A Novel Nanozyme to Enhance Radiotherapy Effects by Lactic Acid Scavenging, ROS Generation, and Hypoxia Mitigation.

Uveal melanoma (UM) is a leading intraocular malignancy with a high 5-year mortality rate, and radiotherapy is the primary approach for UM treatment. However, the elevated lactic acid, deficiency in ROS, and hypoxic tumor microenvironment have severely reduced the radiotherapy outcomes. Hence, this study devised a novel CoMnFe-layered double oxides (LDO) nanosheet with multienzyme activities for UM radiotherapy enhancement. On one hand, LDO nanozyme can catalyze hydrogen peroxide (H2O2) in the tumor microenvironment into oxygen and reactive oxygen species (ROS), significantly boosting ROS production during radiotherapy. Simultaneously, LDO efficiently scavenged lactic acid, thereby impeding the DNA and protein repair in tumor cells to synergistically enhance the effect of radiotherapy. Moreover, density functional theory (DFT) calculations decoded the transformation pathway from lactic to pyruvic acid, elucidating a previously unexplored facet of nanozyme activity. The introduction of this innovative nanomaterial paves the way for a novel, targeted, and highly effective therapeutic approach, offering new avenues for the management of UM and other cancer types.

Novel insights into TCR-T cell therapy in solid neoplasms: optimizing adoptive immunotherapy.

Adoptive immunotherapy in the T cell landscape exhibits efficacy in cancer treatment. Over the past few decades, genetically modified T cells, particularly chimeric antigen receptor T cells, have enabled remarkable strides in the treatment of hematological malignancies. Besides, extensive exploration of multiple antigens for the treatment of solid tumors has led to clinical interest in the potential of T cells expressing the engineered T cell receptor (TCR). TCR-T cells possess the capacity to recognize intracellular antigen families and maintain the intrinsic properties of TCRs in terms of affinity to target epitopes and signal transduction. Recent research has provided critical insight into their capability and therapeutic targets for multiple refractory solid tumors, but also exposes some challenges for durable efficacy. In this review, we describe the screening and identification of available tumor antigens, and the acquisition and optimization of TCRs for TCR-T cell therapy. Furthermore, we summarize the complete flow from  laboratory to clinical applications of TCR-T cells. Last, we emerge future prospects for improving therapeutic efficacy in cancer world with combination therapies or TCR-T derived products. In conclusion, this review depicts our current understanding of TCR-T cell therapy in solid neoplasms, and provides new perspectives for expanding its clinical applications and improving therapeutic efficacy.

Histone lactylation-boosted ALKBH3 potentiates tumor progression and diminished promyelocytic leukemia protein nuclear condensates by m1A demethylation of SP100A.

Albeit N1-Methyladenosine (m1A) RNA modification represents an important regulator of RNA metabolism, the role of m1A modification in carcinogenesis remains enigmatic. Herein, we found that histone lactylation enhances ALKBH3 expression and simultaneously attenuates the formation of tumor-suppressive promyelocytic leukemia protein (PML) condensates by removing the m1A methylation of SP100A, promoting the malignant transformation of cancers. First, ALKBH3 is specifically upregulated in high-risk ocular melanoma due to excessive histone lactylation levels, referring to m1A hypomethylation status. Moreover, the multiomics analysis subsequently identified that SP100A, a core component for PML bodies, serves as a downstream candidate target for ALKBH3. Therapeutically, the silencing of ALKBH3 exhibits efficient therapeutic efficacy in melanoma both in vitro and in vivo, which could be reversed by the depletion of SP100A. Mechanistically, we found that YTHDF1 is responsible for recognition of the m1A methylated SP100A transcript, which increases its RNA stability and translational efficacy. Conclusively, we initially demonstrated that m1A modification is necessary for tumor suppressor gene expression, expanding the current understandings of dynamic m1A function during tumor progression. In addition, our results indicate that lactylation-driven ALKBH3 is essential for the formation of PML nuclear condensates, which bridges our knowledge of m1A modification, metabolic reprogramming, and phase-separation events.

ITGB2-ICAM1 axis promotes liver metastasis in BAP1-mutated uveal melanoma with retained hypoxia and ECM signatures.

