Triple-negative breast cancer (TNBC) is an aggressive form of breast cancer defined by the lack of three key receptors: estrogen, progesterone, and HER2. This lack of receptors makes TNBC difficult to treat with hormone therapy or drugs, and so it is characterised by a poor prognosis compared to other kinds of breast cancer. This study explores photoactive Poly(lactic-co-glycolic acid) (PLGA) nanoparticles as a potential therapeutic strategy for TNBC. The nanoparticles are functionalised with hyaluronic acid (HA) for targeted delivery to CD-44 receptors overexpressed in TNBC cells, especially under hypoxic conditions. Additionally, we co-loaded the nanoparticles with Doxorubicin (Dox) and Indocyanine Green (ICG) to enable combinatorial chemo-photothermal therapy. After carefully optimising the formulation, we propose an effortless and reproducible preparation of the nanodrugs. We demonstrate that HA-conjugated nanoparticles effectively target TNBC cells and inhibit their proliferation while the treatment efficiency is enhanced during near-infrared light irradiation. We also prove that our treatment is effective in a 3D cell culture model, highlighting the importance of tumour architecture and the metabolic stage of the cells in the tumour microenvironment. This approach is promising for a tumour-targeted theragnostic for TNBC with improved efficacy in hypoxic microenvironments.

Intratumour hypoxia is a feature of all heterogenous solid tumours. Increased levels or subregions of tumour hypoxia are associated with an adverse clinical prognosis, particularly when this co-occurs with genomic instability. Experimental evidence points to the acquisition of DNA and chromosomal alterations in proliferating hypoxic cells secondary to inhibition of DNA repair pathways such as homologous recombination, base excision repair and mismatch repair. Cell adaptation and selection in repair-deficient cells give rise to a model whereby novel single-nucleotide mutations, structural variants and copy number alterations coexist with altered mitotic control to drive chromosomal instability and aneuploidy. Whole-genome sequencing studies support the concept that hypoxia is a critical microenvironmental cofactor alongside the driver mutations in MYC, BCL2, TP53 and PTEN in determining clonal and subclonal evolution in multiple tumour types. We propose that the hypoxic tumour microenvironment selects for unstable tumour clones which survive, propagate and metastasize under reduced immune surveillance. These aggressive features of hypoxic tumour cells underpin resistance to local and systemic therapies and unfavourable outcomes for patients with cancer. Possible ways to counter the effects of hypoxia to block tumour evolution and improve treatment outcomes are described.

Microcirculatory heterogeneity plays an essential role in the initiation and progression of glioblastoma (GBM). This study employs super-resolution ultrasound imaging to visualize the microcirculatory heterogeneity in GBM, with the objective of illustrating its predictive value in histological assessments.

This in vivo study explored the microvasculature in GBM models using 15 Sprague-Dawley rats, divided into three groups based on tumor growth stages (12, 18 and 24 d post-implantation). Ultrasound localization microscopy (ULM) was employed to assess microvascular morphology, hemodynamics and heterogeneity. Structural, functional and heterogeneity parameters at different tumor growth stages were quantified using Kruskal-Wallis H tests, or analysis of variance, followed by Bonferroni correction to characterize tumor progression. Linear correlations between these quantitative parameters and pathological indicators, including histological vascular density (VD-H), proliferation index and histological vascular maturity index (VMI-H), were evaluated. A stepwise linear regression model was constructed to assess the predictive performance in relation to histological parameters.

Compared to histology, ULM enabled the earlier detection of tumor progression. The quantitative parameters derived from ULM provided a more comprehensive assessment than conventional metrics such as tumor size and immunohistochemistry. Multivariate analysis exhibited significant correlations among curvature, blood flow orientation variance (OV) and VD-H. Additionally, curvature, blood flow and OV demonstrated significant correlations with the proliferation index, while blood flow and fractal dimension showed significant associations with VMI-H. Heterogeneity parameters exhibited superior predictive power for certain histological features compared to microvascular morphology and functional perfusion.

ULM provides a basis for early, non-invasive in vivo imaging and quantification of microvascular structures in rat GBM and demonstrates super-resolution predictive capability for histological parameters.

In clinical scenarios, bone defects stemming from trauma, infections, degenerative diseases, or hereditary conditions necessitate considerable bone grafts. Researchers ardently focus on creating diverse biomaterials to expedite and enhance these intricate restorative processes. These biomaterials play a pivotal role in aiding osteogenesis and angiogenesis factors for reconstructing stable, fully developed bone tissue. We observed the utilization of Desferoxamine (DFO) facilitated angiogenesis, thereby enabling Kartogenin (KGN) to activate the β-catenin/Runx-2 pathway. Our study introduces a composite hydrogel loaded with KGN and DFO via liposomes to enhance the coupling of angiogenesis and osteogenesis. Within this composite hydrogel system, KGN and DFO undergo effective release. This controlled release substantially promotes a conducive microenvironment for angiogenesis and osteogenesis. Our in vitro studies provide compelling evidence of the synergistic impact between KGN and DFO on osteogenic processes. Moreover, the composite hydrogel exhibits the capability to enhance the expression of proteins and genes associated with both angiogenesis and osteogenesis. In rat skull defect model, the composite hydrogel notably stimulates vascularization and osteogenic differentiation without infection or mortality. In summary, results underscore the potential of this composite hydrogel as an alternative to autografts for bone defect repair, offering a promising approach for future clinical and regenerative applications.

Tumor metastasis regulated by multiple complicated pathways is closely related to variations in the tumor microenvironment. Exosomes can regulate the tumor microenvironment through various mechanisms. Exosomes derived from tumor cells carry a variety of substances, including long non-coding RNAs (lncRNAs), play important roles in intercellular communication and act as critical determinants influencing tumor metastasis. In this review, we elaborate on several pivotal processes through which lncRNAs regulate tumor metastasis, including the regulation of epithelial‒mesenchymal transition, promotion of angiogenesis and lymphangiogenesis, enhancement of the stemness of tumor cells, and evasion of immune clearance. Additionally, we comprehensively summarized a diverse array of potential tumor-derived exosomal lncRNA biomarkers to facilitate accurate diagnosis and prognosis in a clinical setting.

