An ultra-long-acting L-asparaginase synergizes with an immune checkpoint inhibitor in starvation-immunotherapy of metastatic solid tumors.

Metastasis stands as the primary contributor to mortality associated with tumors. Chemotherapy and immunotherapy are frequently utilized in the management of metastatic solid tumors. Nevertheless, these therapeutic modalities are linked to serious adverse effects and limited effectiveness in preventing metastasis. Here, we report a novel therapeutic strategy named starvation-immunotherapy, wherein an immune checkpoint inhibitor is combined with an ultra-long-acting L-asparaginase that is a fusion protein comprising L-asparaginase (ASNase) and an elastin-like polypeptide (ELP), termed ASNase-ELP. ASNase-ELP's thermosensitivity enables it to generate an in-situ depot following an intratumoral injection, yielding increased dose tolerance, improved pharmacokinetics, sustained release, optimized biodistribution, and augmented tumor retention compared to free ASNase. As a result, in murine models of oral cancer, melanoma, and cervical cancer, the antitumor efficacy of ASNase-ELP by selectively and sustainably depleting L-asparagine essential for tumor cell survival was substantially superior to that of ASNase or Cisplatin, a first-line anti-solid tumor medicine, without any observable adverse effects. Furthermore, the combination of ASNase-ELP and an immune checkpoint inhibitor was more effective than either therapy alone in impeding melanoma metastasis. Overall, the synergistic strategy of starvation-immunotherapy holds excellent promise in reshaping the therapeutic landscape of refractory metastatic tumors and offering a new alternative for next-generation oncology treatments.

Fe-doped biodegradable dendritic mesoporous silica nanoparticles for starvation therapy and photothermal-enhanced cascade catalysis in tumor therapy.

Combination therapies have attracted significant attention because they address the limitations of monotherapy while improving overall efficacy. In this study, we designed a novel nanoplatform, named GOx@Fe-DMSN@PDA (GFDP), by integrating Fe2+ into dendritic mesoporous silica nanoparticles (DMSN) and selecting glucose oxidase (GOx) as the model drug loaded into the DMSN pores. Additionally, we coated the surface of the DMSN with polydopamine (PDA) to confer pH/near infrared (NIR) light-responsive controlled-release behavior and photothermal therapy (PTT). The introduction of Fe2+ into the DMSN framework greatly improved biodegradability and enhanced the peroxidase (POD)-like activity of GFDP. In addition, GOx could consume glucose and generate hydrogen peroxide (H2O2) within tumor cells to facilitate starvation therapy and enhance cascade catalysis. The PDA coating provided the DMSN with an intelligent response release ability, promoting efficient photothermal conversion and achieving the PTT effect. Cellular tests showed that under NIR light irradiation, GFDP exhibited a synergistic effect of PTT-enhanced starvation therapy and cascade catalysis, with a half-maximal inhibitory concentration (IC50) of 2.89 µg/mL, which was significantly lower than that of GFDP without NIR light irradiation (18.29 µg/mL). The in vivo anti-tumor effect indicated that GFDP could effectively accumulate at the tumor site for thermal imaging and showed remarkable synergistic therapeutic effects. In summary, GFDP is a promising nanoplatform for multi-modal combination therapy that integrates starvation therapy, PTT, and cascade catalysis.

Influence of multi-stress factors on the growth of Chlorella pyrenoidosa and Scenedesmus abundans using response surface methodology.

This study evaluated the biofuel production potential of two algal species, Chlorella pyrenoidosa and Scenedesmus abundans, under stress conditions induced by nutrient supplementation or starvation at varying light intensities. Central composite face-centered design response surface methodology (CCFD-RSM) was employed to optimize stress conditions by varying the sodium nitrate (NaNO3), potassium dihydrogen phosphate (KH2PO4), dipotassium hydrogen phosphate (K2HPO4), cultivation time, and light intensity. The study included both C. pyrenoidosa and S. abundans, which presented increased biomass yields when subjected to nutrient starvation. Under the optimized conditions, the dry biomass yield was 98.26 mg/L for C. pyrenoidosa and 110 mg/L for S. abundans. Lipid yields were approximately 22.47% for C. pyrenoidosa and 29.06% for S. abundans under these optimized growth conditions. The optimized parameters for maximum biomass and lipid production were identified as C. pyrenoidosa, and the optimized conditions required 0.805 g/L NaNO3, 0.052 g/L K2HPO4, 0.099 g/L KH2PO4, 17 days of culture, and 5168.39 lx of light intensity. For S. abundans, the optimal conditions were 1.065 g/L NaNO3, 0.071 g/L K2HPO4, 0.058 g/L KH2PO4, 22 days of cultivation, and 2897 lx of light intensity. Overall, both C. pyrenoidosa and S. abundans have emerged as promising candidates for sustainable biodiesel production, highlighting their potential under stress conditions induced by nutrient modulation and variable light intensities.

