Metabolic reprogramming and interventions in angiogenesis.

BACKGROUND: Endothelial cell (EC) metabolism plays a crucial role in the process of angiogenesis. Intrinsic metabolic events such as glycolysis, fatty acid oxidation, and glutamine metabolism, support secure vascular migration and proliferation, energy and biomass production, as well as redox homeostasis maintenance during vessel formation. Nevertheless, perturbation of EC metabolism instigates vascular dysregulation-associated diseases, especially cancer. AIM OF REVIEW: In this review, we aim to discuss the metabolic regulation of angiogenesis by EC metabolites and metabolic enzymes, as well as prospect the possible therapeutic opportunities and strategies targeting EC metabolism. KEY SCIENTIFIC CONCEPTS OF REVIEW: In this work, we discuss various aspects of EC metabolism considering normal and diseased vasculature. Of relevance, we highlight that the implications of EC metabolism-targeted intervention (chiefly by metabolic enzymes or metabolites) could be harnessed in orchestrating a spectrum of pathological angiogenesis-associated diseases.

Recent Advances in Detection of Hydroxyl Radical by Responsive Fluorescence Nanoprobes.

Hydroxyl radical (•OH), a highly reactive oxygen species (ROS), is assumed as one of the most aggressive free radicals. This radical has a detrimental impact on cells as it can react with different biological substrates leading to pathophysiological disorders, including inflammation, mitochondrion dysfunction, and cancer. Quantification of this free radical in-situ plays critical roles in early diagnosis and treatment monitoring of various disorders, like macrophage polarization and tumor cell development. Luminescence analysis using responsive probes has been an emerging and reliable technique for in-situ detection of various cellular ROS, and some recently developed •OH responsive nanoprobes have confirmed the association with cancer development. This paper aims to summarize the recent advances in the characterization of •OH in living organisms using responsive nanoprobes, covering the production, the sources of •OH, and biological function, especially in the development of related diseases followed by the discussion of luminescence nanoprobes for •OH detection.

Advances and Perspectives of Responsive Probes for Measuring γ-Glutamyl Transpeptidase.

Gamma-glutamyltransferase (GGT) is a plasma-membrane-bound enzyme that is involved in the γ-glutamyl cycle, like metabolism of glutathione (GSH). This enzyme plays an important role in protecting cells from oxidative stress, thus being tested as a key biomarker for several medical conditions, such as liver injury, carcinogenesis, and tumor progression. For measuring GGT activity, a number of bioanalytical methods have emerged, such as chromatography, colorimetric, electrochemical, and luminescence analyses. Among these approaches, probes that can specifically respond to GGT are contributing significantly to measuring its activity in vitro and in vivo. This review thus aims to highlight the recent advances in the development of responsive probes for GGT measurement and their practical applications. Responsive probes for fluorescence analysis, including "off-on", near-infrared (NIR), two-photon, and ratiometric fluorescence response probes, are initially summarized, followed by discussing the advances in the development of other probes, such as bioluminescence, chemiluminescence, photoacoustic, Raman, magnetic resonance imaging (MRI), and positron emission tomography (PET). The practical applications of the responsive probes in cancer diagnosis and treatment monitoring and GGT inhibitor screening are then highlighted. Based on this information, the advantages, challenges, and prospects of responsive probe technology for GGT measurement are analyzed.

Emerging Trends in Teledermatology Research: A Scientometric Analysis from 2002 to 2021.

Background: With advances in technology, teledermatology (TD) research has increased. However, an updated comprehensive quantitative analysis of TD research, especially one that identifies emerging trends of TD research in the coronavirus disease 2019 (COVID-19) era, is lacking. Objective: To conduct a scientometric analysis of TD research documents between 2002 and 2021 and explore the emerging trends. Methods: CiteSpace was used to perform scientometric analysis and yielded visualized network maps with corresponding metric values. Emerging trends were identified mainly through burst detection of keywords/terms, co-cited reference clustering analysis, and structural variability analysis (SVA). Results: A total of 932 documents, containing 27,958 cited references were identified from 2002 to 2021. Most TD research was published in journals from the "Dermatology" and "Health Care Sciences & Services" categories. American, Australian, and European researchers contributed the most research and formed close collaborations. Keywords/terms with strong burst values to date were "primary care," "historical perspective," "emerging technique," "improve access," "mobile teledermoscopy (TDS)," "access," "skin cancer," "telehealth," "recent finding," "artificial intelligence (AI)," "dermatological care," and "dermatological condition." Co-cited reference clustering analysis showed that the recently active cluster labels included "COVID-19 pandemic," "skin cancer," "deep neural network," and "underserved population." The SVA identified two reviews (Tognetti et al. and Mckoy et al.) that may be highly cited in the future. Conclusion: During and after the COVID-19 era, emerging trends in research on TD (especially mobile TDS) may be related to skin cancer and AI as well as further exploration of primary care in underserved areas.