Hypoxia influences the epithelial-mesenchymal transition (EMT) through the remodeling of the chromatin structure, epigenetics, and alternative splicing. Hypoxia drives CCCTC-binding factor (CTCF) induction through hypoxia-inducible factor 1-alpha (HIF1α), which promotes EMT, although the underlying mechanisms remain unclear. We find that hypoxia significantly increases CTCF occupancy at various EMT-related genes. We present a CTCF-mediated intricate mechanism promoting EMT wherein CTCF binding at the collagen type V alpha 1 chain (COL5A1) promoter is crucial for COL5A1 upregulation under hypoxia. Additionally, hypoxia drives exon64A inclusion in a mutually exclusive alternative splicing event of COL5A1exon64 (exon64A/64B). Notably, CTCF mediates COL5A1 promoter-alternatively spliced exon upstream looping that regulates DNA demethylation at distal exon64A. This further regulates the CTCF-mediated RNA polymerase II pause at COL5A1exon64A, leading to its inclusion in promoting the EMT under hypoxia. Genome-wide study indicates the association of gained CTCF occupancy with the alternative splicing of many cancer-related genes, similar to the proposed model. Specifically, disrupting the HIF1α-CTCF-COL5A1exon64A axis through the dCas9-DNMT3A system alleviates the EMT in hypoxic cancer cells and may represent a novel therapeutic target in breast cancer.

Brain metastases (BMs) are the most common intracranial tumors in adults and the major cause of cancer-related morbidity and mortality. The occurrence of BMs varies according to the type of primary tumors with most frequence in lung cancer, melanoma and breast cancer. Among of them, lung cancer has been reported to have a higher risk of BMs than other types of cancers with 40 ~ 50% of such patients will develop BMs during the course of disease. BMs lead to many neurological complications and result in a poor quality of life and short life span. Although the treatment strategies were improved for brain tumors in the past decades, the prognosis of BMs patients is grim. Poorly understanding of the molecular and cellular characteristics of BMs and the complicated interaction with brain microenvironment are the major reasons for the dismal prognosis of BM patients. Recent studies have enhanced understanding of the mechanisms of BMs. The newly identified potential therapeutic targets and the advanced therapeutic strategies have brought light for a better cure of BMs. In this review, we summarized the mechanisms of BMs during the metastatic course, the molecular and cellular landscapes of BMs, and the advances of novel drug delivery systems for overcoming the obstruction of blood-brain barrier (BBB). We further discussed the challenges of the emerging therapeutic strategies, such as synergistic approach of combining targeted therapy with immunotherapy, which will provide vital clues for realizing the precise and personalized medicine for BM patients in the future.

Bladder cancer (BCa), particularly muscle-invasive bladder cancer (MIBC), is associated with poor prognosis, partly because of immune evasion driven by M2 tumor-associated macrophages (TAMs). Understanding the regulatory mechanisms of M2 macrophage polarization via PRKN-mediated mitophagy and histone lactylation (H3K18la) is crucial for improving treatment strategies.

A single-cell atlas from 46 human BCa samples was constructed to identify macrophage subpopulations. Bioinformatics analysis and experimental validation, including ChIP-seq and lactylation modulation assays, were used to investigate the role of PRKN in M2 macrophage polarization and its regulation by H3K18la.

Single-cell analysis revealed distinct macrophage subpopulations, including M1 and M2 types. PRKN was identified as a critical regulator of mitophagy in M2 macrophages, supporting their immunosuppressive function. Bulk RNA-seq and gene intersection analysis revealed a set of mitophagy-related macrophage polarization genes (Mito_Macro_RGs) enriched in mitophagy and immune pathways. Pseudotime analysis revealed that PRKN was upregulated during the M1-to-M2 transition. siRNA-mediated PRKN knockdown impaired M2 polarization, reducing the expression of CD206 and ARG1. ChIP-seq and histone lactylation modulation confirmed that H3K18la enhanced PRKN expression, promoting mitophagy and M2 polarization and thereby facilitating immune suppression and tumor progression.

Histone lactylation regulated PRKN-mediated mitophagy, promoting M2 macrophage polarization and contributing to immune evasion in BCa.

Sonodynamic therapy (SDT) is a noninvasive approach to tumor treatment, with ongoing efforts being focused on developing highly effective sonosensitizers with low toxicity. Herein, a liquid-phase stripping technique was introduced as a simple reflux method for synthesizing ultrasmall Mn-PCN-224 nanodots (MM NDs). Compared with PCN-224 nanodots, the synthesized MM NDs, which function as renal-clearable nanoagents, produced 2.42 times more reactive oxygen species (ROS) under identical ultrasound (US) irradiation conditions. In vivo and in vitro experiments revealed that A549 lung cancer cells treated with MM NDs under US irradiation and H2O2 exhibited a relative cell viability of ∼9% and a tumor inhibition rate of ∼91%. This result demonstrates that MM NDs can efficiently increase the effectiveness of SDT by leveraging their catalase-like activity and ultrasmall size (4 nm) to prevent ROS quenching. Furthermore, these nanoagents could be effectively utilized for photoacoustic (PA) imaging to track their accumulation in tumors and monitor the alleviation of the hypoxic tumor microenvironment. Notably, MM ND-mediated SDT demonstrated superior penetration depth compared to PDT, making it more effective in inhibiting contralateral tumors while facilitating deep-tissue treatment. Thus, this study introduces renal-clearable nanoagents with promising potential for PA-guided SDT, thereby paving the way for more effective tumor treatment strategies.

Delving into cancer dormancy has been an inherent task that may drive the lethal recurrence of cancer after primary tumor relief. Cells in quiescence can survive for a short or long term in silence, may undergo genetic or epigenetic changes, and can initiate relapse through certain contextual cues. The state of dormancy can be induced by multiple conditions including cancer drug treatment, in turn, undergoes a life cycle that generally occurs through dissemination, invasion, intravasation, circulation, immune evasion, extravasation, and colonization. Throughout this cascade, a cellular machinery governs the fate of individual cells, largely affected by gene regulation. Despite its significance, a precise view of cancer dormancy is yet hampered. Revolutionizing advanced single cell and long read sequencing through analysis methodologies and artificial intelligence, the most recent stage in the research tool progress, is expected to provide a holistic view of the diverse aspects of cancer dormancy.

