Fine-Tuning the d-Band Center Position of Zinc to Increase the Anti-Tumor Activity of Single-Atom Nanozymes.

The exceptional biocompatibility of Zn-based single-atom nanozymes (SAzymes) has led to extensive research in their application for disease diagnosis and treatment. However, the fully occupied 3d10 electron configuration has seriously hampered the enzymatic-like activity of Zn-based SAzymes. Herein, a B-doped Zn-based SAzymes is fabricated by carbonizing zeolite-like Zn-based boron imidazolate framework at different temperatures (Zn-SAs@BNCx, x = 800, 900, 1000, and 1100 °C). The formed B─N bond yielded a local electric field, which changes the position of the d-band center and improved the oxidation state of Zn by facilitating the electron transfer from Zn to N to B. These changes enhanced the adsorption and activation of H2O2 and O2 by Zn-SAs@BNC1000, increasing the nanozymes' multi-enzyme catalytic activity. B doping led to 24.81-, 32.37-, and 13.98-fold increase in the peroxidase-, oxidase- and catalase-like, respectively, catalytic efficiency (Kcat/Km) of Zn-SAs@BNC1000 when compared with no B doping. In addition, Zn-SAs@BNC1000 showed excellent ability to kill tumor cells both in vitro and in vivo. This study demonstrates that the modulation of the electron configuration of Zn is an effective strategy to develop efficient anti-tumor approaches by boosting the enzymatic activity of Zn-based SAzymes.

Clinical features and risk of multiple primary malignancies after endoscopic treatment in patients with early esophageal squamous cell carcinoma: a retrospective cohort study.

Background: The incidence of multiple primary malignancies (MPMs) after early esophageal cancer is increasing. This study aimed to explore the clinical features of patients with MPMs and identify independent risk factors for the development of MPMs after endoscopic treatment in early esophageal squamous cell carcinoma (ESCC) patients. Methods: Patients diagnosed as early ESCC at Beijing Friendship Hospital were retrospectively analyzed. Independent factors affecting MPMs were selected by univariate and multivariate Cox regression analyses. Results: Among 299 patients with early ESCC, the mean age was 64.22 years; 219 were male (73.24%). Of these, 32 patients (10.70%) developed MPMs during a follow-up period of 120 months; 10 were metachronous and 22 synchronous. Multivariate Cox analysis showed that alcohol drinking ≥5 standard drinks/day [hazard ratio (HR) =4.21, 95% confidence interval (CI): 1.79-9.90, P<0.001], lower location (HR =2.49, 95% CI: 1.18-5.22, P=0.02), submucosal infiltration depth (HR =3.38, 95% CI: 1.31-8.69, P=0.01), and multiple lesions (HR =2.41, 95% CI: 1.15-5.04, P=0.02) were independent risk factors for developing MPMs in patients with early esophageal cancer. Conclusions: Early ESCC is associated with a high risk of developing MPMs. Monitoring the development of MPMs in patients with early ESCC based on identified risk factors is of great importance.

Reversing Immune Checkpoint Inhibitor-Associated Cardiotoxicity via Bioorthogonal Metabolic Engineering-Driven Extracellular Vesicle Redirecting.

The cardiotoxicity induced by immune checkpoint inhibitors (ICIs) is associated with high mortality rates. T cells play an important role in ICI-induced cardiac injury. The inhibition of local T-cell activity is considered an effective strategy for alleviating ICI-related cardiotoxicity. Tumor-derived extracellular vesicles (EVs) contribute to immunosuppression via PD-L1 overexpression. In this study, a bioorthogonal metabolic engineering-driven EV redirecting (Biomeder) strategy for in situ engineered EVs with myocardial-targeting peptides is developed. Accumulated tumor-derived EV (TuEVs) reverses the immune environment in the heart by increasing PD-L1 levels in cardiomyocytes and/or by directly inhibiting T-cell activity. More importantly, it is found that the redirection of TuEVs further disrupts immunosuppression in tumors, which facilitates anti-tumor activity. Thus, redirecting TuEVs to the heart simultaneously enhances the antitumor efficacy and safety of ICI-based therapy. Furthermore, the Biomeder strategy is successfully expanded to prevent ICI-induced type 1 diabetes. This Biomeder technique is a universal method for the treatment of various ICI-related adverse events.

Discovery of 2-Aryl-4-aminoquinazolin-Based LSD1 Inhibitors to Activate Immune Response in Gastric Cancer.