PURPOSE: Uveal melanoma (UM) with BAP1 inactivating mutations has a high risk of metastasis, but the mechanism behind BAP1 deficiency driving UM metastasis is unknown. METHODS: We analyzed the single-cell RNA sequencing (scRNA-Seq) data comprised primary and metastatic UM with or without BAP1 mutations (MUTs) to reveal inter- and intra-tumor heterogeneity among different groups. Then, an immune-competent mouse liver metastatic model was used to explore the role of ITGB2-ICAM1 in BAP1-associated UM metastasis. RESULTS: Cluster 1 tumor cells expressed high levels of genes linked to tumor metastasis, such as GDF15, ATF3, and CDKN1A, all of which are associated with poor prognosis. The strength of communication between terminally exhausted CD8+ T cells and GDF15hiATF3hiCDKN1Ahi tumor cells was enhanced in BAP1-mutated UM, with CellChat analysis predicting strong ITGB2-ICAM1 signaling between them. High expression of either ITGB2 or ICAM1 was a worse prognostic indicator. Using an immune-competent mouse liver metastatic model, we indicated that inhibiting either ICAM1 or ITGB2 prevented liver metastasis in the BAP1-mutated group in vivo. The inhibitors primarily inhibited hypoxia- and ECM-related pathways indicated by changes in the expression of genes such as ADAM8, CAV2, ENO1, PGK1, LOXL2, ITGA5, and VCAN. etc. CONCLUSION: This study suggested that the ITGB2-ICAM1 axis may play a crucial role for BAP1-associated UM metastasis by preserving hypoxia- and ECM- related signatures, which provide a potential strategy for preventing UM metastasis in patients with BAP1 mutation.

Amino acid metabolism reprogramming: shedding new light on T cell anti-tumor immunity.

Metabolic reprogramming of amino acids has been increasingly recognized to initiate and fuel tumorigenesis and survival. Therefore, there is emerging interest in the application of amino acid metabolic strategies in antitumor therapy. Tremendous efforts have been made to develop amino acid metabolic node interventions such as amino acid antagonists and targeting amino acid transporters, key enzymes of amino acid metabolism, and common downstream pathways of amino acid metabolism. In addition to playing an essential role in sustaining tumor growth, new technologies and studies has revealed amino acid metabolic reprograming to have wide implications in the regulation of antitumor immune responses. Specifically, extensive crosstalk between amino acid metabolism and T cell immunity has been reported. Tumor cells can inhibit T cell immunity by depleting amino acids in the microenvironment through nutrient competition, and toxic metabolites of amino acids can also inhibit T cell function. In addition, amino acids can interfere with T cells by regulating glucose and lipid metabolism. This crucial crosstalk inspires the exploitation of novel strategies of immunotherapy enhancement and combination, owing to the unprecedented benefits of immunotherapy and the limited population it can benefit. Herein, we review recent findings related to the crosstalk between amino acid metabolism and T cell immunity. We also describe possible approaches to intervene in amino acid metabolic pathways by targeting various signaling nodes. Novel efforts to combine with and unleash potential immunotherapy are also discussed. Hopefully, some strategies that take the lead in the pipeline may soon be used for the common good.

Adenomas of the ciliary body epithelium: clinics, histopathology and management.

AIMS: Adenomas of the ciliary body epithelium, including adenoma of the pigmented ciliary body epithelium (APCE) and adenoma of the non-pigmented ciliary body epithelium (ANPCE), are extremely rare, and most knowledge about them comes from sporadic case reports. The purpose of this study was to provide a comprehensive understanding of adenomas of the ciliary body epithelium and to identify the similarities and differences between APCE and ANPCE. METHODS: This study was a retrospective case series comprising data from 41 patients obtained from retrieved publications and five cases diagnosed at the Shanghai Ninth People's Hospital. The clinicopathological features, treatment and prognosis of APCE and ANPCE were compared using the non-parametric rank sum test, t-test and the χ2 test. RESULTS: The clinical and histopathological features and treatment were analogous between APCE (n=23) and ANPCE (n=23). The overall visual prognosis associated with the two tumours was good, with 63% of the patients having stable or improved vision after treatment. Enucleation was the primary cause of eventual vision loss (three in APCE vs two in ANPCE, p=0.001). Notably, iris invasion was commonly observed in patients with APCE (six in APCE vs zero in ANPCE, p=0.014), and iris invasion was associated with decreased vision eventually (p=0.003). Tumour size was irrelevant to the vision outcome (p=0.65). Metastasis or recurrence did not occur in any of the patients. CONCLUSION: In most cases, the clinicopathological features of ANPCE and APCE were similar. Iris invasion was commonly observed in patients with APCE, which was associated with poor visual prognosis.