Tumor hypoxia drives metabolic shifts, cancer progression, and therapeutic resistance. Challenges in quantifying hypoxia have hindered the exploitation of this potential "Achilles' heel." While gene expression signatures have shown promise as surrogate measures of hypoxia, signature usage is heterogeneous and debated. Here, we present a systematic pan-cancer evaluation of 70 hypoxia signatures and 14 summary scores in 104 cell lines and 5,407 tumor samples using 472 million length-matched random gene signatures. Signature and score choice strongly influenced the prediction of hypoxia in vitro and in vivo. In cell lines, the Tardon signature was highly accurate in both bulk and single-cell data (94% accuracy, interquartile mean). In tumors, the Buffa and Ragnum signatures demonstrated superior performance, with Buffa/mean and Ragnum/interquartile mean emerging as the most promising for prospective clinical trials. This work delivers recommendations for experimental hypoxia detection and patient stratification for hypoxia-targeting therapies, alongside a generalizable framework for signature evaluation.

Hypoxia is a critical microenvironmental condition that plays a major role in driving tumorigenesis and cancer progression. Increasing evidence has revealed novel functions of hypoxia in intercellular communication. The hypoxia induced tumor derived exosomes (hiTDExs) released in high quantities by tumor cells under hypoxia are packed with unique cargoes that are essential for cancer cells' interactions within their microenvironment. These hiTDExs facilitate not only immune evasion but also promote cancer cell growth, survival, angiogenesis, EMT, resistance to therapy, and the metastatic spread of the disease. Nevertheless, direct interventions targeting hypoxia signaling in cancer therapy face challenges related to tumor progression and resistance, limiting their clinical effectiveness. Therefore, deepening our understanding of the molecular processes through which hiTDExs remodels tumors and their microenvironment, as well as how tumor cells adjust to hypoxic conditions, remains essential. This knowledge will pave the way for novel approaches in treating hypoxic tumors. In this review, we discuss recent work revealing the hiTDExs mediated interactions between tumor and its microenvironment. We have described key hiTDExs cargos (lncRNA, circRNAs, cytokines, etc.) and their targets in the receipt cells, responsible for various biological effects. Moreover, we emphasized the importance of hiTDExs as versatile elements of cell communication in the tumor microenvironment. Finally, we highlighted the effects of hiTDExs on the molecular changes in target cells by executing molecular cargo transfer between cells and altering signaling pathways. Currently, hiTDExs show promise in the treatment of diseases. Understanding the molecular processes through which hiTDExs influence tumor behavior and their microenvironment, along with how tumor cells adapt to and survive in low-oxygen conditions, remains a central focus in cancer research, paving the way for innovative strategies in treating hypoxic tumors and enhancing immunotherapy.

Background and Objectives: Von Hippel-Lindau (VHL) disease is caused by mutations in the VHL gene and can develop various cancers. Hypoxia-inducible factors 1 and 2 alphas, regulated by the VHL gene, can increase the levels of vascular endothelial growth factor, thereby activating cancer progression. Here, we demonstrated clinical and prognostic values of VHL expression in rectal cancer (RC). Materials and Methods: Von Hippel-Lindau mRNA expression was examined in 60 patients with RC. Furthermore, we evaluated survival to determine the prognostic significance of VHL mRNA expression levels in RC using the Cancer Genome Atlas (TCGA) data. Results: Lower VHL expression was correlated with the recurrence (p = 0.058) and lymphatic invasion (p = 0.078), although it was not statistically significant. In TCGA data, VHL expression level was correlated with the M stage (p = 0.044); however, it had a possible association with lymphatic invasion (p = 0.068) and N stage (p = 0.104). Survival analysis showed that lower VHL gene expression predicted poorer survival in both patients with RC and TCGA data. Conclusions: This study identified a significant correlation between VHL gene expression and RC for the first time using patient tissues and TCGA data, suggesting that the VHL gene expression level could be a potential biomarker or candidate for the treatment of RC. Further studies are required to identify the molecular pathogenesis and clinical characteristics of VHL disease in RC.

For efficient anticancer drug delivery, cascade physiological barriers must be overcome, which requires the drug delivery vehicles to possess different or even opposite properties at different stages. Poly(tertiary amine-oxide) (PTAO) polymers with the zwitterionic feature have distinct antifouling properties in blood circulation, which can be reduced and protonated in hypoxic tumors to promote cellular internalization. Nevertheless, the effects of various PTAO structures have not been studied systemically and optimized. In this report, the side groups of PTAO are proposed to be optimized by modulating the structures. Poly(2-(N-oxide-hexamethyleneimino)ethyl methacrylate) (POC7A) with a cyclic seven-membered ring is screened as the optimized PTAO structure for in vivo applications. Moreover, the block copolymer POC7A-block-poly(ε-caprolactone) (POC7A-PCL) is prepared for the formation of micelles in aqueous solution for delivery of doxorubicin (DOX). The zwitterionic nature of POC7A shells with efficient bioreductive activity and protonation in the tumor microenvironment endows the micelles with excellent antifouling properties for long blood circulation, efficient tumor accumulation, deep penetration, and effective cellular internalization. Thus, the DOX-loaded micelles exhibit potent antitumor efficacy after intravenous administration. Zwitterionic POC7A can be used as antifouling shells of the anticancer drug delivery nanocarriers to overcome the cascade physiological barriers efficiently.