LSD1 (histone lysine-specific demethylase 1) has been gradually disclosed to act as an immunomodulator to enhance antitumor immune response. Despite the identification of numerous potent LSD1 inhibitors, there remains a lack of LSD1 inhibitors approved for marketing. Novel LSD1 inhibitors with different mechanisms are therefore needed. Herein, we reported a series of novel quinazoline-based LSD1 inhibitors. Among them, compound Z-1 exhibited the best LSD1 inhibitory activity (IC50 = 0.108 µM). Z-1 also acted as a selective and cellular active as an LSD1 inhibitor. Furthermore, Z-1 promoted response of gastric cancer cells to T-cell killing effect by decreasing PD-L1 expression and further attenuated the PD-1/PD-L1 interaction. In vivo, Z-1 exhibited significant suppression effect on the growth of gastric cancer cells without obvious toxicity. Therefore, Z-1 represents a potential novel immunomodulator that targets LSD1, providing a lead compound with new function mechanism for gastric cancer treatment.

Tumour-derived small extracellular vesicles act as a barrier to therapeutic nanoparticle delivery.

Nanoparticles are promising for drug delivery applications, with several clinically approved products. However, attaining high nanoparticle accumulation in solid tumours remains challenging. Here we show that tumour cell-derived small extracellular vesicles (sEVs) block nanoparticle delivery to tumours, unveiling another barrier to nanoparticle-based tumour therapy. Tumour cells secrete large amounts of sEVs in the tumour microenvironment, which then bind to nanoparticles entering tumour tissue and traffic them to liver Kupffer cells for degradation. Knockdown of Rab27a, a gene that controls sEV secretion, decreases sEV levels and improves nanoparticle accumulation in tumour tissue. The therapeutic efficacy of messenger RNAs encoding tumour suppressing and proinflammatory proteins is greatly improved when co-encapsulated with Rab27a small interfering RNA in lipid nanoparticles. Together, our results demonstrate that tumour cell-derived sEVs act as a defence system against nanoparticle tumour delivery and that this system may be a potential target for improving nanoparticle-based tumour therapies.

Leveraging Non-Radiative Transitions in Asphaltenes-Derived Carbon Dots for Cancer Photothermal Therapy.

Cancer photothermal therapy leverages the capability of photothermal agents to convert light to heat for cancer cell ablation and necrosis. However, most conventional photothermal agents (Au, CuS, Pd, mesoporous silica nanoparticles, and indocyanine green dye) either face scalability challenges or photobleached upon prolonged irradiation which jeopardizes practical applications. Here, asphaltenes-derived carbon dots (ACDs, 5 nm) are rationally engineered as a low-cost and photostable photothermal agent with negligible in vivo cytotoxicity. The abundant water-solvating functional groups on the ACDs surface endows them with excellent water re-dispersibility that outperforms those of most commercial nanomaterials. Photothermal therapeutic property of the ACDs is mechanistically described by non-radiative transitions of excited electrons at 808 nm via internal conversions and vibrational relaxations. Consequently, the ACDs offer cancer photothermal therapy in mice within 15 days post-exposure to one-time near infrared irradiation. This pioneering study showcases the first utilization of asphaltenes-based materials for cancer therapy and is expected to arouse further utilization of such materials in various cancer theranostics.

LncRNAs in the Dlk1-Dio3 Domain Are Essential for Mid-Embryonic Heart Development.

The Dlk1-Dio3 domain is important for normal embryonic growth and development. The heart is the earliest developing and functioning organ of the embryo. In this study, we constructed a transcriptional termination model by inserting termination sequences and clarified that the lack of long non-coding RNA (lncRNA) expression in the Dlk1-Dio3 domain caused the death of maternal insertion mutant (MKI) and homozygous mutant (HOMO) mice starting from E13.5. Parental insertion mutants (PKI) can be born and grow normally. Macroscopically, dying MKI and HOMO embryos showed phenomena such as embryonic edema and reduced heart rate. Hematoxylin and eosin (H.E.) staining showed thinning of the myocardium in MKI and HOMO embryos. In situ hybridization (IHC) and quantitative reverse-transcription polymerase chain reaction (qRT-PCR) showed downregulation of lncGtl2, Rian, and Mirg expression in MKI and HOMO hearts. The results of single-cell RNA sequencing (scRNA-Seq) analysis indicated that the lack of lncRNA expression in the Dlk1-Dio3 domain led to reduced proliferation of epicardial cells and may be an important cause of cardiac dysplasia. In conclusion, this study demonstrates that Dlk1-Dio3 domain lncRNAs play an integral role in ventricular development.

