Cold-induced calreticulin OsCRT3 conformational changes promote OsCIPK7 binding and temperature sensing in rice.

Unusually low temperatures caused by global climate change adversely affect rice production. Sensing cold to trigger signal network is a key base for improvement of chilling tolerance trait.  Here, we report that Oryza sativa Calreticulin 3 (OsCRT3) localized at the endoplasmic reticulum (ER) exhibits conformational changes under cold stress, thereby enhancing its interaction with CBL-interacting protein kinase 7 (OsCIPK7) to sense cold. Phenotypic analyses of OsCRT3 knock-out mutants and transgenic overexpression lines demonstrate that OsCRT3 is a positive regulator in chilling tolerance. OsCRT3 localizes at the ER and mediates increases in cytosolic calcium levels under cold stress. Notably, cold stress triggers secondary structural changes of OsCRT3 and enhances its binding affinity with OsCIPK7, which finally boosts its kinase activity. Moreover, Calcineurin B-like protein 7 (OsCBL7) and OsCBL8 interact with OsCIPK7 specifically on the plasma membrane. Taken together, our results thus identify a cold-sensing mechanism that simultaneously conveys cold-induced protein conformational change, enhances kinase activity, and Ca2+ signal generation to facilitate chilling tolerance in rice.

Nanomedicines for an Enhanced Immunogenic Cell Death-Based In Situ Cancer Vaccination Response.

Cancer vaccines have shown tremendous potential in preventing and treating cancer by providing immunogenic antigens to initiate specific tumor immune responses. An in situ vaccine prepared from an autologous tumor can mobilize a patient's own tumor cell lysate as a reservoir of specific antigens, thus triggering a broad immune response and diverse antitumor immunity in an individually tailored manner. Its efficacy is much better than that of conventional vaccines with a limited number of epitopes. Several conventional therapies, including radiotherapy (RT), chemotherapeutics, photodynamic therapy (PDT), and photothermal therapy (PTT) can activate an anticancer in situ vaccine response by inducing immunogenic cell death (ICD), triggering the exposure of tumor-associated antigens (TAAs), cancerous testis antigens, neoantigens, and danger-associated molecular patterns (DAMPs) with low cost. However, the immunogenicity of dying tumor cells is low, making released antigens and DAMPs insufficient to initiate a robust immune response against malignant cancer. Moreover, the immunosuppressive tumor microenvironment (TME) severely hinders the infiltration and sensitization of effector immune cells, causing tolerogenic immunological effects.Herein, we mainly focus on the research in developing nanoplatforms to surmount the major challenges met by ICD-based in situ vaccines. We first summarized a variety of nanotechnologies that enable enhanced immunogenicity of dying cancer cells by enhancing antigenicity and adjuvanticity. The robust antigenicity was obtained via regulating the tumor cells death mode or the dying state to amplify the recognition of tumor debris by professional antigen-presenting cells (APCs). The adjuvanticity was potentiated by raising the level or intensifying the activity of endogenous adjuvants or promoting the intelligent delivery of exogenous immunostimulants to activate immune cell recruitment and promote antigen presentation. Additionally, versatile approaches to reverse immunosuppressive TME to boost the in situ tumor vaccination response are also highlighted in detail. On one hand, by modulating the cell metabolism in TME, the expansion and activity of effector versus immunosuppressive cells can be optimized to improve the efficiency of in situ vaccines. On the other hand, regulating cellular components in TME, such as reversing adverse immune cell phenotypes or inhibiting the activity of interstitial cells, can also significantly enhance the ICD-based antitumor immunotherapy effect. Finally, our viewpoint on the future challenges and opportunities in this hopeful area is presented. We expect that this Account can offer much more insight into the design, planning, and development of cutting-edge in situ tumor vaccine platforms, promoting more attention and academic-industry collaborations, accelerating the advanced progress of in situ tumor vaccine-based immunotherapy in the clinic.

Staphylococcus aureus Enterotoxin B Is a Cofactor of Food Allergy beyond a Superantigen.