Since low oxygen conditions below physiological levels, hypoxia, are associated with various diseases, it is crucial to understand the molecular basis behind cellular response to hypoxia. Hypoxia-inducible factors (HIFs) have been revealed to primarily orchestrate the hypoxic response at the transcription level and have continuously attracted great attention over the past three decades. In addition to these hypoxia-responsive effector proteins, 2-oxoglutarate-dependent dioxygenase (2-OGDD) superfamily including prolyl-4-hydroxylase domain-containing proteins (PHDs) and factor inhibiting HIF-1 (FIH-1) has attracted even greater attention in recent years as factors that act as direct oxygen sensors due to their necessity of oxygen for the regulation of the expression and activity of the regulatory subunit of HIFs. Herein, we present a detailed classification of 2-OGDD superfamily proteins, such as Jumonji C-domain-containing histone demethylases, ten-eleven translocation enzymes, AlkB family of DNA/RNA demethylases and lysyl hydroxylases, and discuss their specific functions and associations with various diseases. By introducing the multifaceted roles of 2-OGDD superfamily proteins in the hypoxic response, this review aims to summarize the accumulated knowledge about the complex mechanisms governing cellular adaptation to hypoxia in various physiological and pathophysiological contexts.

The complex and continuously evolving features of the tumor microenvironment, varying between tumor histotypes, are characterized by the presence of host cells and tumor cells embedded in a milieu shaped by hypoxia and low pH, resulting from the frequent imbalance between vascularity and tumor cell proliferation. These microenvironmental metabolic stressors play a crucial role in remodeling host cells and tumor cells, contributing to the stimulation of cancer cell heterogeneity, clonal evolution, and multidrug resistance, ultimately leading to progression and metastasis. The extracellular vesicles (EVs), membrane-enclosed structures released into the extracellular milieu by tumor/host cells, are now recognized as critical drivers in the complex intercellular communication between tumor cells and the local cellular components in a hypoxic/acidic microenvironment. Understanding the intricate molecular mechanisms governing the interactions between tumor and host cells within a hypoxic and acidic microenvironment, triggered by the release of EVs, could pave the way for innovative strategies to disrupt the complex interplay of cancer cells with their microenvironment. This approach may contribute to the development of an efficient and safe therapeutic strategy to combat cancer progression. Therefore, we review the major findings on the release of EVs in a hypoxic/acidic tumor microenvironment to appreciate their role in tumor progression toward metastatic disease.

Hafnium (Hf)-based nanoscale metal-organic layers (MOLs) enhance radiotherapeutic effects of tissue-penetrating X-rays via a unique radiotherapy-radiodynamic therapy (RT-RDT) process through efficient generation of hydroxy radical (RT) and singlet oxygen (RDT). However, their radiotherapeutic efficacy is limited by hypoxia in deep-seated tumors and short half-lives of reactive oxygen species (ROS). Herein the conjugation of a nitric oxide (NO) donor, S-nitroso-N-acetyl-DL-penicillamine (SNAP), to the Hf12 secondary building units (SBUs) of Hf-5,5'-di-p-benzoatoporphyrin MOL is reported to afford SNAP/MOL for enhanced cancer radiotherapy. Under X-ray irradiation, SNAP/MOL efficiently generates superoxide anion (O2 -.) and releases nitric oxide (NO) in a spatio-temporally synchronized fashion. The released NO rapidly reacts with O2 -. to form long-lived and highly cytotoxic peroxynitrite which diffuses freely to the cell nucleus and efficiently causes DNA double-strand breaks. Meanwhile, the sustained release of NO from SNAP/MOL in the tumor microenvironment relieves tumor hypoxia to reduce radioresistance of tumor cells. Consequently, SNAP/MOL plus low-dose X-ray irradiation efficiently inhibits tumor growth and reduces metastasis in colorectal and triple-negative breast cancer models.

Pancreatic adenocarcinoma (PAAD) is a fatal disease with poor survival. Increasing evidence show that hypoxia-induced exosomes are associated with cancer progression. Here, we aimed to investigate the function of hsa_circ_0007678 (circR3HCC1L) and hypoxic PAAD cell-derived exosomal circR3HCC1L in PAAD progression. Through the exoRBase 2.0 database, we screened for a circular RNA circR3HCC1L related to PAAD. Changes of circR3HCC1L in PAAD samples and cells were analyzed with real-time quantitative polymerase chain reaction (RT-qPCR). Cell proliferation, migration, invasion were analyzed by colony formation, cell counting, and transwell assays. Measurements of glucose uptake and lactate production were done using corresponding kits. Several protein levels were detected by western blotting. The regulation mechanism of circR3HCC1L was verified by dual-luciferase reporter, RNA immunoprecipitation, and RNA pull-down assays. Exosomes were separated by differential ultracentrifugation. Animal experiments were used to verify the function of hypoxia-derived exosomal circR3HCC1L. CircR3HCC1L was upregulated in PAAD samples and hypoxic PAAD cells. Knockdown of circR3HCC1L decreased hypoxia-driven PAAD cell proliferation, migration, invasion, and glycolysis. Hypoxic PAAD cell-derived exosomes had higher levels of circR3HCC1L, hypoxic PAAD cell-derived exosomal circR3HCC1L promoted normoxic cancer cell malignant transformation and glycolysis in vitro and xenograft tumor growth in mouse models in vivo. Mechanistically, circR3HCC1L regulated pyruvate kinase M2 (PKM2) expression via sponging miR-873-5p. Also, PKM2 overexpression or miR-873-5p silencing offset circR3HCC1L knockdown-mediated effects on hypoxia-challenged PAAD cell malignant transformation and glycolysis. Hypoxic PAAD cell-derived exosomal circR3HCC1L facilitated PAAD progression through the miR-873-5p/PKM2 axis, highlighting the contribution of hypoxic PAAD cell-derived exosomal circR3HCC1L in PAAD.

Hypoxia is a critical microenvironmental factor that induces tumorigenesis and cancer progression, including metastasis. The highly dynamic nature of the extracellular matrix (ECM) plays a crucial role in metastasis. Collagens are the predominant component of structural proteins embedded within the ECM. The biosynthesis of collagen typically undergoes a series of posttranslational modifications, such as hydroxylation of lysine and proline residues by procollagen-lysine, 2-oxoglutarate 5-dioxygenases (PLODs) and prolyl 4-hydroxylases (P4Hs), respectively. Collagen hydroxylation is critical for ECM remodeling and maintenance. We recently investigated hypoxia-induced translation in human colon cancer HCT116 cells and identified several collagen-modifying enzymes, including procollagen-lysine, 2-oxoglutarate 5-dioxygenase 2 (PLOD2) and prolyl 4-hydroxylase subunit alpha 1 (P4HA1). Although the translation of bulk mRNAs is repressed in hypoxia, specific mRNAs remain efficiently translated under such conditions. We have found that PLOD2 and P4HA1 are significantly upregulated in hypoxic HCT116 cells compared to normoxic cells. HIF-1 is known to induce the transcription of PLOD2 and P4HA1 during hypoxia. However, the molecular mechanisms of hypoxia-induced translation of PLOD2 and P4HA1 remain largely unclear. We provide evidence that RBM4 and eIF4E2 are required for hypoxia-induced translation of PLOD2 and P4HA1 mRNAs. The 3' UTRs of PLOD2 and P4HA1 mRNAs are involved in translational control during hypoxia in HCT116 cells.