Advances in multifunctional metal-organic framework (MOF)-based nanoplatforms for cancer starvation therapy.

Cancer remains a significant threat to human health today. Even though starvation therapy and other treatment methods have recently advanced to a new level of rapid development in tumour treatment, their limited therapeutic effectiveness and unexpected side effects prevent them from becoming the first option in clinical treatment. With rapid advancement in nanotechnology, the utilization of nanomaterials in therapeutics offers the potential to address the shortcomings in cancer treatment. Notably, multifunctional metal-organic framework (MOF) has been widely employed in cancer therapy due to their customizable shape, adjustable diameter, high porosity, diverse compositions, large specific surface area, high degree of functionalization and strong biocompatibility. This paper reviews the current progress and success of MOF-based multifunctional nanoplatforms for cancer starvation therapy, as well as the prospects and potential barriers for the application of MOF nanoplatforms in cancer starvation therapy.

5-Fluorouracil induces apoptosis in nutritional deprived hepatocellular carcinoma through mitochondrial damage.

5-Fluorouracil (5-FU) is the leading chemotherapeutic drug used to treat hepatocellular carcinoma, one of the major cancer diseases after atherosclerosis. Because of chemo-resistance, the success rate of treatment declines with time due to continuous drug exposure. Though autophagy induction is majorly responsible for acquired resistance, the exact role of this evolutionary conserved mechanism is unknown in cancer cell survival and suppression. The usual practice involves the combinatorial use of chemotherapeutic drugs with autophagy inhibitors like Chloroquine and Bafilomycin A, while neglecting the side effects caused by autophagy impairment in healthy cells. Starvation is a well-known physiological inducer of autophagy. In this study, by caloric modulation, we tried to circumvent the resistance imposed by prolonged drug exposure and investigated the effect of 5-FU in nutrient-sufficient and deficient conditions. Our findings show a substantial correlation between autophagy and increased cancer cell death in the presence of 5-FU, with negligible effects on normal cells. Experimental data revealed that nutritional deprivation augmented cell death in the presence of 5-FU through mitochondrial membrane damage and excessive reactive oxygen species (ROS) production, initiating apoptosis. Lipidation study also unveiled that under such combinatorial treatment cellular metabolism shifts from glucose to lipid biosynthesis. Overall, our experimental findings suggest that nutritional deprivation in combination with chemotherapeutic medication can be a new effective strategy to control hepatocellular carcinoma.

Identification of a novel NADPH generation reaction in the pentose phosphate pathway in Escherichia coli using mBFP.

NADPH is a redox cofactor that drives the anabolic reactions. Although major NADPH generation reactions have been identified in Escherichia coli, some minor reactions have not been identified. In the present study, we explored novel NADPH generation reactions by monitoring the fluorescence dynamics after the addition of carbon sources to starved cells, using a metagenome-derived blue fluorescent protein (mBFP) as an intracellular NADPH reporter. Perturbation analyses were performed on a glucose-6-phosphate isomerase (PGI) deletion strain and its parental strain. Interestingly, mBFP fluorescence increased not only in the parental strain but also in the ΔPGI strain after the addition of xylose. Because the ΔPGI strain cannot metabolize xylose through the oxidative pentose phosphate pathway, this suggests that an unexpected NADPH generation reaction contributes to an increase in fluorescence. To unravel this mystery, we deleted the NADPH generation enzymes including transhydrogenase, isocitrate dehydrogenase, NADP+-dependent malic enzyme, glucose-6-phosphate dehydrogenase (G6PDH), and 6-phosphogluconate dehydrogenase (6PGDH) in the ΔPGI strain, and revealed that G6PDH and 6PGDH contribute to an increase in fluorescence under xylose conditions. In vitro assays using purified enzymes showed that G6PDH can produce NADPH using erythrose-4-phosphate (E4P) as a substitute for glucose-6-phosphate. Because the Km (0.65 mM) for E4P was much higher than the reported intracellular E4P concentrations in E. coli, little E4P must be metabolized through this bypass in the parental strain. However, the flux would increase when E4P accumulates in the cells owing to genetic modifications. This finding provides a metabolic engineering strategy for generating NADPH to produce useful compounds using xylose as a carbon source.IMPORTANCEBecause NADPH is consumed during the synthesis of various useful compounds, enhancing NADPH regeneration is highly desirable in metabolic engineering. In this study, we explored novel NADPH generation reactions in Escherichia coli using a fluorescent NADPH reporter and found that glucose-6-phosphate dehydrogenase can produce NADPH using erythrose-4-phosphate as a substrate under xylose conditions. Xylose is an abundant sugar in nature and is an attractive carbon source for bioproduction. Therefore, this finding contributes to novel pathway engineering strategies using a xylose carbon source in E. coli to produce useful compounds that consume NADPH for their synthesis.