Longitudinal Serum Proteomics Characterization of CD19-CAR-T Cell Therapy for B-Cell Malignancies.

Chimeric antigen receptor (CAR)-modified T cells have demonstrated remarkable efficacy in treating B-cell leukemia. However, treated patients may potentially develop side effects, such as cytokine release syndrome (CRS), the mechanisms of which remain unclear. Here, we collected 43 serum samples from eight patients with B-cell acute lymphoblastic leukemia (B-ALL) before and five time points after CD19-specific CAR-T cell treatment. Using TMTpro 16-plex-based quantitative proteomics, we quantified 1151 proteins and profiled the longitudinal proteomes analysis of each patient. Seven days after therapy, we found the most dysregulated inflammatory proteins. Lipid metabolism proteins, including APOA1, decreased after therapy, reached their minimum after 7 days, and then gradually recovered. Hence, APOA1 has been selected as a potential biomarker of the CRS disease progression. Furthermore, we identified CD163 as a potential biomarker of CRS severity. These two biomarkers were successfully validated using targeted proteomics in an independent cohort. Our study provides new insights into CAR-T cell therapy-induced CRS. The biomarkers we identified may help develop targeted drugs and monitoring strategies.

2D Ultrathin Iron Doped Bismuth Oxychloride Nanosheets with Rich Oxygen Vacancies for Enhanced Sonodynamic Therapy.

Sonodynamic therapy (SDT) combines ultrasound and sonosensitizers to produce toxic reactive oxygen species (ROS) for cancer cell killing. Due to the high penetration depth of ultrasound (US), SDT breaks the depth penetration barrier of conventional photodynamic therapy for the treatment of deeply seated tumors. A key point to enhance the therapeutic efficiency of SDT is the development of novel sonosensitizers with promoted ability for ROS production. Herein, ultrathin Fe-doped bismuth oxychloride nanosheets with rich oxygen vacancies and bovine serum albumin coating on surface are designed as piezoelectric sonosensitizers (BOC-Fe NSs) for enhanced SDT. The oxygen vacancies of BOC-Fe NSs provide electron trapping sites to promote the separation of e- -h+ from the band structure, which facilitates the ROS production under the ultrasonic waves. The piezoelectric BOC-Fe NSs create a built-in field and the bending bands, further accelerating the ROS generation with US irradiation. Furthermore, BOC-Fe NSs can induce ROS generation by a Fenton reaction catalyzed by Fe ion with endogenous H2 O2 in tumor tissues for chemodynamic therapy. The as-prepared BOC-Fe NSs efficiently inhibited breast cancer cell growth in both in vitro and in vivo tests. The successfully development of BOC-Fe NSs provides a new nano-sonosensitiser option for enhanced SDT for cancer therapy.

Functionalized nanozyme with drug loading for enhanced tumour combination treatment of catalytic therapy and chemotherapy.

Nanozyme-based tumour catalytic therapy has attracted widespread attention in recent years, but the therapeutic efficacy is limited due to the trapping of hydroxyl radicals (˙OH) by endogenous glutathione (GSH) in the tumour microenvironment (TME). Zr/Ce-MOFs/DOX/MnO2 is constructed in this work to serve as a new kind of nanozyme for combination chemotherapy and catalytic treatment. Zr/Ce-MOFs can produce ˙OH in a mimic TME, and the MnO2 on the surface could deplete the GSH, further promoting the ˙OH generation. The pH/GSH dual stimulation accelerates the release of anticancer drug doxorubicin (DOX) in tumour tissue for enhanced tumour chemotherapy. Moreover, Mn2+ produced by the reaction of Zr/Ce-MOFs/DOX/MnO2 and GSH can be used as the contrast agent for T1-MRI. The potential antitumour effect of Zr/Ce-MOFs/DOX/MnO2 is demonstrated by in vitro and in vivo cancer treatment tests. This work thus provides a new nanozyme-based platform for enhanced combination chemotherapy and catalytic treatment for tumours.