Amidst the prevalent and notable characteristic of a hypoxic microenvironment present in the majority of solid tumors, a burgeoning number of studies have revealed the significance of noncoding RNAs (ncRNAs) in hypoxic tumor regions. The transcriptome of cancers is highly heterogeneous, with noncoding transcripts playing crucial roles. Long noncoding RNAs (lncRNAs) and circular RNAs (circRNAs) are two distinctive classes of ncRNA that are garnering increasing attention. Biologically, they possess intriguing properties and possess significant regulatory functions. Clinically, they present as promising biomarkers and therapeutic targets. Additionally, recent research has evaluated the clinical applications of these ncRNAs in RNA-based treatments and noninvasive liquid biopsies. This review provides a comprehensive summary of recent studies on lncRNAs and circRNAs within the hypoxic tumor microenvironment. Furthermore, the clinical significance of lncRNAs and circRNAs in cancer diagnosis and treatment is emphasized, which could pave the way for the development of effective targeted therapies.

Preoperative assessment of axillary lymph node (ALN) status is essential for breast cancer management. This study explores the use of photoacoustic (PA) imaging combined with attention-guided deep learning (DL) for precise prediction of ALN status.

This retrospective study included patients with histologically confirmed early-stage breast cancer from 2022 to 2024, randomly divided (8:2) into training and test cohorts. All patients underwent preoperative dual modal photoacoustic-ultrasound (PA-US) examination, were treated with surgery and sentinel lymph node biopsy or ALN dissection, and were pathologically examined to determine the ALN status. Attention-guided DL model was developed using PA-US images to predict ALN status. A clinical model, constructed via multivariate logistic regression, served as the baseline for comparison. Subsequently, a nomogram incorporating the DL model and independent clinical parameters was developed. The performance of the models was evaluated through discrimination, calibration, and clinical applicability.

A total of 324 patients (mean age ± standard deviation, 51.0 ± 10.9 years) were included in the study and were divided into a development cohort (n = 259 [79.9%]) and a test cohort (n = 65 [20.1%]). The clinical model incorporating three independent clinical parameters yielded an area under the curve (AUC) of 0.775 (95% confidence interval [CI], 0.711-0.829) in the training cohort and 0.783 (95% CI, 0.654-0.897) in the test cohort for predicting ALN status. In comparison, the nomogram showed superior predictive performance, with an AUC of 0.906 (95% CI, 0.867-0.940) in the training cohort and 0.868 (95% CI, 0.769-0.954) in the test cohort. Decision curve analysis further confirmed the nomogram's clinical applicability, demonstrating a better net benefit across relevant threshold probabilities.

This study highlights the effectiveness of attention-guided PA imaging in breast cancer patients, providing novel nomograms for individualized clinical decision-making in predicting ALN node status.

Hypoxia, or a state of low tissue oxygenation, has been characterized as an important feature of solid tumors that is related to aggressive phenotypes. The cellular response to hypoxia is controlled by Hypoxia-inducible factors (HIFs), a family of transcription factors. HIFs promote the transcription of gene products that play a role in tumor progression including proliferation, angiogenesis, metastasis, and drug resistance. HIF-1 and HIF-2 are well known and widely described. Although these proteins share a high degree of homology, HIF-1 and HIF-2 have non-redundant roles in cancer. In this review, we summarize the similarities and differences between HIF-1α and HIF-2α in their structure, expression, and DNA binding. We also discuss the canonical and non-canonical regulation of HIF-1α and HIF-2α under hypoxic and normal conditions. Finally, we outline recent strategies aimed at targeting HIF-1α and/or HIF-2α.

Hypoxia and lipid metabolism play crucial roles in the progression of colorectal cancer (CRC). However, the specific functions of hypoxia- and lipid metabolism-related genes (HLPG) in CRC and their relationships with patient prognosis remain unclear. Differential expression analysis using the TCGA-COAD and GEO databases identified 117 HLPGs through the intersection of the two gene sets. After univariate Cox regression analysis, 17 prognostically relevant HLPG were identified. Consensus clustering classified CRC samples into two subtypes, and the immune microenvironment differences between them were evaluated. A risk scoring model utilizing seven prognostically significant HLPGs was created and its predictive performance was assessed through survival analysis and ROC curves. Finally, the key genes ITLN1 and SFRP2 were functionally validated in CRC cell lines. HLPG was closely linked to CRC prognosis. Two molecular subtypes were identified: Cluster A, characterized by enriched immune pathways and higher immune infiltration, and Cluster B, associated with improved overall survival. The seven HLPG-based risk scoring model effectively stratified patients into high- and low-risk groups, with high-risk patients exhibiting significantly poorer survival outcomes. Functional studies confirmed that SFRP2 and ITLN1 play essential roles in CRC cell proliferation, migration, and epithelial-mesenchymal transition (EMT). Furthermore, ITLN1 upregulated PD-L1 expression, increasing sensitivity to immunotherapy. Hypoxia was found to promote lipid metabolic alterations by modulating SFRP2 and ITLN1 expression. This study highlights the prognostic significance of HLPGs in CRC and introduces a robust risk scoring model for patient outcome prediction. ITLN1 could be a target for enhancing immunotherapy response in CRC.

