Dual Starvations Induce Pyroptosis for Orthotopic Pancreatic Cancer Therapy through Simultaneous Deprivation of Glucose and Glutamine.

Pancreatic cancer is a highly fatal disease, and existing treatment methods are ineffective, so it is urgent to develop new effective treatment strategies. The high dependence of pancreatic cancer cells on glucose and glutamine suggests that disrupting this dependency could serve as an alternative strategy for pancreatic cancer therapy. We identified the vital genes glucose transporter 1 (GLUT1) and alanine-serine-cysteine transporter 2 (ASCT2) through bioinformatics analysis, which regulate glucose and glutamine metabolism in pancreatic cancer, respectively. Human serum albumin nanoparticles (HSA NPs) for delivery of GLUT1 and ASCT2 inhibitors, BAY-876/V-9302@HSA NPs, were prepared by a self-assembly process. This nanodrug inhibits glucose and glutamine uptake of pancreatic cancer cells through the released BAY-876 and V-9302, leading to nutrition deprivation and oxidative stress. The inhibition of glutamine leads to the inhibition of the synthesis of the glutathione, which further aggravates oxidative stress. Both of them lead to a significant increase in reactive oxygen species, activating caspase 1 and GSDMD and finally inducing pyroptosis. This study provides a new effective strategy for orthotopic pancreatic cancer treatment by dual starvation-induced pyroptosis. The study for screening metabolic targets using bioinformatics analysis followed by constructing nanodrugs loaded with inhibitors will inspire future targeted metabolic therapy for pancreatic cancer.

Electron ionization mass spectrometry feature peak relationships combined with deep classification model to assist similarity algorithm for fast and accurate identification of compounds.

RATIONALE: Gas chromatography-mass spectrometry (GC-MS) combines chromatography and MS, providing full play to the advantages of high separation efficiency of GC, strong qualitative ability of MS, and high sensitivity of detector. In GC-MS data processing, determining the experimental compounds is one of the most important analytical steps, which is usually realized by one-to-one similarity calculations between the experimental mass spectrum and the standard mass spectrum library. Although the accuracy of the algorithm has been improved in recent years, it is still difficult to distinguish structurally similar mass spectra, especially isomers. At the same time, the library capacity is very large and increasing every year, and the algorithm needs to perform large numbers of calculations with irrelevant compounds in the library to recognize unknown compounds, which leads to a significant reduction in efficiency. METHODS: This work proposed to exclude a large number of irrelevant mass spectra by presearching, perform preliminary similarity calculations using similarity algorithms, and finally improve the accuracy of similarity calculations using deep classification models. The replica library of NIST17 is used as the query data, and the master library is used as the reference database. RESULTS: Compared with the traditional recognition algorithm, the preprocessing algorithm has reduced the time by 4.2 h, and by adding the deep learning models 1 and 2 as the final determination, the recognition accuracy has been improved by 1.9% and 6.5%, respectively, based on the original algorithm. CONCLUSIONS: This method improves the recognition efficiency compared to conventional algorithms and at the same time has better recognition accuracy for structurally similar mass spectra and isomers.

Evaluation of metabolomics-based urinary biomarker models for recognizing major depression disorder and bipolar disorder.

BACKGROUND: Major depressive disorder (MDD) and bipolar disorder (BD) are psychiatric disorders with overlapping symptoms, leading to high rates of misdiagnosis due to the lack of biomarkers for differentiation. This study aimed to identify metabolic biomarkers in urine samples for diagnosing MDD and BD, as well as to establish unbiased differential diagnostic models. METHODS: We utilized a metabolomics approach employing ultra-high performance liquid chromatography-mass spectrometry (UHPLC-MS) to analyze the metabolic profiles of urine samples from individuals with MDD (n = 50), BD (n = 12), and healthy controls (n = 50). The identification of urine metabolites was verified using MS data analysis tools and online metabolite databases. RESULTS: Two diagnostic panels consisting of a combination of metabolites and clinical indicators were identified-one for MDD and another for BD. The discriminative capacity of these panels was assessed using the area under the receiver operating characteristic (ROC) curve, yielding an area under the curve (AUC) of 0.9084 for MDD and an AUC value of 0.9017 for BD. CONCLUSIONS: High-resolution mass spectrometry-based assays show promise in identifying urinary biomarkers for depressive disorders. The combination of urine metabolites and clinical indicators is effective in differentiating healthy controls from individuals with MDD and BD. The metabolic pathway indicating oxidative stress is seen to significantly contribute to depressive disorders.