HSPA5, as a ferroptosis regulator, may serve as a potential therapeutic for head and neck squamous cell carcinoma.

BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) is a ferroptosis sensitive tumor type with high mortality rate. However, it remains largely unknown whether ferroptosis influences the tumor cell in HNSCC. MATERIALS AND METHODS: To investigate how ferroptosis regulators were differentially expressed between normal and tumor tissue, data related to HNSCC was downloaded from The Cancer Genome Atlas. The expression levels of key factors in HNSCC and the relationship between key factors and ferroptosis in HNSCC were conducted in vitro, and then analyzed to correlate with the differences in prognosis and survival. This was then combined with TNM staging data, and the migration effects of key factors in HNSCC were verified by scratch test and transwell test. RESULTS: In this study, gene expression analysis and correlation studies between genes showed that HSPA5 was a potentially key associated ferroptosis regulator in HNSCC. Bioinformatics analysis showed that high expression of HSPA5 in HNSCC was positively correlated with poor prognosis and distal metastasis of HNSCC. In vitro immunohistochemistry and western blot tests confirmed that HSPA5 was highly expressed in HNSCC tissues and cell lines. In vitro inhibition of HSPA5 reduced the viability of HNSCC cells and increased ferroptosis. The results of scratch, transwell, and immunofluorescence tests showed that HSPA5 was related to the migration of HNSCC. In addition, a pan-cancer analysis showed that HSPA5 was also overexpressed in many types of cancer with poor prognoses. CONCLUSION: In total, our study demonstrates the critical role of ferroptosis regulators in HNSCC and that HSPA5, as a ferroptosis regulator, can be regarded as a key molecular target for designing new therapeutic regimens to control HNSCC metastasis and progression.

OTUB1-mediated inhibition of ubiquitination: a growing list of effectors, multiplex mechanisms, and versatile functions.

Protein ubiquitination plays a pivotal role in protein homeostasis. Ubiquitination may regulate the stability, activity, protein-protein interaction, and localization of a protein. Ubiquitination is subject to regulation by two groups of counteracting enzymes, the E3 ubiquitin ligases and deubiquitinases. Consistently, deubiquitinases are involved in essentially all biological processes. OTUB1, an OTU-family deubiquitinase, is a critical regulator of development, cancer, DNA damage response, and immune response. OTUB1 antagonizes the ubiquitination of a wide-spectrum of proteins through at least two different mechanisms. Besides direct deubiquitination, OTUB1 can also inhibit ubiquitination by non-canonically blocking ubiquitin transfer from certain ubiquitin-conjugases (E2). In this review, we start with a general background of protein ubiquitination and deubiquitination. Next, we introduce the basic characteristics of OTUB1 and then elaborate on the updated biological functions of OTUB1. Afterwards, we discuss potential mechanisms underlying the versatility and specificity of OTUB1 functions. In the end, we discuss the perspective that OTUB1 can be a potential therapeutic target for cancer.

Design, Preparation, and Evaluation of Osthol Poly-Butyl-Cyanoacrylate Nanoparticles with Improved In Vitro Anticancer Activity in Neuroblastoma Treatment.

Osthol (osthole), known as a neuroprotective drug, has shown potent anticancer activity. However, the potential clinical application of osthol is limited due to its low water solubility and low bioavailability. Polybutyl cyanoacrylate (PBCA) has been widely used to improve the solubility of drugs with poor water solubility. In this study, an orthogonal experimental design (OED) was applied to design the preparation process of PBCA nanoparticles (NPs). Then, nanoparticles were prepared and evaluated in terms of physicochemical properties, in vitro release, and cellular uptake, etc. Further, the anti-cancer activity of osthol-PBCA NPs was demonstrated in SH-SY5Y cells. The pharmacokinetics and area under the curve (AUC) were investigated. The obtained osthol-NPs presented a spherical shape with a particle size of 110 ± 6.7 nm, a polydispersity index (PDI) of 0.126, and a zeta potential of −13 ± 0.32 mV. Compared with the free osthol, the drugs in osthol-NPs presented better stability and sustained release pattern activity. In vitro analysis using SH-SY5Y neuroblastoma cells showed that osthol-loaded nanoparticles displayed a significantly enhanced intracellular absorption process (three times) and cytotoxicity compared with free osthol (p < 0.05, increased 10−20%). The in vivo pharmacokinetic study revealed that the AUC of osthol-NPs was 3.3-fold higher than that of free osthol. In conclusion, osthol-PBCA NPs can enhance the bioactivity of osthol, being proposed as a novel, promising vehicle for drug delivery.