Normal tissues typically maintain partial oxygen pressure within a range of 3-10% oxygen, ensuring homeostasis through a well-regulated oxygen supply and responsive vascular network. However, in solid tumors, rapid growth often outpaces angiogenesis, creating a hypoxic microenvironment that fosters tumor progression, altered metabolism and resistance to therapy. Hypoxic tumor regions experience uneven oxygen distribution with severe hypoxia in the core due to poor vascularization and high metabolic oxygen consumption. Cancer cells adapt to these conditions through metabolic shifts, predominantly relying on glycolysis, and by upregulating antioxidant defenses to mitigate reactive oxygen species (ROS)-induced oxidative damage. Hypoxia-induced ROS, resulting from mitochondrial dysfunction and enzyme activation, exacerbates genomic instability, tumor aggressiveness, and therapy resistance. Overcoming hypoxia-induced ROS cancer resistance requires a multifaceted approach that targets various aspects of tumor biology. Emerging therapeutic strategies target hypoxia-induced resistance, focusing on hypoxia-inducible factors, ROS levels, and tumor microenvironment subpopulations. Combining innovative therapies with existing treatments holds promise for improving cancer outcomes and overcoming resistance mechanisms.

Ferroptosis is an iron-dependent form of programmed cell death induced by lipid peroxidation. This process is regulated by signaling pathways associated with redox balance, iron metabolism, and lipid metabolism. Cancer cells' increased iron demand makes them especially susceptible to ferroptosis, significantly influencing cancer development, therapeutic response, and metastasis. Recent findings indicate that cancer cells can evade ferroptosis by downregulating key signaling pathways related to this process, contributing to drug resistance. This underscores the possibility of modulating ferroptosis as an approach to counteract drug resistance and enhance therapeutic efficacy. This review outlines the signaling pathways involved in ferroptosis and their interactions with cancer-related signaling pathways. We also highlight the current understanding of ferroptosis in cancer drug resistance, offering insights into how targeting ferroptosis can provide novel therapeutic approaches for drug-resistant cancers. Finally, we explore the potential of ferroptosis-inducing compounds and examine the challenges and opportunities for drug development in this evolving field.

Photodynamic immunotherapy (PIT) has emerged as a promising approach for efficient eradication of primary tumors and inhibition of tumor metastasis. However, most of photosensitizers (PSs) for PIT exhibit notable oxygen dependence. Herein, a concept emphasizing on transition from molecular PSs into semiconductor-like photocatalysts is proposed, which converts the PSs from type II photoreaction to efficient type I photoreaction. Detailed mechanism studies reveal that the nanostructured phthalocyanine aggregate (NanoNMe) generates radical ion pairs through a photoinduced symmetry breaking charge separation process, achieving charge separation through a self-substrate approach and leading to exceptional photocatalytic charge transfer activity. Additionally, a reformed phthalocyanine aggregate (NanoNMO) is fabricated to improve the stability in physiological environments. NanoNMO showcases significant photocytotoxicities under both normoxic and hypoxic conditions and exhibits remarkable tumor targeting ability. Notably, the NanoNMO-based photodynamic therapy and PD-1 checkpoint inhibitor-based immunotherapy synergistically triggers the infiltration of cytotoxic T lymphocytes into the tumor sites of female mice, leading to the effective inhibition of breast tumor growth.

Castration-resistant prostate cancer (CRPC) is incurable and fatal, making prostate cancer the second leading cancer-related cause of death for American men. CRPC results from therapeutic resistance to standard-of-care androgen deprivation (AD) treatments, through incompletely understood molecular mechanisms, and lacks durable therapeutic options. In this study, we identified enhanced soluble guanylyl cyclase (sGC) signaling as a mechanism that restrains CRPC initiation and growth. Patients with aggressive, fatal CRPC exhibited significantly lower serum levels of the sGC catalytic product cyclic GMP (cGMP) compared with the castration-sensitive stage. In emergent castration-resistant cells isolated from castration-sensitive prostate cancer populations, the obligate sGC heterodimer was repressed via methylation of its β subunit. Genetically abrogating sGC complex formation in castration-sensitive prostate cancer cells promoted evasion of AD-induced senescence and concomitant castration-resistant tumor growth. In established castration-resistant cells, the sGC complex was present but in a reversibly oxidized and inactive state. Subjecting CRPC cells to AD regenerated the functional complex, and cotreatment with riociguat, an FDA-approved sGC agonist, evoked redox stress-induced apoptosis. Riociguat decreased castration-resistant tumor growth and increased apoptotic markers, with elevated cGMP levels correlating significantly with lower tumor burden. Riociguat treatment reorganized the tumor vasculature and eliminated hypoxic tumor niches, decreasing CD44+ tumor progenitor cells and increasing the radiosensitivity of castration-resistant tumors. Thus, this study showed that enhancing sGC activity can inhibit CRPC emergence and progression through tumor cell-intrinsic and extrinsic effects. Riociguat can be repurposed to overcome CRPC, with noninvasive monitoring of cGMP levels as a marker for on-target efficacy. Significance: Soluble guanylyl cyclase signaling inhibits castration-resistant prostate cancer emergence and can be stimulated with FDA-approved riociguat to resensitize resistant tumors to androgen deprivation, providing a strategy to prevent and treat castration resistance.

Ischemic conditions such as hypoxia and nutrient starvation, together with interactions with stromal cells, are critical drivers of metastasis. These conditions arise deep within tumor tissues, and thus, observing nascent metastases is exceedingly challenging. We thus developed the 3MIC-an ex vivo model of the tumor microenvironment-to study the emergence of metastatic features in tumor cells in a 3-dimensional (3D) context. Here, tumor cells spontaneously create ischemic-like conditions, allowing us to study how tumor spheroids migrate, invade, and interact with stromal cells under different metabolic conditions. Consistent with previous data, we show that ischemia increases cell migration and invasion, but the 3MIC allowed us to directly observe and perturb cells while they acquire these pro-metastatic features. Interestingly, our results indicate that medium acidification is one of the strongest pro-metastatic cues and also illustrate using the 3MIC to test anti-metastatic drugs on cells experiencing different metabolic conditions. Overall, the 3MIC can help dissecting the complexity of the tumor microenvironment for the direct observation and perturbation of tumor cells during the early metastatic process.