Biomimetic Single-Atom Nanozyme for Dual Starvation-Enhanced Breast Cancer Immunotherapy.

Cold exposure (CE) therapy is an innovative and cost-efficient cancer treatment that activates brown adipose tissue to compete for glucose uptake, leading to metabolic starvation in tumors. Exploring the combined antitumor mechanisms of CE and traditional therapies (such as nanocatalysis) is exciting and promising. In this study, a platelet membrane biomimetic single-atom nanozyme (SAEs) nanodrug (PFB) carrying bis-2-(5-phenylacetamido-1, 2, 4-thiadiazol-2-yl) ethyl sulfide (BPTES) is developed for use in cancer CE therapy. Owing to the platelet membrane modification, PFB can effectively target tumors. Upon entering cancer cells, the dual starvation effect induced by CE treatment and BPTES can significantly diminish intracellular glucose and ATP levels, resulting in a substantial reduction in cellular (glutathione) GSH, which can enhance the cytotoxic efficacy of reactive oxygen species generated by SAEs. This strategy not only boosts ROS production in tumors, but also strengthens immune responses, particularly by increasing memory T-cell abundance and suppressing distant tumor growth and tumor metastasis. Compared with SAEs therapy alone, this combined approach offers superior benefits for tumor immunotherapy. This study achieves a combination of CE and nanomedicines for the first time, providing new ideas for future nanomedicine combination therapy modalities.

Multiplex Genomic Tagging of Mammalian ATG8s to Study Autophagy.

Atg8 proteins play a crucial role in autophagy. There is a single Atg8 isoform in yeast, while mammals have up to seven homologs categorized into LC3s and GABARAPs. The GABARAP subfamily consists of GABARAP, GABARAPL1, and GABARAPL2/GATE16, implicated in various stages along the pathway. However, the intricacies among GABARAP proteins are complex and require a more precise delineation. Here, we introduce a new cellular platform to study autophagy using CRISPR/Cas9-mediated tagging of endogenous genes of the GABARAP subfamily with different fluorescent proteins. This platform allows robust examination of autophagy by flow cytometry of cell populations and monitoring of GABARAP homologs at single-cell resolution using fluorescence microscopy. Strikingly, the simultaneous labeling of the different endogenous GABARAPs allows the identification and isolation of autophagosomes differentially marked by these proteins. Using this system, we found that the different GABARAPs are associated with different autophagosomes. We argue that this new cellular platform will be crucial in studying the unique roles of individual GABARAP proteins in autophagy and other putative cellular processes.

A red cell membrane-camouflaged nanoreactor for enhanced starvation/chemodynamic/ion interference therapy for breast cancer.

In this study, a multifunctional Cu-doped CaO2 nanoreactor loaded with GOx and camouflaged with a folic acid-modified cell membranewas developed for breast cancer treatment. The as-developed composite nanoreactor showed a synergistic effect on calcium overload to damage mitochondria, thus killing tumor cells to achieve ion interference therapy (IIT). The loaded GOx could deplete glucose to "starve" tumor cells. The H2O2 released by CaO2 decomposition and enzyme catalytic reactions from GOx could not only be highly toxic in the tumor microenvironment but also enhance the efficiency of chemodynamic therapy (CDT) with Cu2+. The red blood cell membranes modified by folic acid achieved a combination of active targeting and passive targeting, thereby enhancing the targeting ability of the as-prepared multifunctional composite nanoreactor and prolonging its retention time at the tumor sites for more than 48 h.

Impact of Nutrient Starvation on Biofilm Formation in Pseudomonas aeruginosa: An Analysis of Growth, Adhesion, and Spatial Distribution.