Clay nanoparticles efficiently deliver small interfering RNA to intact plant leaf cells.

RNA interference is triggered in plants by the exogenous application of double-stranded RNA or small interfering RNA (siRNA) to silence the expression of target genes. This approach can potentially provide insights into metabolic pathways and gene function and afford plant protection against viruses and other plant pathogens. However, the effective delivery of biomolecules such as siRNA into plant cells is difficult because of the unique barrier imposed by the plant cell wall. Here, we demonstrate that 40-nm layered double hydroxide (LDH) nanoparticles are rapidly taken up by intact Nicotiana benthamiana leaf cells and by chloroplasts, following their application via infiltration. We also describe the distribution of infiltrated LDH nanoparticles in leaves and demonstrate their translocation through the apoplast and vasculature system. Furthermore, we show that 40-nm LDH nanoparticles can greatly enhance the internalization of nucleic acids by N. benthamiana leaf cells to facilitate siRNA-mediated downregulation of targeted transgene mRNA by >70% within 1 day of exogenous application. Together, our results show that 40-nm LDH nanoparticle is an effective platform for delivery of siRNA into intact plant leaf cells.

Noncirrhotic portal hypertension due to peripheral T-cell lymphoma, not otherwise specified: A case report.

BACKGROUND: Peripheral T-cell lymphoma (PTCL), an aggressive and rare disease that belongs to a heterogeneous group of mature T-cell lymphomas, develops rapidly and has a poor prognosis. Early detection and treatment are essential to improve patient cure and survival rates. Here, we report a rare case of PTCL with clinical presentation of noncirrhotic portal hypertension, which provides a basis for early vigilance of lymphomas in the future. CASE SUMMARY: A 65-year-old Chinese woman was admitted to our hospital because of abdominal distension for 3 months and pitting oedema of both lower limbs for 2 months. Physical examinations and associated auxiliary examinations showed the presence of hepatosplenomegaly, and her hepatic venous pressure gradient was 10 mmHg. Immunohistochemical analysis of the liver biopsy confirmed the diagnosis of PTCL. The patient underwent combination therapy with dexamethasone, VP-16, and chidamide. Unfortunately, after 41 days of chemotherapy, the patient died of multiple organ failure. CONCLUSION: PCTL accompanied by noncirrhotic portal hypertension is rarely reported. This case report discusses the diagnosis of a patient according to the literature.

Alteration of intestinal microecology by oral antibiotics promotes oral squamous cell carcinoma development.

Oral antibiotics can influence cancers and immunotherapy by interfering with the intestinal microbiota. However, the association between oral antibiotics and oral squamous cell carcinoma (OSCC) as well as the mechanisms underlying the effects of oral antibiotics on OSCC remain unclear. Here, we found that oral antibiotics cocktail (4Abx) promoted the tumor development and shifted the microbiota, decreasing the abundance of probiotic bacteria, and altered microbial metabolism in the gut of OSCC mice, increasing tyrosine and decreasing glutamate levels. In vitro experiments showed that tyrosine upregulated the PD-1 expression in T cells, SCC7 cell proliferation, and necroptosis expression. IL-10 expression level in CD11c+ cells was reduced by glutamate. Furthermore, the expression of the necroptosis-related proteins, including receptor-interacting protein kinase 1 (RIPK1), RIPK3, and mixed lineage kinase domain-like (MLKL), was higher in the OSCC mice treated with 4Abx. Supplementation with glutamate or healthy mouse feces by gavage alleviated the tumor-promoting effect of 4Abx with restored balance of microbial metabolism. Overall, we identified the detrimental role of oral antibiotics in promoting OSCC development through altered intestinal microbiota, microbial metabolism, and immune dysbiosis, implying the need for antibiotic stewardship in OSCC treatment.

Neisseria sicca and Corynebacterium matruchotii inhibited oral squamous cell carcinomas by regulating genome stability.