Staphylococcus aureus enterotoxin B (SEB), one of the most common bacterial toxins in food contamination, has been poorly understood in relationship to food allergy outcomes. To investigate whether the ingestion of enterotoxins in food allergens could affect the development of food allergy, OVA-sensitized female BALB/c mice were challenged with OVA added with different doses of SEB or LPS. Allergic symptoms, such as diarrhea rate and hypothermia, could be aggravated in mice challenged with OVA and a low dose of SEB. The increased differentiation of Th2 and reduced expression of CD103 in dendritic cells was found in mice coexposed to SEB and OVA. Additionally, there was an increasing differentiation of Th1 induced by a high dose of SEB. The expression of ST2+ in intestinal mast cells was also increased in mice sensitized with a low dose of SEB and OVA. Employing several in vitro cell culture models showed that the secretion of IL-33 from intestinal epithelial cells and IL-4 from group 2 innate lymphoid cells, activation of bone marrow-derived dendritic cells, and differentiation of naive T cells were induced by SEB and OVA. Our work proved that challenge with low-dose SEB and OVA partly aggravated the food allergy, suggesting a (to our knowledge) new finding of the potential cofactor of food allergy and that the contamination of SEB in food allergens deserves attention for allergic and normal individuals.

A Dual-Cascade Activatable Near-Infrared Fluorescent Probe for Precise Intraoperative Imaging of Tumor.

Accurate intraoperative tumor delineation is critical to achieving successful surgical outcomes. However, conventional techniques typically suffer from poor specificity and low sensitivity and are time-consuming, which greatly affects intraoperative decision-making. Here, we report a cascade activatable near-infrared fluorescent (NIRF) probe IR780SS@CaP that can sequentially respond to tumor acidity and elevated glutathione levels for accurate intraoperative tumor localization. Compared with nonactivatable and single-factor activatable probes, IR780SS@CaP with a cascade strategy can minimize nonspecific activation and false positive signals in a complicated biological environment, affording a superior tumor-to-normal tissue ratio to facilitate the delineation of abdominal metastases. Small metastatic lesions that were less than 1 mm in diameter can be precisely identified by IR780SS@CaP and completely excised under NIRF imaging guidance. This study could benefit tumor diagnosis and image-guided tumor surgery by providing real-time information and reliable decision support, thus reducing the risk of both recurrence and complications to improve patient outcomes.

Goblet cell-associated antigen passage: A gatekeeper of the intestinal immune system.

Effective delivery of luminal antigens to the underlying immune system is the initial step in generating antigen-specific responses in the gut. However, a large body of information regarding the immune response activation process remains unknown. Recently, goblet cells (GCs) have been reported to form goblet cell-associated antigen passages (GAPs). Luminal antigens can be transported inside GAPs and reach subepithelial immune cells to induce antigen-specific immune responses, contributing largely to gut homeostasis and the prevention of some intestinal diseases like allergic enteritis and bacterial translocation. In this article, we summarized recent observations on the formation of intestinal GAPs and their roles in mucosal immunity. We hope that this review can offer a fresh perspective and valuable insights for clinicians and researchers interested in studying the intestinal immune system.

Specific and nonspecific nutritional interventions enhance the development of oral tolerance in food allergy.

The goal of food allergy (FA) prevention and treatment is to induce oral tolerance (OT). Appropriate nutritional interventions are essential to induce OT to food allergens. This review introduces the mechanism of OT and the importance of early nutritional interventions, and then firstly summarizes specific nutritional factors to induce the development of OT of FA, including proteins, vitamins, fatty acids, saccharides and probiotics. The regulatory mechanism mainly induces the development of tolerance by increasing local or systemic protective regulatory T cells (Tregs) to suppress FA, while the gut microbiota may also be changed to maintain intestinal homeostasis. For allergens-specific OT, the disruption to the structure of proteins and epitopes is critical for the induction of tolerance by hydrolyzed and heated proteins. Vitamins (vitamin A, D), fatty acids, saccharides and probiotics as allergens nonspecific OT also induce the development of OT through immunomodulatory effects. This review contributes to our understanding of OT in FA through nutritional interventions. Nutritional interventions play an important role in the induction of OT, and offer promising approaches to reduce allergy risk and alleviate FA. Moreover, due to the importance and diversity of nutrition, it must be the future trend of induction of OT in FA.