Objectives: This study investigates the impact of nutrient availability on the growth, adhesion, and biofilm formation of Pseudomonas aeruginosa ATCC 27853 under static conditions. Methods: Bacterial behaviour was evaluated in nutrient-rich Luria-Bertani (LB) broth and nutrient-limited M9 media, specifically lacking carbon (M9-C), nitrogen (M9-N), or phosphorus (M9-P). Bacterial adhesion was analysed microscopically during the transition from reversible to irreversible attachment (up to 120 min) and during biofilm production/maturation stages (up to 72 h). Results: Results demonstrated that LB and M9 media supported bacterial growth, whereas nutrient-starved conditions halted growth, with M9-C and M9-N inducing stationary phases and M9-P leading to cell death. Fractal analysis was employed to characterise the spatial distribution and complexity of bacterial adhesion patterns, revealing that nutrient-limited conditions affected both adhesion density and biofilm architecture, particularly in M9-C. In addition, live/dead staining confirmed a higher proportion of dead cells in M9-P over time (at 48 and 72 h). Conclusions: This study highlights how nutrient starvation influences biofilm formation and bacterial dispersion, offering insights into the survival strategies of P. aeruginosa in resource-limited environments. These findings should contribute to a better understanding of biofilm dynamics, with implications for managing biofilm-related infections and industrial biofouling.

Understanding the crucial role of phosphate and iron availability in regulating root nodule symbiosis.

The symbiosis between legumes and nitrogen-fixing bacteria (rhizobia) is instrumental in sustaining the nitrogen cycle and providing fixed nitrogen to the food chain. Both partners must maintain an efficient nutrient exchange to ensure a successful symbiosis. This mini-review highlights the intricate phosphate and iron uptake and homeostasis processes taking place in legumes during their interactions with rhizobia. The coordination of transport and homeostasis of these nutrients in host plants and rhizobia ensures an efficient nitrogen fixation process and nutrient use. We discuss the genetic machinery controlling the uptake and homeostasis of these nutrients in the absence of rhizobia and in symbiotic conditions with this soil bacteria. We also highlight the genetic impact of the availability of phosphate and iron to coordinate the activation of the genetic programs that allow legumes to engage in symbiosis with rhizobia. Finally, we discuss how the transcription factor Phosphate Starvation Response (PHR) might be a crucial genetic element to integrate the nitrogen, iron, and phosphate plant's needs while interacting with rhizobia. Understanding the coordination of the iron and phosphate uptake and homeostasis can lead us to better harness the ecological benefits of the legume-rhizobia symbiosis, even under adverse environmental conditions.

Comparation on the responses and resilience of single-anammox system and synergistic partial-denitrification/anammox system to long-term nutrient starvation: Performance and metagenomic insights.

Starvation disturbance was a common problem in biological sewage treatment processes. However, understanding about the responses and resilience of different active anammox biomass in autotrophic and heterotrophic systems to long-term nutrient starvation remains limited. This study compared responses and potential recovery mechanisms of autotrophic single-Anammox and heterotrophic synergistic partial-denitrification/anammox (PD/anammox) systems to prolonged starvation (31-40 days). After starvation, total inorganic nitrogen (TIN) removal efficiency of single-Anammox and synergistic PD/anammox systems decreased to 62.16 % and 78.52 %, respectively, of their original level. After the nutrient resupply, the performance of both systems gradually recovered to a similar-to-pre-starvation level at the rate of 1.26 %/day and 1.89 %/day, respectively. Compared with single-Anammox system, complex synergistic relationship of microorganisms and effective quorum sensing (QS) regulation strategies might mitigate the negative influences were caused by starvation and ensure the performance quickly return of synergistic PD/anammox system. This study would contribute to promote the application of Anammox technology.

Enhancement of the reactivation process of long-term starved anammox granular sludge with gravel balls: Microbial succession and metabolic impact.

Anaerobic ammonium oxidation (Anammox) process is an economical and energy-efficient method of wastewater nitrogen removal. However, they are highly susceptible to starvation stress caused by sudden environmental changes. Rapid reactivation of starved anammox sludge is a crucial method to address seed sludge shortages and expand practical applications. This study investigated the impact of gravel balls on the reactivation of long-term starved anammox granular sludge (628 days). The results showed that gravel balls enhanced the recovery of nitrogen removal performance in starved anammox sludge, with nitrogen removal efficiency being 19.88% higher than the control group at the end of the recovery phase. The gravel balls also increased extracellular polymeric substance (EPS) secretion, contributing to the stability of the anammox system. Furthermore, the gravel balls promoted the proliferation of anammox bacteria, with the relative abundance of anammox bacteria reaching 38.25% on the 80th day. The analyses of microbial functions indicated that gravel balls facilitated cross-feeding and co-metabolism among microbes, while enhancing quorum sensing associated with anammox bacteria, forming a multifunctional community network centered on anammox bacteria. This indicates that gravel balls can effectively accelerate the reactivation process of long-term starved anammox sludge, aiding the reutilization of long-term starved anammox sludge.