Metallacage-based enhanced PDT strategy for bacterial elimination via inhibiting endogenous NO production.

Antibiotics are among the most used weapons in fighting microbial infections and have greatly improved the quality of human life. However, bacteria can eventually evolve to exhibit antibiotic resistance to almost all prescribed antibiotic drugs. Photodynamic therapy (PDT) develops little antibiotic resistance and has become a promising strategy in fighting bacterial infection. To augment the killing effect of PDT, the conventional strategy is introducing excess ROS in various ways, such as applying high light doses, high photosensitizer concentrations, and exogenous oxygen. In this study, we report a metallacage-based PDT strategy that minimizes the use of ROS by jointly using gallium-metal organic framework rods to inhibit the production of bacterial endogenous NO, amplify ROS stress, and enhance the killing effect. The augmented bactericidal effect was demonstrated both in vitro and in vivo. This proposed enhanced PDT strategy will provide a new option for bacterial ablation.

Targeting histone deacetylase suppresses tumor growth through eliciting METTL14-modified m6 A RNA methylation in ocular melanoma.

BACKGROUND: Diversified histone deacetylation inhibitors (HDACis) have demonstrated encouraging outcomes in multiple malignancies. N6-methyladenine (m6 A) is the most prevalent messenger RNA modification that plays an essential role in the regulation of tumorigenesis. Howbeit, an in-depth understanding of the crosstalk between histone acetylation and m6 A RNA modifications remains enigmatic. This study aimed to explore the role of histone acetylation and m6 A modifications in the regulation of tumorigenesis of ocular melanoma. METHODS: Histone modification inhibitor screening was used to explore the effects of HDACis on ocular melanoma cells. Dot blot assay was used to detect the global m6 A RNA modification level. Multi-omics assays, including RNA-sequencing, cleavage under targets and tagmentation, single-cell sequencing, methylated RNA immunoprecipitation-sequencing (meRIP-seq), and m6 A individual nucleotide resolution cross-linking and immunoprecipitation-sequencing (miCLIP-seq), were performed to reveal the mechanisms of HDACis on methyltransferase-like 14 (METTL14) and FAT tumor suppressor homolog 4 (FAT4) in ocular melanoma. Quantitative real-time polymerase chain reaction (qPCR), western blotting, and immunofluorescent staining were applied to detect the expression of METTL14 and FAT4 in ocular melanoma cells and tissues. Cell models and orthotopic xenograft models were established to determine the roles of METTL14 and FAT4 in the growth of ocular melanoma. RNA-binding protein immunoprecipitation-qPCR, meRIP-seq, miCLIP-seq, and RNA stability assay were adopted to investigate the mechanism by which m6 A levels of FAT4 were affected. RESULTS: First, we found that ocular melanoma cells presented vulnerability towards HDACis. HDACis triggered the elevation of m6 A RNA modification in ocular melanoma. Further studies revealed that METTL14 served as a downstream candidate for HDACis. METTL14 was silenced by the hypo-histone acetylation status, whereas HDACi restored the normal histone acetylation level of METTL14, thereby inducing its expression. Subsequently, METTL14 served as a tumor suppressor by promoting the expression of FAT4, a tumor suppressor, in a m6 A-YTH N6-methyladenosine RNA-binding protein 1-dependent manner. Taken together, we found that HDACi restored the histone acetylation level of METTL14 and subsequently elicited METTL14-mediated m6 A modification in tumorigenesis. CONCLUSIONS: These results demonstrate that HDACis exert anti-cancer effects by orchestrating m6 A modification, which unveiling a "histone-RNA crosstalk" of the HDAC/METTL14/FAT4 epigenetic cascade in ocular melanoma.

Metformin and cancer hallmarks: shedding new lights on therapeutic repurposing.

Metformin is a well-known anti-diabetic drug that has been repurposed for several emerging applications, including as an anti-cancer agent. It boasts the distinct advantages of an excellent safety and tolerability profile and high cost-effectiveness at less than one US dollar per daily dose. Epidemiological evidence reveals that metformin reduces the risk of cancer and decreases cancer-related mortality in patients with diabetes; however, the exact mechanisms are not well understood. Energy metabolism may be central to the mechanism of action. Based on altering whole-body energy metabolism or cellular state, metformin's modes of action can be divided into two broad, non-mutually exclusive categories: "direct effects", which induce a direct effect on cancer cells, independent of blood glucose and insulin levels, and "indirect effects" that arise from systemic metabolic changes depending on blood glucose and insulin levels. In this review, we summarize an updated account of the current knowledge on metformin antitumor action, elaborate on the underlying mechanisms in terms of the hallmarks of cancer, and propose potential applications for repurposing metformin for cancer therapeutics.

