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The tumor microenvironment (TME) is a complex and dynamic entity, comprising stromal cells, immune cells, blood vessels and extracellular matrix, which is intimately associated with the occurrence and development of cancers, as well as their therapy. Utilizing the shared characteristics of tumors, such as an acidic environment, enzymes and hypoxia, researchers have developed a promising cancer therapy strategy known as responsive release of nano-loaded drugs, specifically targeted at tumor tissues or cells. In this comprehensive review, we provide an in-depth overview of the current fundamentals and state-of-the-art intelligent strategies of TME-responsive nanoplatforms, which include acidic pH, high GSH levels, high-level adenosine triphosphate, overexpressed enzymes, hypoxia and reductive environment. Additionally, we showcase the latest advancements in TME-responsive nanoparticles. In conclusion, we thoroughly examine the immediate challenges and prospects of TME-responsive nanopharmaceuticals, with the expectation that the progress of these targeted nanoformulations will enable the exploitation, overcoming or modulation of the TME, ultimately leading to significantly more effective cancer therapy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Wang et al.)

Metastasis is the leading cause of cancer-related death. The interactions between circulating tumor cells and endothelial adhesion molecules in distant organs is a key step during extravasation in hematogenous metastasis. Surgery is a common intervention for most primary solid tumors. However, surgical trauma-related systemic inflammation facilitates distant tumor metastasis by increasing the spread and adhesion of tumor cells to vascular endothelial cells (ECs). Currently, there are no effective interventions to prevent distant metastasis. Here, we show that HECTD3 deficiency in ECs significantly reduces tumor metastasis in multiple mouse models. HECTD3 depletion downregulates expression of adhesion molecules, such as VCAM-1, ICAM-1 and E-selectin, in mouse primary ECs and HUVECs stimulated by inflammatory factors and inhibits adhesion of tumor cells to ECs both in vitro and in vivo. We demonstrate that HECTD3 promotes stabilization, nuclear localization and kinase activity of IKKα by ubiquitinating IKKα with K27- and K63-linked polyubiquitin chains at K296, increasing phosphorylation of histone H3 to promote NF-κB target gene transcription. Knockout of HECTD3 in endothelium significantly inhibits tumor cells lung colonization, while conditional knockin promotes that. IKKα kinase inhibitors prevented LPS-induced pulmonary metastasis. These findings reveal the promotional role of the HECTD3-IKKα axis in tumor hematogenous metastasis and provide a potential strategy for tumor metastasis prevention., (© 2022. The Author(s).)

Optoelectronic science and 2D nanomaterial technologies are currently at the forefront of multidisciplinary research and have numerous applications in electronics and photonics. The unique energy and optically induced interfacial electron transfer in these nanomaterials, enabled by their relative band alignment characteristics, can provide important therapeutic modalities for healthcare. Given that nano-heterostructures can facilitate photoinduced electron-hole separation and enhance generation of reactive oxygen species (ROS), 2D nano-heterostructure-based photosensitizers can provide a major advancement in photodynamic therapy (PDT), to overcome the current limitations in hypoxic tumor microenvironments. Herein, a bismuthene/bismuth oxide (Bi/BiOx)-based lateral nano-heterostructure synthesized using a regioselective oxidation process is introduced, which, upon irradiation at 660 nm, effectively generates 1 O 2 under normoxia but produces cytotoxic •OH and H 2 under hypoxia, which synergistically enhances PDT. Furthermore, this Bi/BiOx nano-heterostructure is biocompatible and biodegradable, and, with the surface molecular engineering used here, it improves tumor tissue penetration and increases cellular uptake during in vitro and in vivo experiments, yielding excellent oxygen-independent tumor ablation with 660 nm irradiation, when compared with traditional PDT agents., (© 2021 Wiley-VCH GmbH.)

Photodynamic therapy (PDT) has been extensively investigated for decades for tumor treatment because of its non-invasiveness, spatiotemporal selectivity, lower side-effects, and immune activation ability. It can be a promising treatment modality in several medical fields, including oncology, immunology, urology, dermatology, ophthalmology, cardiology, pneumology, and dentistry. Nevertheless, the clinical application of PDT is largely restricted by the drawbacks of traditional photosensitizers, limited tissue penetrability of light, inefficient induction of tumor cell death, tumor resistance to the therapy, and the severe pain induced by the therapy. Recently, various photosensitizer formulations and therapy strategies have been developed to overcome these barriers. Significantly, the introduction of nanomaterials in PDT, as carriers or photosensitizers, may overcome the drawbacks of traditional photosensitizers. Based on this, nanocomposites excited by various light sources are applied in the PDT of deep-seated tumors. Modulation of cell death pathways with co-delivered reagents promotes PDT induced tumor cell death. Relief of tumor resistance to PDT with combined therapy strategies further promotes tumor inhibition. Also, the optimization of photosensitizer formulations and therapy procedures reduces pain in PDT. Here, a systematic summary of recent advances in the fabrication of photosensitizers and the design of therapy strategies to overcome barriers in PDT is presented. Several aspects important for the clinical application of PDT in cancer treatment are also discussed.