Coronavirus hijacks STX18-ATG14 axis-regulated lipophagy to evade an anti-viral effect.

ATG14 is a core subunit of the class III phosphatidylinositol 3-kinase complex I (PtdIns3K-C1) for macroautophagy/autophagy initiation and also binds to the STX17 to promote autophagosome-lysosome fusion. Our recent work found that ATG14 also targets lipid droplets (LDs) and interacts with mammalian Atg8-family proteins (ATG8s) to mediate lipophagy (selective autophagic degradation of lipid droplets). We also demonstrated that STX18 (syntaxin 18) acts as a negative regulator that disrupts the interactions of ATG14-ATG8s and the formation of the PtdIns3K-C1 through binding to ATG14. Furthermore, we found that knockdown of STX18 induces LD-associated anti-viral protein RSAD2/Viperin degradation dependent on ATG14-mediated lipophagy. Additionally, coronavirus M protein hijacks STX18 to induce lipophagy and degrade RSAD2, facilitating virus production. In summary, our findings reveal new roles of ATG14 in lipid metabolism and viral replication as an autophagic receptor.

Glutathione Induced In situ Synthesis of Cu Single-Atom Nanozymes with Anaerobic Glycolysis Metabolism Interference for Boosting Cuproptosis.

Single-atom nanozyme (SAzyme) has sparked increasing interest for catalytic antitumor treatment due to their more tunable and diverse active sites than natural metalloenzymes in complex physiological conditions. However, it is usually a hard task to precisely conduct catalysis at tumor sites after intravenous injection of those SAzyme with high reactivity. Moreover, the explorations of SAzymes in the anticancer application are still in its infancy and need to be developed. Herein, an in situ synthesis strategy for Cu SAzyme was constructed to convert adsorbed copper ions into isolated atoms anchored by oxygen atoms (Cu-O2/Cu-O4) via GSH-responsive deformability of supports. Our results suggest that the in situ activation process could further facilitate the dissociation of copper ions and the consumption of glutathione, thereby leading to copper deposition in cytoplasm and triggering cuproptosis. Moreover, the in situ synthesis of Cu SAzyme with peroxidase-like activity enabled the intracellular reactive oxygen species production, resulting in specifically disturbance of copper metabolism pathway. Meanwhile, the in situ exposed glucose transporter (GLUT) inhibitor phloretin (Ph) can block the glycose uptake to boost cuproptosis efficacy. Overall, this in situ activation strategy effectively diminished the off-target effects of SACs-induced catalytic therapies and introduced a promising treatment paradigm for advancing cuproptosis-associated therapies.

NADPH Oxidase-Like Nanozyme for High-Efficiency Tumor Therapy Through Increasing Glutathione Consumption and Blocking Glutathione Regeneration.

To counteract the high level of reactive oxygen species (ROS) caused by rapid growth, tumor cells resist oxidative stress by accelerating the production and regeneration of intracellular glutathione (GSH). Numerous studies focus on the consumption of GSH, but the regeneration of GSH will enhance the reduction level of tumor cells to resist oxidative stress. Therefore, inhibiting the regeneration of GSH; while, consuming GSH is of great significance for breaking the redox balance of tumor cells. Herein, a simple termed MnOx-coated Au (AMO) nanoflower, as a nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) nanoenzyme, is reported for efficient tumor therapy. Au nanoparticles exhibit the capability to catalyze the oxidation of NADPH, hindering GSH regeneration; while, concurrently functioning as a photothermal agent. During the process of eliminating intracellular GSH, MnOx releases Mn2+ that subsequently engages in Fenton-like reactions, ultimately facilitating the implementation of chemodynamic therapy (CDT). Overall, this NOX enzyme-based nanoplatform enhances ROS generation and disrupts the state of reduction equilibrium, inducing apoptosis and ferroptosis by blocking GSH regeneration and increasing GSH consumption, thereby achieving collaborative treatments involving photothermal therapy (PTT), CDT, and catalytic therapy. This research contributes to NADPH and GSH targeted tumor therapy and showcases the potential of nanozymes.

ATG14 targets lipid droplets and acts as an autophagic receptor for syntaxin18-regulated lipid droplet turnover.