NSUN2-mediated m5 C RNA methylation dictates retinoblastoma progression through promoting PFAS mRNA stability and expression.

BACKGROUND: The precise temporal and spatial regulation of N5 -methylcytosine (m5 C) RNA modification plays essential roles in RNA metabolism, and is necessary for the maintenance of epigenome homeostasis. Howbeit, the mechanism underlying the m5 C modification in carcinogenesis remains to be fully addressed. METHODS: Global and mRNA m5 C levels were determined by mRNA isolation and anti-m5 C dot blot in both retinoblastoma (RB) cells and clinical samples. Orthotopic intraocular xenografts were established to examine the oncogenic behaviours of RB. Genome-wide multiomics analyses were performed to identify the functional target of NSUN2, including proteomic analysis, transcriptome screening and m5 C-methylated RNA immunoprecipitation sequencing (m5 C-meRIP-seq). Organoid-based single-cell analysis and gene-correlation analysis were performed to verify the NSUN2/ALYREF/m5 C-PFAS oncogenic cascade. RESULTS: Herein, we report that NSUN2-mediated m5 C RNA methylation fuels purine biosynthesis during the oncogenic progression of RB. First, we discovered that global and mRNA m5 C levels were significantly enriched in RBs compared to normal retinas. In addition, tumour-specific NSUN2 expression was noted in RB samples and cell lines. Therapeutically, targeted correction of NSUN2 exhibited efficient therapeutic efficacy in RB both in vitro and in vivo. Through multiomics analyses, we subsequently identified phosphoribosylformylglycinamidine synthase (PFAS), a vital enzyme in purine biosynthesis, as a downstream candidate target of NSUN2. The reintroduction of PFAS largely reversed the inhibitory phenotypes in NSUN2-deficient RB cells, indicating that PFAS was a functional downstream target of NSUN2. Mechanistically, we found that the m5 C reader protein ALYREF was responsible for the recognition of the m5 C modification of PFAS, increasing its expression by enhancing its RNA stability. CONCLUSIONS: Conclusively, we initially demonstrated that NSUN2 is necessary for oncogenic gene activation in RB, expanding the current understanding of dynamic m5 C function during tumour progression. As the NSUN2/ALYREF/m5 C-PFAS oncogenic cascade is an important RB trigger, our study suggests that a targeted m5 C reprogramming therapeutic strategy may be a novel and efficient anti-tumour therapy approach.

Nuclear PD-L1 promotes EGR1-mediated angiogenesis and accelerates tumorigenesis.

Targeting programmed cell death protein ligand 1 (PD-L1) remains one of the most essential immunotherapies in cancer1,2. PD-L1 has been detected in the nucleus in multiple malignancies, playing an oncogenic role independent of immune checkpoint regulation3-5. Howbeit, the regulatory function of nuclear PD-L1 (nPD-L1) remains to be fully understood. Here, we report that nPD-L1 is an endogenous accelerator for cancer angiogenesis. First, we found that an abundant proportion of PD-L1 was distributed within the nucleus of uveal melanoma samples, which is associated with an unfavorable outcome. Moreover, the capacity of promoting angiogenesis was largely attenuated in the nPD-L1-deficient cells both in vivo and in vitro. Mechanistically, nPD-L1 facilitates p-STAT3 binding to the promoter of early growth response-1 (EGR1), resulting in the activation of EGR1-mediated angiogenesis. Therapeutically, the inhibition of histone deacetylase 2 restores the normal acetylation level of PD-L1, blocking its nuclear translocation and thereby attenuating tumor angiogenesis. Conclusively, we reveal that nPD-L1 promotes angiogenesis in malignancies, and provide a novel anti-vascularization strategy through blocking aberrant PD-L1 nuclear translocation for tumor therapy.

Epigenetic drug library screening reveals targeting DOT1L abrogates NAD+ synthesis by reprogramming H3K79 methylation in uveal melanoma.