Hypoxia is a typical hallmark of solid tumors and plays a crucial role in the progression of esophageal squamous cell carcinogenesis (ESCC). Nevertheless, the precise mechanisms underlying the involvement of hypoxia in tumor development remain unclear. In the present study, a novel hypoxia-induced long noncoding RNA (lncRNA) is identified first, lnc191, which is highly expressed in clinical ESCC tissues and is positively correlated with poor prognosis of ESCC patients. These findings provide evidence that the hypoxia-inducible factor-1α (HIF-1α)-mediated transcriptional activation of lnc191 enhances the growth and metastasis of ESCC cells both in vitro and in vivo. Mechanistically, lnc191 interacts with GRP78 (78-kDa glucose-regulated protein), one of the endoplasmic reticulum chaperone proteins, leading to its translocation to the membrane, where GRP78 binds with EGFR and enhances its phosphorylation (Y845), further activates ERK/MAPK signaling pathway, and thereby in favor of the progression of ESCC. Overall, this data proposes lnc191 as a key driver during the development of ESCC and reveals the participation of the activated GRP78/ERK/MAPK axis in the ESCC progression mediated by lnc191. These findings indicate the potential of lnc191 as a promising diagnostic biomarker and therapeutic target in ESCC.

The hypoxic microenvironment of tumor cells is closely related to the progression of ovarian cancer (OV). Hypoxia (HY)-related matrix-remodeling associated 5 (MXRA5) was expressed at elevated levels in many tumors, but research on the impact of MXRA5 in OV remains limited. This study aims to explore the role of MXRA5 in regulating cellular HY in OV. The MXRA5 expression and its clinical significance in OV were evaluated using GEPIA2, Kaplan-Meier plotter databases, and immunohistochemistry assay. OV cells were treated with normoxia and HY conditions. The siRNAs were designed to knock down the MXRA5 expression in hypoxic cells. The cellular capacities were detected by CCK-8 assay, EdU assay, Transwel assay, and TUNEL assay, each method targeting a different aspect of cellular behavior. The MXRA5 level was increased in OV and associated with the progression free survival and overall survival of OV patients. The proliferation and invasion abilities of OV cells were promoted, while apoptosis capacities were inhibited in hypoxic cells. After the knockdown of MXRA5 in hypoxic cells, the proliferative capacities and invasive abilities of the cells were reduced, and the apoptosis capacities were enhanced. Moreover, mechanistically, HIF-1α is a key transcription factor in response to HY that binds to the MXRA5 promoter. MXRA5 expression was induced by HY and had prognostic performance in OV. Knockdown of MXRA5 can inhibit proliferation and invasion in OV cells caused by HIF-1α, revealing that MXRA5 is one potential targets for tumor HY regulation in OV.

Metastatic cancer accounts for most cancer-related deaths, and identifying specific molecular targets that contribute to metastatic progression is crucial for the development of effective treatments. Hypoxia, a feature of solid tumors, plays a role in cancer progression by inducing resistance to therapy and accelerating metastasis. Here, we report that CCAAT/enhancer-binding protein beta (C/EBPβ) transcriptionally regulates hypoxia-inducible factor 1 subunit alpha (HIF1A) and thus promotes migration and invasion of non-small-cell lung cancer (NSCLC) cells under hypoxic conditions. Our results show that knockdown or forced expression of C/EBPβ was correlated with HIF-1α expression and that C/EBPβ directly bound to the promoter region of HIF1A. Silencing HIF1A inhibited the enhanced migration and invasion induced by C/EBPβ overexpression in NSCLC cells under hypoxia. Expression of the HIF-1α target gene, SLC2A1, was also altered in a C/EBPβ-dependent manner, and knockdown of SLC2A1 reduced migration and invasion enhanced by C/EBPβ overexpression. These results indicate that C/EBPβ is a critical regulator for the invasion of NSCLC cells in the hypoxic tumor microenvironment. Collectively, the C/EBPβ-HIF-1α-GLUT1 axis represents a potential therapeutic target for preventing metastatic progression of NSCLC and improving patient outcomes.

Efforts to deconvolve the complex interactions of cancer cells with other components of the tumor micro- and macro-environment have exposed a common tendency for cancers to subvert systems physiology and exploit endogenous programs involved in homeostatic control of metabolism, immunity, regeneration, and repair. Many such programs are engaged in the healing response to surgery which, together with other abrupt biochemical changes in the perioperative period, provide an opportunity for the macroevolution of residual disease. This review relates contemporary perspectives of cancer as a systemic disease with the overlapping biology of host responses to surgery and events within the perioperative period. With a particular focus on examples of cancer cell plasticity and changes within the host, we explore how perioperative inflammation and acute metabolic, neuroendocrine, and immune dyshomeostasis might contribute to cancer evolution within this contextually short, yet crucially influential timeframe, and highlight potential therapeutic opportunities within to further optimize surgical cancer care and its long-term oncological outcomes.

Lung cancer remains the primary cause of cancer-related mortality, with factors such as postoperative tumor recurrence, metastasis, and therapeutic drug resistance exacerbating patient outcomes. Immunotherapy has emerged as a transformative approach, challenging conventional treatment paradigms for lung cancer. Consequently, advancing research in lung cancer immunotherapy is imperative. Recent studies indicate that numerous regulators within the tumor microenvironment (TME) drive tumor angiogenesis and epithelial-mesenchymal transition (EMT); these processes are interdependent, reciprocal, and collectively contribute to tumor progression. Tumor angiogenesis not only supplies adequate oxygen and nutrients for cellular proliferation but also establishes pathways facilitating tumor metastasis and creating hypoxic regions that foster drug resistance. Concurrently, EMT enhances metastatic potential and reinforces drug-resistance genes within tumor cells, creating a reciprocal relationship with angiogenesis. This interplay ultimately results in tumor invasion, metastasis, and therapeutic resistance. This paper reviews key regulators of angiogenesis and EMT, examining their impact on lung cancer immunotherapy and progression, and investigates whether newly identified regulators could influence lung cancer treatment, thus offering valuable insights for developing future therapeutic strategies.