Lipid droplets (LDs) are dynamic lipid storage organelles that can be degraded by autophagy machinery to release neutral lipids, a process called lipophagy. However, specific receptors and regulation mechanisms for lipophagy remain largely unknown. Here, we identify that ATG14, the core unit of the PI3KC3-C1 complex, also targets LD and acts as an autophagic receptor that facilitates LD degradation. A negative regulator, Syntaxin18 (STX18) binds ATG14, disrupting the ATG14-ATG8 family members interactions and subverting the PI3KC3-C1 complex formation. Knockdown of STX18 activates lipophagy dependent on ATG14 not only as the core unit of PI3KC3-C1 complex but also as the autophagic receptor, resulting in the degradation of LD-associated anti-viral protein Viperin. Furthermore, coronavirus M protein binds STX18 and subverts the STX18-ATG14 interaction to induce lipophagy and degrade Viperin, facilitating virus production. Altogether, our data provide a previously undescribed mechanism for additional roles of ATG14 in lipid metabolism and virus production.

Oxygen-Vacancy-Engineered W18 O49-x Nanobrush with a Suitable Band Structure for Highly Efficient Sonodynamic Therapy.

With the rapid development of external minimally invasive or noninvasive therapeutic modalities, ultrasound-based sonodynamic therapy (SDT) is a new alternative for treating deep tumors. However, inadequate sonosensitizer efficiency and poor biosecurity limit clinical applications. In this study, we prepared an oxygen-vacancy-engineered W18 O49-x nanobrush with a band gap of 2.79 eV for highly efficient SDT using a simple solvothermal method. The suitable band structures of the W18 O49-x nanobrush endows it with the potential to simultaneously produce singlet oxygen (1 O2 ), superoxide anions (⋅O2 - ), and hydroxyl radicals (⋅OH) under ultrasound irradiation. Additionally, abundant oxygen vacancies that serve as further charge traps that inhibit electron-hole recombination are incidentally introduced through one-step thermal reduction. Collectively, the in vitro and in vivo results demonstrate that the oxygen-vacancy-engineered W18 O49-x nanobrush delivers highly efficient reactive oxygen species (ROS) for SDT in a very biosafe manner. Overall, this study provides a new avenue for discovering and designing inorganic nanosonosensitizers with enhanced therapeutic efficiencies for use in SDT.

Effects of Skeleton Structure of Mesoporous Silica Nanoadjuvants on Cancer Immunotherapy.

Mesoporous silica nanoparticles (MSNs) have been widely praised as nanoadjuvants in vaccine/tumor immunotherapy thanks to their excellent biocompatibility, easy-to-modify surface, adjustable particle size, and remarkable immuno-enhancing activity. However, the application of MSNs is still greatly limited by some severe challenges including the unclear and complicated relationships of structure and immune effect. Herein, three commonly used MSNs with different skeletons including MSN with tetrasulfide bonds (TMSN), MSN containing ethoxy framework (EMSN), and pure -Si-O-Si- framework of MSN (MSN) are comprehensively compared to study the impact of chemical construction on immune effect. The results fully demonstrate that the three MSNs have great promise in improving cellular immunity for tumor immunotherapy. Moreover, the TMSN performs better than the other two MSNs in antigen loading, cellular uptake, reactive oxygen species (ROS) generation, lymph node targeting, immune activation, and therapeutic efficiency. The findings provide a new paradigm for revealing the structure-function relationship of mesoporous silica nanoadjuvants, paving the way for their future clinical application.

NIR-Activatable Heterostructured Nanoadjuvant CoP/NiCoP Executing Lactate Metabolism Interventions for Boosted Photocatalytic Hydrogen Therapy and Photoimmunotherapy.

Near-infrared (NIR) laser-induced photoimmunotherapy has aroused great interest due to its intrinsic noninvasiveness and spatiotemporal precision, while immune evasion evoked by lactic acid (LA) accumulation severely limits its clinical outcomes. Although several metabolic interventions have been devoted to ameliorate immunosuppression, intracellular residual LA still remains a potential energy source for oncocyte proliferation. Herein, an immunomodulatory nanoadjuvant based on a yolk-shell CoP/NiCoP (CNCP) heterostructure loaded with the monocarboxylate transporter 4 inhibitor fluvastatin sodium (Flu) is constructed to concurrently relieve immunosuppression and elicit robust antitumor immunity. Under NIR irradiation, CNCP heterojunctions exhibit superior photothermal performance and photocatalytic production of reactive oxygen species and hydrogen. The continuous heat then facilitates Flu release to restrain LA exudation from tumor cells, whereas cumulative LA can be depleted as a hole scavenger to improve photocatalytic efficiency. Subsequently, potentiated photocatalytic therapy can not only initiate systematic immunoreaction, but also provoke severe mitochondrial dysfunction and disrupt the energy supply for heat shock protein synthesis, in turn realizing mild photothermal therapy. Consequently, LA metabolic remodeling endows an intensive cascade treatment with an optimal safety profile to effectually suppress tumor proliferation and metastasis, which offers a new paradigm for the development of metabolism-regulated immunotherapy.