Uveal melanoma (UM) is the most frequent and life-threatening ocular malignancy in adults. Aberrant histone methylation contributes to the abnormal transcriptome during oncogenesis. However, a comprehensive understanding of histone methylation patterns and their therapeutic potential in UM remains enigmatic. Herein, using a systematic epi-drug screening and a high-throughput transcriptome profiling of histone methylation modifiers, we observed that disruptor of telomeric silencing-1-like (DOT1L), a methyltransferase of histone H3 lysine 79 (H3K79), was activated in UM, especially in the high-risk group. Concordantly, a systematic epi-drug library screening revealed that DOT1L inhibitors exhibited salient tumor-selective inhibitory effects on UM cells, both in vitro and in vivo. Combining Cleavage Under Targets and Tagmentation (CUT&Tag), RNA sequencing (RNA-seq), and bioinformatics analysis, we identified that DOT1L facilitated H3K79 methylation of nicotinate phosphoribosyltransferase (NAPRT) and epigenetically activated its expression. Importantly, NAPRT served as an oncogenic accelerator by enhancing nicotinamide adenine dinucleotide (NAD+) synthesis. Therapeutically, DOT1L inhibition epigenetically silenced NAPRT expression through the diminishment of dimethylation of H3K79 (H3K79me2) in the NAPRT promoter, thereby inhibiting the malignant behaviors of UM. Conclusively, our findings delineated an integrated picture of the histone methylation landscape in UM and unveiled a novel DOT1L/NAPRT oncogenic mechanism that bridges transcriptional addiction and metabolic reprogramming.

Surgical repair of large orbital floor and medial wall fractures with destruction of the inferomedial strut: Initial experience with a combined endoscopy navigation technique.

The application of navigation and endoscope is an area of intense interest in the surgical repair of orbital fractures. This study explored the advantages of a combined endoscopy navigation technique (ENT) for repairing large orbital floor and medial wall fractures (OFMWFs) with destruction of the inferomedial strut (IMS). Fifty-two consecutive patients with large OFMWFs with the destruction of the IMS underwent ENT-assisted surgical repair from January 2013 to February 2016. Patient demographics, causes of injury, clinical features, imaging data, and follow-up information (diplopia, ocular dysmotility, enophthalmos, infraorbital hypoesthesia, and other conditions) were collected and analyzed. Orbital volumes and implant positions were also evaluated. The median follow-up duration was 21 (range, 16-29) months. At the end of the follow-up visits, orbital reconstruction was demonstrated by orbital computed tomography. Of the 30 patients with diplopia within the 30-degree visual field of gaze, 27 (90%) reached diplopia remission. Of 40 patients, 34 (85%) achieved complete elimination of ocular dysmotility. Of 47 patients with enophthalmos of >2 mm, 43 (91%) acquired good symmetry with a mean improvement of 3.00 ± 1.00 mm. Of 33 patients, 27 (82%) recovered from infraorbital hypoesthesia. The postoperative orbital volumes of the two sides showed no significant differences (p = 0.087, paired t-test). Early surgical repair showed better outcomes of diplopia, ocular motility, and enophthalmos than late repair (p = 0.001, p = 0.007, and p = 0.000, generalized estimated equations). No patient developed surgery-related complications of visual acuity compromise, strabismus, ectropion, entropion, or lacrimal canaliculus injuries. ENT-assisted surgery appears to be safe, precise, and effective for the repair of large OFMWFs with destruction of the IMS.

Delayed Cerebrospinal Fluid Leaks Complicating Endoscopic Orbital Surgeries.

OBJECTIVE: To report cerebrospinal fluid leak as an uncommon but noteworthy delayed complication after endoscopic orbital surgeries and to describe its incidence, mechanism, prevention, diagnosis, and management. METHODS: Case series of 3 patients who underwent endoscopic orbital surgery in the Department of Ophthalmology, Shanghai Ninth People's Hospital affiliated to Shanghai JiaoTong University School of Medicine from January 2003 to December 2020. A review of the literature was also conducted. RESULTS: Three cases of delayed cerebrospinal fluid leaks occurred 10 years, 3 months, and 4 months after endoscopic orbital surgeries, respectively, were reviewed and reported. Two patients developed cerebrospinal fluid leaks after surgical repair of orbital blowout fractures with titanium mesh and porous polyethylene (Medpor), respectively, and 1 patient developed cerebrospinal fluid leak after transantral optic canal decompression. In the first case, head computed tomography (CT) cisternography and magnetic resonance imaging confirmed the site of the leak that required surgical repair. In the second case, a coronal CT showed that the implanted titanium mesh was tightly against the cribriform plate, which might cause defect of skull base and dura. In the third case, orbital CT identified a dehiscence on the sphenoidal wall as the leak site, which was repaired in a secondary endoscopic surgery. CONCLUSIONS: A cerebrospinal fluid leak, as an uncommon but noteworthy complication, can occur as delayed as 10 more years after surgery. For patients with specific anatomic characteristics, such as Kero type III, surgeons should perform meticulous preoperative evaluation and intraoperative procedures to prevent this complication.