Delivery Systems Developed for Treatment Combinations to Improve Adoptive Cell Therapy.

Adoptive cell therapy (ACT) has shown great success in the clinic for treating hematologic malignancies. However, solid tumor treatment with ACT monotherapy is still challenging, owing to insufficient expansion and rapid exhaustion of adoptive cells, tumor antigen downregulation/loss, and dense tumor extracellular matrix. Delivery strategies for combination cell therapy have great potential to overcome these hurdles. The delivery of vaccines, immune checkpoint inhibitors, cytokines, chemotherapeutics, and photothermal reagents in combination with adoptive cells, have been shown to improve the expansion/activation, decrease exhaustion, and promote the penetration of adoptive cells in solid tumors. Moreover, the delivery of nucleic acids to engineer immune cells directly in vivo holds promise to overcome many of the hurdles associated with the complex ex vivo cell engineering strategies. Here, these research advance, as well as the opportunities and challenges for integrating delivery technologies into cell therapy s are discussed, and the outlook for these emerging areas are criticlly analyzed.

Anticancer effects of Erzhimaoling decoction in high-grade serous ovarian cancer in vitro and in vivo.

BACKGROUND: High-grade serous ovarian cancer (HGSOC) is a common gynecologic malignancy with a poor prognosis. The traditional Chinese medicine formula Erzhimaoling decoction (EZMLD) has anticancer potential. This study aims to elucidate the anticancer effects of EZMLD on HGSOC in vitro and in vivo. MATERIALS AND METHODS: EZMLD-containing serum was prepared from Sprague-Dawley rats for treating SKOV3 ovarian cancer cells at varying concentrations for 24 h and 48 h to determine the IC50. Concentrations of 0%, 5%, and 10% for 24 h were chosen for subsequent in vitro experiments. The roles of METTL3 and METTL14 in SKOV3 cells were explored by overexpressing these genes and combining EZMLD with METTL3/14 knockdown. Investigations focused on cell viability and apoptosis, apoptosis-related protein expression, and KRT8 mRNA m6A modification. For in vivo studies, 36 BALB/c nude mice were divided into six groups involving EZMLD (6.75, 13.5, and 27 g/kg) and METTL3 or METTL14 knockdowns, with daily EZMLD gavage for two weeks. RESULTS: In vitro, EZMLD-containing serum had IC50 values of 8.29% at 24 h and 5.95% at 48 h in SKOV3 cells. EZMLD-containing serum decreased SKOV3 cell viability and increased apoptosis. EZMLD upregulated METTL3/14 and FAS-mediated apoptosis proteins, while downregulating Keratin 8 (KRT8). EZMLD increased KRT8 mRNA m6A methylation. METTL3/14 overexpression reduced SKOV3 cell viability and increased apoptosis, while METTL3/14 knockdown mitigated EZMLD's effects. In vivo, EZMLD suppressed SKOV3 xenografts growth, causing significant apoptosis and modulating protein expression. CONCLUSIONS: EZMLD has therapeutic potential for ovarian cancer and may be considered for other cancer types. Future research may explore its broader effects beyond cell apoptosis.

Enzyme-like nanoparticle-engineered mesenchymal stem cell secreting HGF promotes visualized therapy for idiopathic pulmonary fibrosis in vivo.

Stem cell therapy is being explored as a potential treatment for idiopathic pulmonary fibrosis (IPF), but its effectiveness is hindered by factors like reactive oxygen species (ROS) and inflammation in fibrotic lungs. Moreover, the distribution, migration, and survival of transplanted stem cells are still unclear, impeding the clinical advancement of stem cell therapy. To tackle these challenges, we fabricate AuPtCoPS trimetallic-based nanocarriers (TBNCs), with enzyme-like activity and plasmid loading capabilities, aiming to efficiently eradicate ROS, facilitate delivery of therapeutic genes, and ultimately improve the therapeutic efficacy. TBNCs also function as a computed tomography contrast agent for tracking mesenchymal stem cells (MSCs) during therapy. Accordingly, we enhanced the antioxidant stress and anti-inflammatory capabilities of engineered MSCs and successfully visualized their biological behavior in IPF mice in vivo. Overall, this study provides an efficient and forward-looking treatment approach for IPF and establishes a framework for a stem cell-based therapeutic system aimed at addressing lung disease.