Qa-SNARE syntaxin 18 mediates lipid droplet fusion with SNAP23 and SEC22B.

Lipid droplets (LDs) are dynamic lipid storage organelles that can sense and respond to changes in systemic energy balance. The size and number of LDs are controlled by complex and delicate mechanisms, among which, whether and which SNARE proteins mediate LD fusion, and the mechanisms governing this process remain poorly understood. Here we identified a SNARE complex, syntaxin 18 (STX18)-SNAP23-SEC22B, that is recruited to LDs to mediate LD fusion. STX18 targets LDs with its transmembrane domain spanning the phospholipid monolayer twice. STX18-SNAP23-SEC22B complex drives LD fusion in adiposome lipid mixing and content mixing in vitro assays. CIDEC/FSP27 directly binds STX18, SEC22B, and SNAP23, and promotes the lipid mixing of SNAREs-reconstituted adiposomes by promoting LD clustering. Knockdown of STX18 in mouse liver via AAV resulted in smaller liver and reduced LD size under high-fat diet conditions. All these results demonstrate a critical role of the SNARE complex STX18-SNAP23-SEC22B in LD fusion.

Sodium Citrate Nanoparticles Induce Dual-Path Pyroptosis for Enhanced Antitumor Immunotherapy through Synergistic Ion Overload and Metabolic Disturbance.

Metabolic reprogramming, as one of the characteristics of cancer, is associated with tumorigenesis, growth, or migration, and the modulation of metabolic pathways has emerged as a novel approach for cancer therapy. However, the conventional metabolism-mediated apoptosis process in tumor cells exhibits limited immunogenicity and inadequate activation of antitumor immunity. Herein, phospholipid-coated sodium citrate nanoparticles (PSCT NPs) are successfully prepared, which dissolve in tumor cells and then release significant amounts of citrate ions and Na+ ions. Massive quantities of ions lead to increased intracellular osmotic pressure, which activates the caspase-1/gasdermin D (GSDMD) mediated pyroptosis pathway. Simultaneously, citrate induces activation of the caspase-8/gasdermin C (GSDMC) pathway. The combined action of these two pathways synergistically causes intense pyroptosis, exhibiting remarkable antitumor immune responses and tumor growth inhibition. This discovery provides new insight into the potential of nanomaterials in modulating metabolism and altering cell death patterns to enhance antitumor immunotherapy.

Tumor Microenvironment-Activated Nanocomposite for Self-Amplifying Chemodynamic/Starvation Therapy Enhanced IDO-Blockade Tumor Immunotherapy.

Disrupting intracellular redox homeostasis combined with immune checkpoint blockade therapy is considered as an effective way to accelerate tumor cell death. However, suppressed tumor immune microenvironment and lower cargo delivery restrict the efficiency of tumor therapy. In this study, a multifunctional tumor microenvironment (TME)-responsive nanocomposite is constructed using manganese tetroxide (Mn3 O4 )-decorated disulfide-bond-incorporated dendritic mesoporous organosilica nanoparticles (DMONs) to co-deliver indoleamine 2,3-dioxygenase (IDO) inhibitor Epacadostat (IDOi) and glucose oxidase (GOx) following modification with polyethylene glycol. Owing to the responsiveness of Mn3 O4 -decorated DMONs to the mildly acidic and glutathione (GSH) overexpressed TME, the nanocomposite can rapidly decompose and release inner contents, thus substantially improving the cargo release ability. Mn3 O4 can effectively catalyze hydrogen peroxide (H2 O2 ) decomposition to generate oxygen, enhance the ability of GOx to consume glucose to produce H2 O2 , and further promote the generation of hydroxyl radicals (•OH) by Mn2+ . Furthermore, Mn2+ -mediated GSH depletion and the production of •OH can disrupt intracellular redox homeostasis, contributing to immunogenic cell death. Simultaneously, IDOi can inhibit IDO to reverse inhibited immune response. The results show that self-amplifying chemodynamic/starvation therapy combined IDO-blockade immunotherapy synergistically inhibits tumor growth and metastasis in vivo.