Injectable Anti-Inflammatory Supramolecular Nanofiber Hydrogel to Promote Anti-VEGF Therapy in Age-Related Macular Degeneration Treatment.

Age-related macular degeneration (AMD) is a major cause of visual impairment and severe vision loss worldwide, while the currently available treatments are often unsatisfactory. Previous studies have demonstrated both inflammation and oxidative-stress-induced damage to the retinal pigment epithelium are involved in the pathogenesis of aberrant development of blood vessels in wet AMD (wet-AMD). Although antivascular endothelial growth factor (VEGF) therapy (e.g., Ranibizumab) can impair the growth of new blood vessels, side effects are still found with repeated monthly intravitreal injections. Here, an injectable antibody-loaded supramolecular nanofiber hydrogel is fabricated by simply mixing betamethasone phosphate (BetP), a clinic anti-inflammatory drug, anti-VEGF, the gold-standard anti-VEGF drug for AMD treatment, with CaCl2 . Upon intravitreal injection, such BetP-based hydrogel (BetP-Gel), while enabling long-term sustained release of anti-VEGF to inhibit vascular proliferation in the retina and attenuate choroidal neovascularization, can also scavenge reactive oxygen species to reduce local inflammation. Remarkably, such BetP-Gel can dramatically prolong the effective treatment time of conventional anti-VEGF therapy. Notably, anti-VEGF-loaded supramolecular hydrogel based on all clinically approved agents may be readily translated into clinical use for AMD treatment, with the potential to replace the current anti-VEGF therapy.

A non-invasive smart scaffold for bone repair and monitoring.

Existing strategies for bone defect repair are difficult to monitor. Smart scaffold materials that can quantify the efficiency of new bone formation are important for bone regeneration and monitoring. Carbon nanotubes (CNT) have promising bioactivity and electrical conductivity. In this study, a noninvasive and intelligent monitoring scaffold was prepared for bone regeneration and monitoring by integrating carboxylated CNT into chemically cross-linked carboxymethyl chitosan hydrogel. CNT scaffold (0.5% w/v) demonstrated improved mechanical properties with good biocompatibility and electrochemical responsiveness. Cyclic voltammetry and electrochemical impedance spectroscopy of CNT scaffold responded sensitively to seed cell differentiation degree in both cellular and animal levels. Interestingly, the CNT scaffold could make up the easy deactivation shortfall of bone morphogenetic protein 2 by sustainably enhancing stem cell osteogenic differentiation and new bone tissue formation through CNT roles. This research provides new ideas for the development of noninvasive and electrochemically responsive bioactive scaffolds, marking an important step in the development of intelligent tissue engineering.

An injectable vitreous substitute with sustained release of metformin for enhanced uveal melanoma immunotherapy.

Uveal melanoma (UM) is the most prevalent primary intraocular malignant tumor in adults with a high rate of metastasis. Conventional treatments have limited effects on metastasis and cause permanent ocular tissue defects. Here, a novel strategy based on an injectable vitreous substitute with sustained metformin release ability (IVS-Met) was reported for efficient UM therapy as well as for repairing vitreous deficiency and preserving visual function. IVS-Met showed an excellent long-term anti-tumor effect by direct tumor attack and modulation of the tumor microenvironment (TME). IVS-Met reduced the proportion of pro-tumor M2 tumor-associated macrophages and induced the pro-inflammatory M1 phenotype, thus reversing the immunosuppressive TME and eliciting robust anti-tumor immune responses. Notably, IVS-Met demonstrated high performance in the inhibition of UM metastasis and significantly extended the survival time of mice. In addition, the vitreous substitute achieved facile administration via direct injection and exhibited excellent rheological and optical properties with the key parameters very close to those of the vitreous body to repair vitreous deficiency and preserve visual function. In summary, this strategy has realized effective UM treatment while retaining eyeballs and vision for the first time, revealing great potential for translation to clinical practice.