Iron-based metal-organic framework co-loaded with buthionine sulfoximine and oxaliplatin for enhanced cancer chemo-ferrotherapy via sustainable glutathione elimination.

BACKGROUND: Emerging ferroptosis-driven therapies based on nanotechnology function either by increasing intracellular iron level or suppressing glutathione peroxidase 4 (GPX4) activity. Nevertheless, the therapeutic strategy of simultaneous iron delivery and GPX4 inhibition remains challenging and has significant scope for improvement. Moreover, current nanomedicine studies mainly use disulfide-thiol exchange to deplete glutathione (GSH) for GPX4 inactivation, which is unsatisfactory because of the compensatory effect of continuous GSH synthesis. METHODS: In this study, we design a two-in-one ferroptosis-inducing nanoplatform using iron-based metal-organic framework (MOF) that combines iron supply and GPX4 deactivation by loading the small molecule buthionine sulfoxide amine (BSO) to block de novo GSH biosynthesis, which can achieve sustainable GSH elimination and dual ferroptosis amplification. A coated lipid bilayer (L) can increase the stability of the nanoparticles and a modified tumor-homing peptide comprising arginine-glycine-aspartic acid (RGD/R) can achieve tumor-specific therapies. Moreover, as a decrease in GSH can alleviate resistance of cancer cells to chemotherapy drugs, oxaliplatin (OXA) was also loaded to obtain BSO&OXA@MOF-LR for enhanced cancer chemo-ferrotherapy in vivo. RESULTS: BSO&OXA@MOF-LR shows a robust tumor suppression effect and significantly improved the survival rate in 4T1 tumor xenograft mice, indicating a combined effect of dual amplified ferroptosis and GSH elimination sensitized apoptosis. CONCLUSION: BSO&OXA@MOF-LR is proven to be an efficient ferroptosis/apoptosis hybrid anti-cancer agent. This study is of great significance for the clinical development of novel drugs based on ferroptosis and apoptosis for enhanced cancer chemo-ferrotherapy.

Real-time risk ranking of emerging epidemics based on optimized moving average prediction limit-taking the COVID-19 pandemic as an example.

BACKGROUND: Mathematical models to forecast the risk trend of the COVID-19 pandemic timely are of great significance to control the pandemic, but the requirement of manual operation and many parameters hinders their efficiency and value for application. This study aimed to establish a convenient and prompt one for monitoring emerging infectious diseases online and achieving risk assessment in real time. METHODS: The Optimized Moving Average Prediction Limit (Op-MAPL) algorithm model analysed real-time COVID-19 data online and was validated using the data of the Delta variant in India and the Omicron in the United States. Then, the model was utilized to determine the infection risk level of the Omicron in Shanghai and Beijing. RESULTS: The Op-MAPL model can predict the epidemic peak accurately. The daily risk ranking was stable and predictive, with an average accuracy of 87.85% within next 7 days. Early warning signals were issued for Shanghai and Beijing on February 28 and April 23, 2022, respectively. The two cities were rated as medium-high risk or above from March 27 to April 20 and from April 24 to May 5, indicating that the pandemic had entered a period of rapid increase. After April 21 and May 26, the risk level was downgraded to medium and became stable by the algorithm, indicating that the pandemic had been controlled well and mitigated gradually. CONCLUSIONS: The Op-MAPL relies on nothing but an indicator to assess the risk level of the COVID-19 pandemic with different data sources and granularities. This forward-looking method realizes real-time monitoring and early warning effectively to provide a valuable reference to prevent and control infectious diseases.