Periodontitis is a risk factor for the development of oral squamous cell carcinomas (OSCC). Both DNA damage response (DDR) and activation of inflammasomes induced by the microbiome might play important roles in the development of tumors, in relation to genome stability of tumor cells. Herein, we explored whether periodontitis negative-associated bacteria (Neisseria sicca and Corynebacterium matruchotii, namely called 'PNB'), which were highly abundant in healthy populations, could inhibit OSCC by promoting genome stability. Firstly, a murine SCC-7 tumor-bearing model that colonized with PNB was designed and used in this study. Then, cyclin D1 was detected by immunohistochemistry. Levels of DDR, NLRP3 inflammasomes and pro-inflammatory cytokines in tumors were detected by RT-qPCR or Western blot. Immune cells in spleens were detected by immunohistochemistry or immunofluorescence. Finally, the anti-cancer activity of PNB was assessed in vitro using CCK-8 assays and flow cystometry. Compared with the control, PNB decreased tumor weights from 0.77 ± 0.26 g to 0.42 ± 0.15 g and downregulated the expression of Cyclin D1. PNB activated the DDR by up-regulating γ-H2AX, p-ATR, and p-CHK1. PNB activated NLRP3 inflammasome-mediated pyroptosis via increases of NLRP3, gasdermin D, and mRNA levels of apoptosis-associated speck-like protein, Caspase-1. PNB suppressed the inflammatory response by down-regulating mRNA levels of NF-κΒ and IL-6 in tumors as well as the populations of CD4+ T cells and CD206+ immune cells in spleens. PNB inhibited proliferation and promoted cell death of HSC-3 cells. In conclusion, Neisseria sicca and Corynebacterium matruchotii showed a 'probiotic bacterial' potential to inhibit OSCC by regulating genome stability.

Poly(ethylene glycol)-functionalized 3D covalent organic frameworks as solid-state polyelectrolytes.

Existing lithium-ion-conducting covalent organic frameworks (COFs) are mainly two-dimensional, in which the one-dimensional channels are difficult to completely and uniformly stack in the same direction, particularly in the case of powdered COFs, resulting in the hindrance of ion transport at the grain boundary or at the interface of the powder contact. In this contribution, poly(ethylene glycol) (PEG)-functionalized three-dimensional COFs with 3D channels were successfully constructed for ion conduction in different directions, which is conducive to reducing the grain boundary and interface contact resistance. Combined with the coupling behaviour between the PEG chain segments and Li-ions, the 3D COF incorporated with LiTFSI achieves a high ionic conductivity of 3.6 × 10-4 S cm-1 at 260 °C. The maximum operating temperature is higher than the boiling point of commercial organic electrolytes, indicating the excellent security of PEG-based COFs as Li-ion polyelectrolytes at high temperature.

Two-dimensional nanomaterials for tumor microenvironment modulation and anticancer therapy.

The development of two-dimensional (2D) nanomaterials for cancer therapy has attracted increasing attention due to their high specific surface area, unique ultrathin structure, electronic and photonic properties. For biomedical applications, investigations into the family of 2D materials have been sparked by graphene and its derivatives. Many 2D nanomaterials, including layered double hydroxides, transition metal dichalcogenides, nitrides and carbonitrides, black phosphorus nanosheets, and metal-organic framework nanosheets, are extensively explored as cancer theranostic platforms. In addition to the high drug loading, 2D nanomaterials are featured with improved physiological properties of drugs, prolonged blood circulation, and increased tumor accumulation and bioavailability. As a consequence, 2D nanomaterials have been widely examined in pre-clinical tumor therapy, particularly through the tumor microenvironment (TME) modulation. This review summarizes recent progresses in developing 2D nanomaterials for TME modulating-based cancer diagnosis and therapy. It is anticipated that this review will benefit researchers to obtain a deeper understanding of interactions between 2D nanomaterials and TME components and develop rational and reliable 2D nanomedicines for pre/clinical cancer theranostics.

Hepatocyte-specific deletion of cellular repressor of E1A-stimulated genes 1 exacerbates alcohol-induced liver injury by activating stress kinases.