Actomyosin-dependent cell contractility orchestrates Zika virus infection.

Emerging pathogen infections, such as Zika virus (ZIKV), pose an increasing threat to human health, but the role of mechanobiological attributes of host cells during ZIKV infection is largely unknown. Here, we reveal that ZIKV infection leads to increased contractility of host cells. Importantly, we investigated whether host cell contractility contributes to ZIKV infection efficacy, from both the intracellular and extracellular perspective. By performing drug perturbation and gene editing experiments, we confirmed that disruption of contractile actomyosin compromises ZIKV infection efficiency, viral genome replication and viral particle production. By culturing on compliant matrix, we further demonstrate that a softer substrate, leading to less contractility of host cells, compromises ZIKV infection, which resembles the effects of disrupting intracellular actomyosin organization. Together, our work provides evidence to support a positive correlation between host cell contractility and ZIKV infection efficacy, thus unveiling an unprecedented layer of interplay between ZIKV and the host cell.

Sodium Bicarbonate Nanoparticles for Amplified Cancer Immunotherapy by Inducing Pyroptosis and Regulating Lactic Acid Metabolism.

Although immunotherapy has a broad clinical application prospect, it is still hindered by low immune responses and immunosuppressive tumor microenvironment. Herein, a simple and drug-free inorganic nanomaterial, alkalescent sodium bicarbonate nanoparticles (NaHCO3 NPs), is prepared via a fast microemulsion method for amplified cancer immunotherapy. The obtained alkalescent NaHCO3 regulates lactic acid metabolism through acid-base neutralization so as to reverse the mildly acidic immunosuppressive tumor environment. Additionally, it can further release high amounts of Na+ ions inside tumor cells and induce a surge in intracellular osmolarity, and thus activate the pyroptosis pathway and immunogenic cell death (ICD), release damage-associated molecular patterns (DAMPs) and inflammatory factors, and improve immune responses. Collectively, NaHCO3 NPs observably inhibit primary/distal tumor growth and tumor metastasis through acid neutralization remitted immunosuppression and pyroptosis induced immune activation, showing an enhanced antitumor immunity efficiency. This work provides a new paradigm for lactic acid metabolism and pyroptosis mediated tumor treatment, which has a potential for application in clinical tumor immunotherapy.

Coronaviral ORF6 protein mediates inter-organelle contacts and modulates host cell lipid flux for virus production.

Lipid droplets (LDs) form inter-organelle contacts with the endoplasmic reticulum (ER) that promote their biogenesis, while LD contacts with mitochondria enhance ß-oxidation of contained fatty acids. Viruses have been shown to take advantage of lipid droplets to promote viral production, but it remains unclear whether they also modulate the interactions between LDs and other organelles. Here, we showed that coronavirus ORF6 protein targets LDs and is localized to the mitochondria-LD and ER-LD contact sites, where it regulates LD biogenesis and lipolysis. At the molecular level, we find that ORF6 inserts into the LD lipid monolayer via its two amphipathic helices. ORF6 further interacts with ER membrane proteins BAP31 and USE1 to mediate ER-LDs contact formation. Additionally, ORF6 interacts with the SAM complex in the mitochondrial outer membrane to link mitochondria to LDs. In doing so, ORF6 promotes cellular lipolysis and LD biogenesis to reprogram host cell lipid flux and facilitate viral production.

Iron oxide-EDTA nanoparticles for chelation-enhanced chemodynamic therapy and ion interference therapy.

As an emerging anti-tumor strategy, chemodynamic therapy (CDT) utilizes a Fenton/Fenton-like reaction to generate highly toxic hydroxyl radicals to kill tumor cells. However, the efficiency of CDT is still hindered by the low Fenton/Fenton-like reaction rate. Herein, we report the combination of ion interference therapy (IIT) and chemodynamic therapy (CDT) via an amorphous iron oxide (AIO) nanomedicine with encapsulated EDTA-2Na (EDTA). Iron ions and EDTA are released from the nanomedicine in acidic tumors and chelate to form iron ion-EDTA, which improves the efficiency of CDT and promotes the generation of reactive oxygen species (ROS). In addition, EDTA can disrupt the homeostasis of Ca2+ in tumor cells by chelating with Ca2+ ions, which induces the separation of tumor cells and affects normal physiological activities. Both in vitro and in vivo experiments show that the nano chelating drugs exhibit significant improvement in Fenton reaction performance and excellent anti-tumor activity. This study based on chelation provides a new idea for designing efficient catalysts to enhance the Fenton reaction and provides more revelations on future research on CDT.