Post-Remedial Oxygen Supply: A New Perspective on Photodynamic Therapy to Suppress Tumor Metastasis.

Photodynamic therapy (PDT) holds great promise in tumor therapy due to high safety, efficacy, and specificity. However, the risk of increased metastasis in hypoxic tumors after oxygen-dependent PDT remains underestimated. Here, we propose a post-PDT oxygen supply (POS) strategy to reduce the risk of metastasis. Herein, biocompatible and tumor-targeting Ce6@BSA and PFC@BSA nanoparticles were constructed for PDT and POS in a 4T1-orthotropic breast cancer model. PDT with Ce6@BSA nanoparticles increased tumor metastasis via the HIF-1α signaling pathway, whereas POS significantly reduced the PDT-triggered metastasis by blocking this pathway. Furthermore, POS, with clinical protocols and an FDA-approved photosensitizer (hypericin), and oxygen inhalation reduced PDT-induced metastasis. Our study findings indicate that PDT may increase the risk of tumor metastasis and that POS may solve this problem. POS can reduce the metastasis resulting not only from PDT but also from other oxygen-dependent treatments such as radiotherapy and sonodynamic therapy.

Effective removal of phosphorus from high phosphorus steel slag using carbonized rice husk.

High phosphorus steel slag and carbonized rice husk are two common wastes characterized by high generation and low secondary use values. Through the reduction of high phosphorus steel slag by biomass, both wastes were fully utilized, thus reducing the negative impact on the environment. In this study, variables such as temperature, time, and amount of reactants were changed to determine the optimal conditions for the reaction of steel slag with carbonized rice husk at high temperatures. The actual amount of reducing agent consumed during the reduction was significantly greater than that predicted by theoretical calculations. Adding three carbon equivalent of carbonized rice husk and maintaining at 1500°C for 30 min could remove 79.25% of P2O5 in the slag. By modeling the material cycle in which high phosphorus steel slag was treated with biomass, the product could be used for crop growth. Meanwhile, the reduced iron and residual steel slag can be used to make steel again, thereby leading to a sharp reduction in fossil fuel usage and greenhouse gas emissions in this process.

Two-stage cultivation strategies for optimal production of Ganoderma pellets with potential application in the vegan food industry.

The vegan food industry is gaining popularity nowadays. Ganoderma sp. is mainly used in the health and food industries as a medicinal, edible mushroom with high nutritional potential. Through two-stage cultivation methods, the study optimized the production of mycelial pellets for vegetarian food. When soybean powder was used as an alternative to egg yolk powder to meet vegetarian requirements, the number of pellets increased from 1100 to 1800 particles/dL, however, the pellet diameter reduced up to 22% (3.2-2.6 mm). The culture was expanded to the second stage using the Taguchi method coupled with Plackett-Burman Design and quantification by ImageJ software for enlarging pellets size. The optimal conditions were 10 mL of the first-stage broth inoculum, yeast powder (0.5 g/dL), glucose (0.5 g/dL), and MgSO4 (0.2 g/dL) at 100 rpm in the dark for 7 days. In 500 mL pilot scale production, the biomass yield was 0.31 g/dL and 3400 mycelium pellets/dL with a 5.2 mm diameter with appearance characteristics suitable for direct development as food. The study may help to develop a novel pellet food of filamentous fungi for the vegetarian market. Supplementary Information: The online version contains supplementary material available at 10.1007/s13197-023-05719-x.

An Activatable Near-Infrared Fluorescent Probe for Precise Detection of the Pulmonary Metastatic Tumors: A Traditional Molecule Having a Stunning Turn.