Clinical and pathological characteristics of and predictive model for colorectal neuroendocrine tumors.

Background: The incidence of colorectal neuroendocrine tumors (NETs) is increasing, causing a social burden. At present, there is no specific prognostic model for colorectal NETs. Thus, an accurate model is needed to predict the prognosis of patients with colorectal NETs. Aim: We aimed to create a new nomogram to predict the prognosis of patients with colorectal NETs. Furthermore, we compared nomogram we established and the 8th edition of the AJCC TNM staging system in terms of prediction ability and accuracy. Methods: A total of 3353 patients with colorectal NETs were selected from the Surveillance, Epidemiology, and End Results (SEER) database. Kaplan-Meier analyses were used to assess overall survival (OS) and cancer-specific survival (CSS). Additionally, LASSO regression was used to select variables for constructing the nomogram. Furthermore, the C-index and time-dependent receiver operating characteristic (tdROC) curve were used to evaluate the nomogram. Decision curve analysis (DCA) was performed to compare the clinical utility of the nomogram with that of the TNM system. An external validation cohort (N = 61) was established to evaluate the nomogram's prediction accuracy. Results: A total of 9 factors (age, sex, marital status, tumor size, T stage, M stage, N stage, grade, and surgery) were selected based on the results of LASSO analysis. The C-indexes of the nomogram in the training and validation sets were 0.807 and 0.775, respectively, which indicated that the nomogram had better prediction accuracy than TNM staging (C-index = 0.700 in the training set and 0.652 in the validation set). The C-index of the nomogram in the external validation cohort was 0.954, indicating that the nomogram had satisfactory prediction accuracy. The results of DCA revealed that the survival nomogram possessed greater utility in clinical practice. Conclusion: We determined the OS and CSS of patients with colorectal NETs and developed a robust and clinically useful survival nomogram.

Recent advanced lipid-based nanomedicines for overcoming cancer resistance.

The increasing prevalence of cancer drug resistance not only critically limits the efficiency of traditional therapies but also causes relapses or recurrences of cancer. Consequently, there remains an urgent need to address the intricate landscape of drug resistance beyond traditional cancer therapies. Recently, nanotechnology has played an important role in the field of various drug delivery systems for the treatment of cancer, especially therapy-resistant cancer. Among advanced nanomedicine technologies, lipid-based nanomaterials have emerged as effective drug carriers for cancer treatment, significantly improving therapeutic effects. Due to their biocompatibility, simplicity of preparation, and potential for functionalization, lipid-based nanomaterials are considered powerful competitors for resistant cancer. In this review, an overview of lipid-based nanomaterials for addressing cancer resistance is discussed. We summarize the recent progress in overcoming drug resistance in cancer by these lipid-based nanomaterials, and highlight their potential in future applications to reverse cancer resistance.

The p38/MAPK pathway as a therapeutic target to prevent therapeutic escape of breast cancer stem cells.

Cancer stem cells (CSCs) play an important role in metastasis development, tumor recurrence, and treatment resistance, and are essential for the eradication of cancer. Currently, therapies fail to eradicate CSCs due to their therapeutic stress-induced cellular escape, which leads to enhanced aggressive behaviors compared with CSCs that have never been treated. However, the underlying mechanisms regulating the therapeutic escape remain unknown. To this end, we established a model to isolate the therapeutic escaped CSCs (TSCSCs) from breast CSCs and performed the transcription profile to reveal the mechanism. Mechanistically, we demonstrated that the behavior of therapeutic escape was regulated through the p38/MAPK signaling pathway, resulting in TSCSCs exhibiting enhanced motility and metastasis. Notably, blocking the p38/MAPK signaling pathway effectively reduced motility and metastasis ability both in vitro and in vivo, which were further supported by downregulated motility-related genes and epithelial-mesenchymal transition (EMT)-related proteins vimentin and N-cadherin. The obtained findings reveal the p38/MAPK pathway as a potential therapeutic target for TSCSCs and would provide profound implications for cancer therapy.

Near-Infrared Light-Activatable DNA Tentacles for Efficient Inhibition of Tumor Metastasis by Bio-Orthogonal Cell Assembly.