Controlled photooxidation-mediated disruption of collagens in the tumor microenvironment can reduce desmoplasia and enhance immune responsiveness. However, achieving effective light delivery to solid tumors, particularly those with dynamic volumetric changes like pancreatic ductal adenocarcinoma (PDAC), remains challenging and limits the repeated and sustained photoactivation of drugs. Here, 3D, shape-morphing, implantable photonic devices (IPDs) are introduced that enable tumor-specific and continuous light irradiation for effective metronomic photodynamic therapy (mPDT). This IPD adheres seamlessly to the surface of orthotopic PDAC tumors, mitigating issues related to mechanical mismatch, delamination, and internal lesions. In freely moving mouse models, mPDT using the IPD with close adhesion significantly reduces desmoplastic tumor volume without causing cytotoxic effects in healthy tissues. These promising in vivo results underscore the potential of an adaptable and unidirectional IPD design in precisely targeting cancerous organs, suggesting a meaningful advance in light-based therapeutic technologies.

Photoactivatable metallodrugs combining tumor cell eradication and immune stimulation hold immense promise for targeted cancer therapy. However, limitations such as oxygen dependence, narrow visible light responsiveness, and poor immunogenicity hinder their efficacy in deep solid tumors with hypoxic and immunosuppressive microenvironments. Herein, we present a novel design strategy for transition metal(II)-coordinated ligand radicals exhibiting intense near-infrared-II (NIR-II) absorption, unique endoplasmic reticulum-targeting capability, and oxygen-independent photothermal performance, effectively addressing these constraints. Proof-of-concept results demonstrate the potent efficacy of our cobalt(II)-coordinated ligand radical (BPDP-Co) in inducing highly immunogenic pyroptosis in tumor cells under both normoxic and severe hypoxic conditions upon 1064 nm laser irradiation. This NIR-II activation triggers the release of damage-associated molecular patterns (DAMPs) and proinflammatory cytokines, fueling a robust antitumor immune response. In vivo studies demonstrate that treatment with BPDP-Co/NIR-II significantly inhibited 4T1 tumor growth in BALB/c mice with a high inhibitory rate of 85.7%, highlighting its therapeutic potential in tumor immunotherapy.

Hypoxia-induced tumor metastasis severely hinders the efficacy of photodynamic therapy (PDT) in cancer treatment. Current strategies predominantly offer palliative suppression of the HIF-1α pathway, emphasizing the urgent need for innovative PDT approaches to prevent metastasis from the outset. Our study revealed that typical PDT triggers an increase in cytoplasmic Ca2+ levels, activating HIF-1α, and that reducing Ca2+ levels can, in turn, mitigate metastasis. Considering cytoplasm's role in Ca2+ storage and regulation, we propose that PDT-induced metastasis can be addressed at its source by precise intracellular localization of photosensitizers (PSs). We developed near-infrared (NIR) cyanine PSs with inherent nucleus targeting capabilities. These PSs effectively inhibit cytoplasmic Ca2+ elevation and reduce HIF-1α activity upon irradiation, achieving remarkable antimetastatic effects in 4T1 tumors. Consequently, our findings highlight the pivotal role of Ca2+ in PDT-induced metastasis and provide a robust approach for circumventing metastasis from the outset using new nucleus-targeting organic PSs.

The SMAD-specific E3 ubiquitin protein ligase 2 (SMURF2) has emerged as a critical regulator in cancer biology, modulating the stability of Hypoxia-Inducible Factor 1-alpha (HIF1α) and influencing a network of hypoxia-driven pathways within the tumor microenvironment (TME). SMURF2 targets HIF1α for ubiquitination and subsequent proteasomal degradation, disrupting hypoxic responses that promote cancer cell survival, metabolic reprogramming, angiogenesis, and resistance to therapy. Beyond its role in HIF1α regulation, SMURF2 exerts extensive control over cellular processes central to tumor progression, including chromatin remodeling, DNA damage repair, ferroptosis, and cellular stress responses. Notably, SMURF2's ability to promote ferroptotic cell death through GSTP1 degradation offers an alternative pathway to overcome apoptosis resistance, expanding therapeutic options for refractory cancers. This review delves into the multifaceted interactions between SMURF2 and HIF1α, emphasizing how their interplay impacts metabolic adaptations like the Warburg effect, immune evasion, and therapeutic resistance. We discuss SMURF2's dual functionality as both a tumor suppressor and, in certain contexts, an oncogenic factor, underscoring its potential as a highly versatile therapeutic target. Furthermore, modulating the SMURF2-HIF1α axis presents an innovative approach to destabilize hypoxia-dependent pathways, sensitizing tumors to chemotherapy, radiotherapy, and immune-based treatments. However, the complexity of SMURF2's interactions necessitate a thorough assessment of potential off-target effects and challenges in specificity, which must be addressed to optimize its clinical application. This review concludes by proposing future directions for research into the SMURF2-HIF1α pathway, aiming to refine targeted strategies that exploit this axis and address the adaptive mechanisms of aggressive tumors, ultimately advancing the landscape of precision oncology.

Uveal melanoma (UM) poses a significant lethality, with approximately 50% of those developing metastases surviving less than one year. In the progression of UM, vasculogenic mimicry (VM) induced by hypoxia plays a pivotal role, which also partially explains the resistance of UM to anti-angiogenic therapies. Nevertheless, the crucial molecular mechanisms underlying VM in the progression of UM remain unclear. We identified ubiquitin conjugating enzyme E2 G2 (UBE2G2) as a critical suppressor through transcriptomic sequencing and metastasis correlation screening. In UM, hypoxia-induced VM and metastasis are markedly exacerbated by UBE2G2 knockdown and significantly alleviated by its overexpression. Mechanistically, UBE2G2 directly binds to galectin 3 binding protein (LGALS3BP) and forms a complex with the E3 ubiquitin ligase tripartite motif containing 38 (TRIM38), facilitating ubiquitination-mediated degradation of LGALS3BP at the K104 residue. Furthermore, UBE2G2 inhibits oncogenic phenotypes by inactivating intracellular PI3K/AKT signaling and reprogramming the tumor microenvironment. Therefore, targeting intercellular and intracellular molecular mechanisms of the hypoxia-UBE2G2-LGALS3BP axis may contribute to developing various therapeutic strategies for UM.