia and inducing pro-death autophagy

Backgrounds Sonodynamic therapy (SDT) as an emerging reactive oxygen species (ROS)-mediated antitumor strategy is challenged by the rapid depletion of oxygen, as well as the hypoxic tumor microenvironment. Instead of the presently available coping strategies that amplify the endogenous O2 level, we have proposed a biodegradable O2 economizer to reduce expenditure for augmenting SDT efficacy in the present study. Results We successfully fabricated the O2 economizer (HMME@HMONs-3BP-PEG, HHBP) via conjugation of respiration inhibitor 3-bromopyruvate (3BP) with hollow mesoporous organosilica nanoparticles (HMONs), followed by the loading of organic sonosensitizers (hematoporphyrin monomethyl ether; HMME) and further surface modification of poly(ethylene glycol) (PEG). The engineered HHBP features controllable pH/GSH/US-sensitive drug release. The exposed 3BP could effectively inhibit cell respiration for restraining the oxygen consumption, which could alleviate the tumor hypoxia conditions. More interestingly, it could exorbitantly elevate the autophagy level, which in turn induced excessive activation of autophagy for promoting the therapeutic efficacy. As a result, when accompanied with suppressing O2-consumption and triggering pro-death autophagy strategy, the HHBP could achieve the remarkable antitumor activity, which was systematically validated both in vivo and in vitro assays. Conclusions This work not only provides a reduce expenditure means for enduring SDT, but also represents an inquisitive strategy for tumor treatments by inducing pro-death autophagy. Graphical Abstract