Tumor metastasis remains a major challenge in cancer management. Among various treatment strategies, immune cell-based cancer therapy holds a great potential for inhibiting metastasis. However, its wide application in cancer therapy is restricted by complex preparations, as well as inadequate homing and controllability. Herein, we present a groundbreaking approach for bioorthogonally manipulating tumor-NK (natural killer) cell assembly to inhibit tumor metastasis. Multiple dibenzocyclootyne (DBCO) groups decorated long single-stranded DNA were tail-modified on core-shell upconversion nanoparticles (CSUCNPs) and condensed by photosensitive chemical linker (PC-Linker) DNA to shield most of the DBCO groups. On the one hand, the light-triggered DNA scaffolds formed a cross-linked network by click chemistry, effectively impeding tumor cell migration. On the other hand, the efficient cellular assembly facilitated the effective communication between tumor cells and NK-92 cells, leading to enhanced immune response against tumors and further suppression of tumor metastasis. These features make our strategy highly applicable to a wide range of metastatic cancers.

M6A demethylase FTO-stabilized exosomal circBRCA1 alleviates oxidative stress-induced granulosa cell damage via the miR-642a-5p/FOXO1 axis.

BACKGROUND: Premature ovarian insufficiency (POI) is an important cause of female infertility and seriously impacts the physical and psychological health of patients. Human umbilical cord mesenchymal stem cell-derived exosomes (HucMSCs-Exs, H-Exs) have exhibited protective effects on ovarian function with unclear mechanisms. METHODS: A comprehensive analysis of the Gene Expression Omnibus (GEO) database were used to identify POI-associated circRNAs and miRNAs. The relationship between HucMSC-derived exosomal circBRCA1/miR-642a-5p/FOXO1 axis and POI was examined by RT-qPCR, Western blotting, reactive oxygen species (ROS) staining, senescence-associated ß-gal (SA-ß-gal) staining, JC-1 staining, TEM, oxygen consumption rate (OCR) measurements and ATP assay in vivo and in vitro. RT-qPCR detected the expression of circBRCA1 in GCs and serum of patients with normal ovarian reserve function (n = 50) and patients with POI (n = 50); then, the correlation of circBRCA1 with ovarian reserve function indexes was analyzed. RESULTS: Herein, we found that circBRCA1 was decreased in the serum and ovarian granulosa cells (GCs) of patients with POI and was associated with decreased ovarian reserve. H-Exs improved the disorder of the estrous cycles and reproductive hormone levels, reduced the number of atretic follicles, and alleviated the apoptosis and senescence of GCs in rats with POI. Moreover, H-Exs mitigated mitochondrial damage and reversed the reduced circBRCA1 expression induced by oxidative stress in GCs. Mechanistically, FTO served as an eraser to increase the stability and expression of circBRCA1 by mediating the m6A demethylation of circBRCA1, and exosomal circBRCA1 sponged miR-642a-5p to block its interaction with FOXO1. CircBRCA1 insufficiency aggravated mitochondrial dysfunction, mimicking FTO or FOXO1 depletion effects, which was counteracted by miR-642a-5p inhibition. CONCLUSION: H-Exs secreted circBRCA1 regulated by m6A modification, directly sponged miR-642a-5p to upregulate FOXO1, resisted oxidative stress injuries in GCs and protected ovarian function in rats with POI. Exosomal circBRCA1 supplementation may be a general prospect for the prevention and treatment of POI.

The involvement and application potential of exosomes in breast cancer immunotherapy.

Breast cancer has a high incidence and a heightened propensity for metastasis. The absence of precise targets for effective intervention makes it imperative to devise enhanced treatment strategies. Exosomes, characterized by a lipid bilayer and ranging in size from 30 to 150 nm, can be actively released by various cells, including those in tumors. Exosomes derived from distinct subsets of immune cells have been shown to modulate the immune microenvironment within tumors and influence breast cancer progression. In addition, tumor-derived exosomes have been shown to contribute to breast cancer development and progression and may become a new target for breast cancer immunotherapy. Tumor immunotherapy has become an option for managing tumors, and exosomes have become therapeutic vectors that can be used for various pathological conditions. Edited exosomes can be used as nanoscale drug delivery systems for breast cancer therapy, contributing to the remodeling of immunosuppressive tumor microenvironments and influencing the efficacy of immunotherapy. This review discusses the regulatory role of exosomes from different cells in breast cancer and the latest applications of exosomes as nanoscale drug delivery systems and immunotherapeutic agents in breast cancer, showing the development prospects of exosomes in the clinical treatment of breast cancer.