Notch signaling pathway suppresses mRNA expression of hexokinase 2 under nutrient-poor conditions in U87-MG glioma cells.

Control of nutrient homeostasis plays a central role in cell proliferation/survival during embryonic development and tumor growth. Activation of the Notch signaling pathway, a major contributor to cell-cell interactions, is a potential mechanism for cell adaptation to nutrient-poor conditions. Our previous study also demonstrated that during embryogenesis when nutrients such as glutamine and growth factors are potentially maintained at lower levels, Notch signaling suppresses mRNA expression of hexokinase 2 (hk2), which is a glycolysis-associated gene, in the central nervous system. However, whether and how the genetic regulation of HK2 via Notch signaling contributes to cellular adaptability to nutrient-poor environments remains unknown. In this study, we performed gene expression analysis using a U87-MG human glioma cell line and revealed that under conditions where both glutamine and serum were absent, Notch signaling was activated and HK2 expression was downregulated by Notch signaling. We also found that Notch-mediated HK2 suppression was triggered in a Notch ligand-selective manner. Furthermore, HK2 was shown to inhibit cell proliferation of U87-MG gliomas, which might depend on Notch signaling activity. Together, our findings suggest the involvement of Notch-mediated HK2 suppression in an adaptive mechanism of U87-MG glioma cells to nutrient-poor conditions.

Impact of Sulfur Deficiency and Excess on the Growth and Development of Soybean Seedlings.

Sulfur is a critical element for plant growth and development, serving as a component of amino acids (cysteine and methionine), iron-sulfur clusters, proteins, glutathione, coenzymes, and auxin precursors. Deficiency or low concentrations of sulfur in the soil can lead to significant growth retardation in plants. The objective of our study was to examine the effects of sulfur (S) deficiency and excess on morphological symptoms, sulfur and nitrogen (N) metabolism, as well as antioxidant activity in soybean. We found that S starvation decreased the fine root length, biomass, and activity, and the chlorophyll content was reduced, while excess sulfur promotes lateral root growth. In contrast to sulfur excess, sulfur deficiency inhibits N and S metabolism levels in both subsurface and above-ground parts, and induced the expression of some sulfur transporters (SULTRs). In this study, we created soybean hairy root lines overexpressing the SULTR gene (GmSULTR2;1a) to observe metabolic changes following sulfur deficiency treatment. The results showed that GmSULTR2;1a saved the sulfur-deficient phenotype, and the antioxidant enzyme activity was much higher than that of the wildtype in the absence of sulfur. Our study revealed the important role of sulfur element in soybean growth and development and the regulation of sulfur deficiency by GmSULTR2;1a.

Inferring the feeding history of the castor bean tick, Ixodes ricinus from lipid and body measurements.

The ability to determine when ticks last fed and assign them to a specific feeding cohort is important in attempts to explain their population dynamics; the biochemical measurement of stored lipid, has been widely used for this purpose. However, when relating feeding history to behaviour or infection status, a non-destructive approach to its assessment would be of value and, to this end, previous studies have attempted to use morphometric indices. Within any instar, the sclerotised scutal components of the body will not vary with increasing starvation while the alloscutal components will, and the resulting ratio should provide a measure of time since feeding. Here, the aim was to determine whether such a morphological ratio (described here as the hunger index) changed predictably with starvation in Ixodes ricinus L. (Ixodida: Ixodidae). For this a cohort of 300 I. ricinus nymphs was collected from the field in February 2021 and starved in a humidified incubator at 15°C and 80% relative humidity (RH). Every 2 weeks, 50 nymphs selected at random were removed and killed by freezing; morphometric measurement was followed by the measurement of lipid using a standard spectrophotometric approach. Both hunger index and stored lipid changed significantly with increasing starvation and were positively correlated with each other. However, the change in morphometric ratio was relatively slight (11%) over 9 weeks and the variation was high. The data suggest therefore that morphological measurements could be used to provide, at best, only broad categorisation of the hunger status of individual I. ricinus ticks in the field.