Crosstalk between metabolic reprogramming and epigenetics in cancer: updates on mechanisms and therapeutic opportunities.

Reversible, spatial, and temporal regulation of metabolic reprogramming and epigenetic homeostasis are prominent hallmarks of carcinogenesis. Cancer cells reprogram their metabolism to meet the high bioenergetic and biosynthetic demands for vigorous proliferation. Epigenetic dysregulation is a common feature of human cancers, which contributes to tumorigenesis and maintenance of the malignant phenotypes by regulating gene expression. The epigenome is sensitive to metabolic changes. Metabolism produces various metabolites that are substrates, cofactors, or inhibitors of epigenetic enzymes. Alterations in metabolic pathways and fluctuations in intermediate metabolites convey information regarding the intracellular metabolic status into the nucleus by modulating the activity of epigenetic enzymes and thus remodeling the epigenetic landscape, inducing transcriptional responses to heterogeneous metabolic requirements. Cancer metabolism is regulated by epigenetic machinery at both transcriptional and post-transcriptional levels. Epigenetic modifiers, chromatin remodelers and non-coding RNAs are integral contributors to the regulatory networks involved in cancer metabolism, facilitating malignant transformation. However, the significance of the close connection between metabolism and epigenetics in the context of cancer has not been fully deciphered. Thus, it will be constructive to summarize and update the emerging new evidence supporting this bidirectional crosstalk and deeply assess how the crosstalk between metabolic reprogramming and epigenetic abnormalities could be exploited to optimize treatment paradigms and establish new therapeutic options. In this review, we summarize the central mechanisms by which epigenetics and metabolism reciprocally modulate each other in cancer and elaborate upon and update the major contributions of the interplays between epigenetic aberrations and metabolic rewiring to cancer initiation and development. Finally, we highlight the potential therapeutic opportunities for hematological malignancies and solid tumors by targeting this epigenetic-metabolic circuit. In summary, we endeavored to depict the current understanding of the coordination between these fundamental abnormalities more comprehensively and provide new perspectives for utilizing metabolic and epigenetic targets for cancer treatment.

Extrachromosomal circular DNA: biogenesis, structure, functions and diseases.

Extrachromosomal circular DNA (eccDNA), ranging in size from tens to millions of base pairs, is independent of conventional chromosomes. Recently, eccDNAs have been considered an unanticipated major source of somatic rearrangements, contributing to genomic remodeling through chimeric circularization and reintegration of circular DNA into the linear genome. In addition, the origin of eccDNA is considered to be associated with essential chromatin-related events, including the formation of super-enhancers and DNA repair machineries. Moreover, our understanding of the properties and functions of eccDNA has continuously and greatly expanded. Emerging investigations demonstrate that eccDNAs serve as multifunctional molecules in various organisms during diversified biological processes, such as epigenetic remodeling, telomere trimming, and the regulation of canonical signaling pathways. Importantly, its special distribution potentiates eccDNA as a measurable biomarker in many diseases, especially cancers. The loss of eccDNA homeostasis facilitates tumor initiation, malignant progression, and heterogeneous evolution in many cancers. An in-depth understanding of eccDNA provides novel insights for precision cancer treatment. In this review, we summarized the discovery history of eccDNA, discussed the biogenesis, characteristics, and functions of eccDNA. Moreover, we emphasized the role of eccDNA during tumor pathogenesis and malignant evolution. Therapeutically, we summarized potential clinical applications that target aberrant eccDNA in multiple diseases.

Phase separation drives tumor pathogenesis and evolution: all roads lead to Rome.

Cells coordinate numerous biochemical reactions in space and time, depending on the subdivision of the intracellular space into functional compartments. Compelling evidence has demonstrated that phase separation induces the formation of membrane-less compartments to partition intracellular substances in a strictly regulated manner and participates in various biological processes. Based on the strong association of cancer with the dysregulation of intracellular physiological processes and the occurrence of phase separation in cancer-associated condensates, phase separation undoubtedly plays a significant role in tumorigenesis. In this review, we summarize the drivers and functions of phase separation, elaborate on the roles of phase separation in tumor pathogenesis and evolution, and propose substantial research and therapeutic prospects for phase separation in cancer.