Synchronous profiling of mRNA N6-methyladenosine modifications and mRNA expression in high-grade serous ovarian cancer: a pilot study.

This study aimed to synchronously determine epitranscriptome-wide RNA N6-methyladenosine (m6A) modifications and mRNA expression profile in high grade serous ovarian cancer (HGSOC). The methylated RNA immunoprecipitation sequencing (MeRIP-seq) was used to comprehensively examine the m6A modification profile and the RNA-sequencing (RNA-seq) was performed to analyze the mRNA expression profile in HGSOC and normal fallopian tube (FT) tissues. Go and KEGG analyses were carried out in the enrichment of those differentially methylated and expressed genes. MeRIP-seq data showed 53,794 m6A methylated peaks related to 19,938 genes in the HGSOC group and 51,818 m6A peaks representing 19,681 genes in the FT group. RNA-seq results revealed 2321 upregulated and 2486 downregulated genes in HGSOC. Conjoint analysis of MeRIP-seq and RNA-seq data identified differentially expressed genes in which 659 were hypermethylated (330 up- and 329 down-regulated) and 897 were hypomethylated (475 up- and 422 down-regulated). Functional enrichment analysis indicated that these differentially modulated genes are involved in pathways related to cancer development. Among methylation regulators, the m6A eraser (FTO) expression was significantly lower, but the m6A readers (IGF2BP2 and IGF2BP3) were higher in HGSOC, which was validated by the subsequent real-time PCR assay. Exploration through public databases further corroborated their possible clinical application of certain methylation regulators and differentially expressed genes. For the first time, our study screens the epitranscriptome-wide m6A modification and expression profiles of their modulated genes and signaling pathways in HGSOC. Our findings provide an alternative direction in exploring the molecular mechanisms of ovarian pathogenesis and potential biomarkers in the diagnosis and predicting the prognosis of the disease.

Expression profiling and bioinformatics analysis of serum exosomal circular RNAs in lymph node metastasis of papillary thyroid carcinoma.

Most papillary thyroid carcinoma (PTC) patients have a good prognosis, but lymph node metastasis (LNM) is the most common progressive manifestation and often leads to a poor-prognosis. However, few studies focused on the underlying mechanisms of LNM. This study aimed to identity the potential role of exosomal circRNAs that contribute to LNM in PTC. We found that 9000 aberrantly expressed exosomal circRNAs in PTC patients with LNM, including 684 observably upregulation and 2193 notably downregulation. Functional enrichment analyses indicated that these aberrantly expressed circRNAs were mainly enriched in a variety of molecules and signaling pathways related to the progression and LNM of PTC. Bioinformatics analysis screened 14 circRNA-miRNA-mRNA networks associated with LNM-related signaling pathways in PTC. Moreover, circTACC2-miR-7-EGFR and circBIRC6-miR-24-3p-BCL2L11 axes were verified for potential involvement in PTC with LNM. Additionally, 4 upregulated circRNAs-related hub genes and 8 hub genes associated with downregulated circRNAs were screened, some of which were involved in LNM of PTC through verification. Collectively, our data provided a novel framework for in-depth investigation of the function of dysregulated exosomal circRNAs and their potential biomarkers in PTC patients with LNM.

A natural killer T cell nanoagonist-initiated immune cascade for hepatocellular carcinoma synergistic immunotherapy.

Natural killer T (NKT) cell-mediated immunotherapy shows great promise in hepatocellular carcinoma featuring an inherent immunosuppressive microenvironment. However, targeted delivery of NKT cell agonists remains challenging. Here, we developed a hyaluronic acid (HA) modified metal organic framework (zeolitic imidazolate framework-8, ZIF-8) to encapsulate α-galactosylceramide (α-Galcer), a classic NKT cell agonist, and doxorubicin (DOX) for eliminating liver cancer, denoted as α-Galcer/DOX@ZIF-8@HA. In the tumor microenvironment (TME), these pH-responsive nano-frameworks can gradually collapse to release α-Galcer for activating NKT cells and further boosting other immune cells in order to initiate an antitumor immune cascade. Along with DOX, the released α-Galcer enabled efficient NKT cell activation in TME for synergistic immunotherapy and tumor elimination, leading to evident tumor suppression and prolonged animal survival in both subcutaneous and orthotopic liver tumor models. Manipulating NKT cell agonists into functional nano-frameworks in TME may be matched with other advanced managements applied in a wider range of cancer therapies.