Usnea Acid-Incorporated Ca2+ /Mn2+ Ions Reservoirs for Elevated Ion-Interference Therapy through Synergetic Biocatalysis and Osmolarity Imbalance.

Ion-interference therapy (IIT) utilizes ions to disturb intracellular biological processes and has been received increasing attention in tumor treatments recently. However, the low therapeutic efficiency still hinders its further biological applications. Herein, via a simple and one-pot gas diffusion process, polyethylene glycol (PEG)-modified Mn2+ ions and usnic acid (UA)-incorporated CaCO3 nanomaterials (PEG CaMnUA) as Ca2+ /Mn2+ ions reservoirs are prepared for magnetic resonance imaging (MRI)-guided UA-elevated IIT. Among PEG CaMnUA, UA not only increases cytoplasmic Ca2+ ions to amplify Ca2+ overload caused by CaCO3 decomposition, but also enhances Mn2+ ions-participated Fenton-like biocatalysis by intracellular H2 O2 generation and glutathione consumption. Then increasing the intracellular oxidative stress and decreasing the triphosadenine supply induce apoptosis together, resulting in UA-boosted IIT. The simple and efficient design of the dual ions reservoirs will contribute to improve the antitumor activity of IIT and further development of calcium-based nanomaterials in the future.

Coronavirus subverts ER-phagy by hijacking FAM134B and ATL3 into p62 condensates to facilitate viral replication.

ER-phagy is a form of autophagy that is mediated by ER-phagy receptors and selectively degrades endoplasmic reticulum (ER). Coronaviruses have been shown to use the ER as a membrane source to establish their double-membrane vesicles (DMVs). However, whether viruses modulate ER-phagy to drive viral DMV formation and its underlying molecular mechanisms remains largely unknown. Here, we demonstrate that coronavirus subverts ER-phagy by hijacking the ER-phagy receptors FAM134B and ATL3 into p62 condensates, resulting in increased viral replication. Mechanistically, we show that viral protein ORF8 binds to and undergoes condensation with p62. FAM134B and ATL3 interact with homodimer of ORF8 and are aggregated into ORF8/p62 liquid droplets, leading to ER-phagy inhibition. ORF8/p62 condensates disrupt ER-phagy to facilitate viral DMV formation and activate ER stress. Together, our data highlight how coronavirus modulates ER-phagy to drive viral replication by hijacking ER-phagy receptors.

Heterostructural Nanoadjuvant CuSe/CoSe2 for Potentiating Ferroptosis and Photoimmunotherapy through Intratumoral Blocked Lactate Efflux.

The desirable curative effect in clinical immunotherapy has been challenging due to the immunosuppressive tumor microenvironment (TME) with high lactic acid (LA) metabolism in solid tumors. Although targeting metabolic reprogramming of tumor cells can restore the survival and function of immune cells in the TME, it is also plagued by insufficient immunogenicity. Herein, an activatable immunomodulatory nanoadjuvant CuSe/CoSe2@syrosingopine (CSC@Syro) is constructed for simultaneously relieving immunosuppressive TME and boosting tumor immune response. Specifically, CuSe/CoSe2 (CSC) exhibits TME-activated glutathione (GSH) depletion and hydroxyl radical (•OH) generation for potential ferroptosis. Meanwhile, the remarkable photothermal conversion efficiency and elevated photocatalytic ROS level both promote CSC heterostructures to induce robust immunogenic cell death (ICD). Besides, the loaded syrosingopine inhibitor achieves LA metabolism blockade in cancer cells by downregulating the expression of monocarboxylate transporter 4 (MCT4), which could sensitize ferroptosis by intracellular milieu acidification and neutralize the acidic TME to alleviate immunosuppression. Hence, advanced metabolic modulation confers the potentiated immune infiltration of ICD-stimulated T lymphocytes and further reinforces antitumor therapy. In brief, CSC@Syro-mediated synergistic therapy could elicit potent immunogenicity and suppress tumor proliferation and metastasis effectually by integrating the tumor metabolic regulation and ferroptosis with immunotherapy.