Background: Abnormal metabolic pathways have been considered as one of the hallmarks of cancer. While numerous metabolic pathways have been studied in various cancers, the direct link between metabolic pathway gene expression and cancer prognosis has not been established., Results: Using two recently developed bioinformatics analysis methods, we evaluated the prognosis potential of metabolic pathway expression and tumor-vs-normal dysregulations for up to 29 metabolic pathways in 33 cancer types. Results show that increased metabolic gene expression within tumors corresponds to poor cancer prognosis. Meta differential co-expression analysis identified four metabolic pathways with significant global co-expression network disturbance between tumor and normal samples. Differential expression analysis of metabolic pathways also demonstrated strong gene expression disturbance between paired tumor and normal samples., Conclusion: Taken together, these results strongly suggested that metabolic pathway gene expressions are disturbed after tumorigenesis. Within tumors, many metabolic pathways are upregulated for tumor cells to activate corresponding metabolisms to sustain the required energy for cell division.

Optical techniques using developed laser and optical devices have made a profound impact on modern medicine, with "biomedical optics" becoming an emerging field. Sophisticated technologies have been developed in cancer nanomedicine, such as photothermal therapy and photodynamic therapy, among others. However, single-mode phototherapy cannot completely treat persistent tumors, with the challenges of relapse or metastasis remaining; therefore, combinatorial strategies are being developed. In this review, the role of light in cancer therapy and the challenges of phototherapy are discussed. The development of combinatorial strategies with other therapeutic methods, including chemotherapy, immunotherapy, gene therapy, and radiotherapy, is presented and future directions are further discussed. This review aims to highlight the significance of light in cancer therapy and discuss the combinatorial strategies that show promise in addressing the challenges of phototherapy.

In recent years, nanomaterials and nanotechnology have emerged as vital factors in the medical field with a unique contribution to cancer medicine. Given the increasing number of cancer patients, it is necessarily required to develop innovative strategies and therapeutic modalities to tackle hypoxia, which forms a hallmark and great barrier in treating solid tumors. The present review details the challenges in nanotechnology-based hypoxia, targeting the strategies and solutions for better therapeutic performances. The interaction between hypoxia and tumor is firstly introduced. Then, we review the recently developed engineered nanomaterials towards multimodal hypoxia tumor therapies, including chemotherapy, radiotherapy, and sonodynamic treatment. In the next part, we summarize the nanotechnology-based strategies for overcoming hypoxia problems. Finally, current challenges and future directions are proposed for successfully overcoming the hypoxia tumor problems.

Immunomodulation of macrophages against cancer has emerged as an encouraging therapeutic strategy. However, there exist two major challenges in effectively activating macrophages for antitumor immunotherapy. First, ligation of signal regulatory protein alpha (SIRPα) on macrophages to CD47, a "don't eat me" signal on cancer cells, prevents macrophage phagocytosis of cancer cells. Second, colony stimulating factors, secreted by cancer cells, polarize tumor-associated macrophages (TAMs) to a tumorigenic M2 phenotype. Here, it is reported that genetically engineered cell-membrane-coated magnetic nanoparticles (gCM-MNs) can disable both mechanisms. The gCM shell genetically overexpressing SIRPα variants with remarkable affinity efficiently blocks the CD47-SIRPα pathway while the MN core promotes M2 TAM repolarization, synergistically triggering potent macrophage immune responses. Moreover, the gCM shell protects the MNs from immune clearance; and in turn, the MN core delivers the gCMs into tumor tissues under magnetic navigation, effectively promoting their systemic circulation and tumor accumulation. In melanoma and breast cancer models, it is shown that gCM-MNs significantly prolong overall mouse survival by controlling both local tumor growth and distant tumor metastasis. The combination of cell-membrane-coating nanotechnology and genetic editing technique offers a safe and robust strategy in activating the body's immune responses for cancer immunotherapy., (© 2020 Wiley-VCH GmbH.)