Crystal structure and function of a phosphate starvation responsive protein phosphatase, GmHAD1-2 regulating soybean root development and flavonoid metabolism.

Phosphate (Pi) availability is well known to regulate plant root growth. However, it remains largely unknown how flavonoid synthesis participates in affecting plant root growth in response to Pi starvation. In the study, the crystal structure of a plant protein phosphatase, GmHAD1-2, was dissected using X-ray crystallography for the first time. It was revealed that GmHAD1-2 contained a modified Rossmannoid class of α/ß folds with three layered α/ß sandwich. Transcripts of GmHAD1-2 were increased by Pi starvation in soybean roots, especially in lateral root tips. GmHAD1-2 suppression or overexpression significantly influenced soybean lateral root length and number, as well as phosphorus (P) content. Furthermore, GmHAD1-2 was found to interact with a chalcone reductase, GmCHR1. Suppression of GmHAD1-2 significantly changed the flavonoid biosynthesis pathway in soybean roots. Taken together, the results highlight that GmHAD1-2 can regulate soybean root growth by influencing flavonoid metabolism.

Translational profiling of stress-induced small proteins uncovers an unexpected connection among distinct signaling systems.

Signaling networks in bacteria enable sensing and adaptation to challenging environments by activating specific genes that help counteract stressors. Small proteins (≤ 50 amino acids long) are a rising class of bacterial stress response regulators. Escherichia coli encodes over 150 small proteins, most of which lack known phenotypes and their biological roles remain elusive. Using magnesium limitation as a stressor, we investigate small proteins induced in response to stress using ribosome profiling, RNA sequencing, and transcriptional reporter assays. We uncover 17 small proteins with increased translation initiation, a majority of which are transcriptionally upregulated by the PhoQ-PhoP two-component signaling system, crucial for magnesium homeostasis. Next, we describe small protein-specific deletion and overexpression phenotypes, which underscore the physiological significance of their expression in low magnesium stress. Most remarkably, our study reveals that a small membrane protein YoaI is an unusual connector of the major signaling networks - PhoR-PhoB and EnvZ-OmpR in E. coli, advancing our understanding of small protein regulators of cellular signaling.

Impact of extended starvation conditions on bioelectrocatalytic activity of a methane-producing microbial electrolysis cell.

The performance of a methane-producing microbial electrolysis cell (MEC) markedly relies on the activity and resilience of its electroactive anodic biofilm. Here, the capability of an MEC anodic biofilm to recover following extended starvation periods (90 days) and to function under different applied anode potentials (i.e., +0.20 and -0.10 V, vs. Standard Hydrogen Electrode-SHE) was investigated. Cyclic voltammetry proved to be an insightful means to characterize the biofilm electrocatalytic activity and to track the dynamics of biofilm reactivation. Under all tested conditions the anodic biofilm rapidly and completely recovered from starvation in less than 144 h. However, starvation reduced the electron transfer redundancy of the biofilm causing the disappearance of redox sites operating at the more positive potentials (around 0.0 V vs. SHE) and retaining those having a formal potential lower than -0.18 V vs. SHE. This study presents compelling evidence for the resilience and efficiency of methane-producing MEC.

One-Pot Synthesis of a pH-Sensitive MOF Integrated with Glucose Oxidase for Amplified Tumor Photodynamic/Photothermal Therapy.

Photothermal therapy (PTT) and photodynamic therapy (PDT) provide targeted approaches to cancer treatment, but each therapy has inherent limitations such as insufficient tissue penetration, uneven heat distribution, extreme hypoxia, and overexpressed HSP90 in tumor cells. To address these issues, herein, by encapsulating the IR780 dye and glucose oxidase (GOx) enzyme within ZIF-8 nanoparticles, we created a versatile system capable of combining photodynamic and enhanced photothermal therapy. The integration of the IR780 dye facilitated the generation of reactive oxygen species and hyperthermia upon light activation, enabling dual-mode cancer cell ablation. Moreover, GOx catalyzes the decomposition of glucose into gluconic acid and hydrogen peroxide, leading to the inhibition of ATP production and downregulation of heat shock protein 90 (HSP90) expression, sensitizing cancer cells to heat-induced cytotoxicity. This synergistic combination resulted in significantly improved therapeutic outcomes. Both in vitro and in vivo results validated that the nanoplatform demonstrated superior specificity and favorable therapeutic responses. Our innovative approach represents a promising strategy for overcoming current limitations in cancer treatments and offers the potential for clinical translation in the future.