Alcohol-associated liver disease (ALD) encompasses a wide range of pathologies from simple steatosis to cirrhosis and hepatocellular carcinoma and is a global health problem. Currently, there are no effective pharmacological treatments for ALD. We have previously demonstrated that aging exacerbates the pathogenesis of ALD, but the underlying mechanisms are still poorly understood. Cellular repressor of E1A-stimulated genes 1 protein (CREG1) is a recently identified small glycoprotein that has been implicated in aging process by promoting cellular senescence and activating stress kinases. Thus, the current study aimed to explore the role of aging associated CREG1 in ALD pathogenesis and CREG1 as a potential therapeutic target. Hepatic and serum CREG1 protein levels were elevated in ALD patients. Elevation of hepatic CREG1 protein and mRNA was also observed in a mouse model of Gao-binge alcohol feeding. Genetic deletion of the Creg1 gene in hepatocytes (Creg1∆hep ) markedly exacerbated ethanol-induced liver injury, apoptosis, steatosis and inflammation. Compared to wild-type mice, Creg1∆hep mice had increased phosphorylation of hepatic stress kinases such as apoptosis signal-regulating kinase 1 (ASK1), c-Jun N-terminal kinase (JNK) and p38 but not TGF-ß-activated kinase 1 (TAK1) or extracellular signal-regulated kinase (ERK) after alcohol feeding. In vitro, ethanol treatment elevated the phosphorylation of ASK1, JNK, and p38 in mouse hepatocyte AML-12 cells. This elevation was further enhanced by CREG1 knockdown but alleviated by CREG1 overexpression. Last, treatment with an ASK1 inhibitor abolished ethanol-induced liver injury and upregulated hepatic lipogenesis, proinflammatory genes and stress kinases in Creg1∆hep mice. Taken together, our data suggest that CREG1 protects against alcoholic liver injury and inflammation by inhibiting the ASK1-JNK/p38 stress kinase pathway and that CREG1 is a potential therapeutic target for ALD.

Hepatic NCoR1 deletion exacerbates alcohol-induced liver injury in mice by promoting CCL2-mediated monocyte-derived macrophage infiltration.

Nuclear receptor corepressor 1 (NCoR1) is a corepressor of the epigenetic regulation of gene transcription that has important functions in metabolism and inflammation, but little is known about its role in alcohol-associated liver disease (ALD). In this study, we developed mice with hepatocyte-specific NCoR1 knockout (NCoR1Hep-/-) using the albumin-Cre/LoxP system and investigated the role of NCoR1 in the pathogenesis of ALD and the underlying mechanisms. The traditional alcohol feeding model and NIAAA model of ALD were both established in wild-type and NCoR1Hep-/- mice. We showed that after ALD was established, NCoR1Hep-/- mice had worse liver injury but less steatosis than wild-type mice. We demonstrated that hepatocyte-specific loss of NCoR1 attenuated liver steatosis by promoting fatty acid oxidation by upregulating BMAL1 (a circadian clock component that has been reported to promote peroxisome proliferator activated receptor alpha (PPARα)-mediated fatty ß-oxidation by upregulating de novo lipid synthesis). On the other hand, hepatocyte-specific loss of NCoR1 exacerbated alcohol-induced liver inflammation and oxidative stress by recruiting monocyte-derived macrophages via C-C motif chemokine ligand 2 (CCL2). In the mouse hepatocyte line AML12, NCoR1 knockdown significantly increased ethanol-induced CCL2 release. These results suggest that hepatocyte NCoR1 plays distinct roles in controlling liver inflammation and steatosis, which provides new insights into the development of treatments for steatohepatitis induced by chronic alcohol consumption.

Activation of Cascade-Like Antitumor Immune Responses through In Situ Doxorubicin Stimulation and Blockade of Checkpoint Coinhibitory Receptor TIGIT.

Although T cell centered immune checkpoint blockade (ICB) therapies have shown unprecedented success in various cancer types, only a minority of patients benefit from these treatments due to the lack of neoantigen burden and exhaustion of tumor-infiltrating immune stimulating cells. Inspired by the crucial role of NK cell based immunity and potential immunostimulating effect of chemotherapeutic drugs, the therapeutic efficiency on tumor inhibition through combination of doxorubicin (DOX) and blockade of TIGIT (T-cell Ig and ITIM domain), a coinhibitory receptor expressed by both NK and T cells, in a matrix metalloproteinase 2 (MMP-2)-degradable hydrogel is thoroughly evaluated in this study. Due to the distinct release kinetics from destructed framework of hydrogels, the differentially released DOX and anti-TIGIT monoclonal antibody (aTIGIT) molecules can elicit immunogenic tumor microenvironment and reverse the exhaustion of NK and effector T cells to realize not only durable localized tumor inhibition but also systemic and long-lasting immune memory responses. Thus, this work pioneers the union of chemotherapeutic drugs and NK cell centered ICB therapies for activating cascade-like antitumor immune responses through eliciting immunogenic tumor microenvironment and boosting both innate and adaptive immunity.