An accurate detection of lung metastasis is of great significance for making better treatment choices and improving cancer prognosis, but remains a big challenge in clinical practice. In this study, we propose a reinventing strategy to develop a pH-activatable near-infrared (NIR) fluorescent nanoprobe, pulmonary metastasis tracer (denoted as PMT), based on assembly of NIR dye IR780 and calcium phosphate (CaP). By delicately tuning the intermolecular interactions during the assembly process and dye doping content, as well as the synthetic condition of probe, the fluorescence of PMT could be finely adjusted via the tumor acidity-triggered disassembly. Notably, the selected PMT9 could sharply convert subtle pH variations into a distinct fluorescence signal to generate high fluorescence ON/OFF contrast, dramatically reducing the background signals. Benefiting from such preferable features, PMT9 is able to precisely identify not only the tumor sites in orthotopic lung cancer models but also the pulmonary metastases in mice with remarkable signal-to-background ratio (SBR). This study provides a unique strategy to turn shortcomings of traditional dye IR780 during in vivo imaging into advantages and further expand the application of fluorescent probe to image lung associated tumor lesions.

A Potent Strategy of Combinational Blow Toward Enhanced Cancer Chemo-Photodynamic Therapy via Sustainable GSH Elimination.

Excessive glutathione (GSH), which is produced owing to abnormal metabolism of tumor cells, scavenges photo-induced reactive oxygen species (ROS) and consumes chemotherapeutic drugs, thereby attenuating the efficacy of photodynamic therapy and chemotherapy, respectively. Predominant strategies for GSH inhibition involve its chemical depletion, which only leads to a temporary therapeutic effect because GSH is replenished via various compensatory routes in tumor cells. Here, a versatile GSH-inhibiting nanosystem (termed PCNPs) for persistent synergistic therapy of cancer is reported. The porous skeleton of PCNPs allows easy encapsulation of buthionine sulfoximine (BSO) to sustainably suppress the biosynthesis of GSH. Thus, PCNPs not only demonstrate a prolonged release of BSO and improve drug utilization for efficient chemotherapy, but also act as an efficient photo-induced singlet oxygen radical generator that prevents the loss of ROS, thereby enhancing photodynamic therapy. In addition, the liposomal coating prevents cargo release in the blood, improves the accumulation of PCNPs at the tumor site, and promotes the cellular uptake of oxaliplatin and BSO. This strategy is applicable to ROS-based therapy and chemotherapy, which are suppressed by GSH, and may further enhance the synergistic effect of GSH-restrained therapy.

Novel perspective on the regulation of food allergy by probiotic: The potential of its structural components.

Food allergy (FA) is a global public health issue with growing prevalence. Increasing evidence supports the strong correlation between intestinal microbiota dysbiosis and food allergies. Probiotic intervention as a microbiota-based therapy could alleviate FA effectively. In addition to improving the intestinal microbiota disturbance and affecting microbial metabolites to regulate immune system, immune responses induced by the recognition of pattern recognition receptors to probiotic components may also be one of the mechanisms of probiotics protecting against FA. In this review, it is highlighted in detail about the regulatory effects on the immune system and anti-allergic potential of probiotic components including the flagellin, pili, peptidoglycan, lipoteichoic acid, exopolysaccharides, surface (S)-layer proteins and DNA. Probiotic components could enhance the function of intestinal epithelial barrier as well as regulate the balance of cytokines and T helper (Th) 1/Th2/regulatory T cell (Treg) responses. These evidences suggest that probiotic components could be used as nutritional or therapeutic agents for maintaining immune homeostasis to prevent FA, which will contribute to providing new insights into the resolution of FA and better guidance for the development of probiotic products.

A C1q domain-containing protein in Pinctada fucata contributes to the innate immune response and elimination of the pathogen.

The C1q domain-containing proteins (C1qDCs) in bivalve mollusks primarily exist as the globular head C1q proteins (ghC1qs), for the N-terminal collagen domains were very rare in bivalves, although widespread in C1qDCs of vertebrates. In this work, the C1qDC protein with only a ghC1q domain (named as Pf-ghC1q) was identified from Pinctada fucata, and molecular characterization, gene expression, and functional studies were also conducted. The full-length cDNA sequence of Pf-ghC1q was 738 bp long, containing a signal peptide of 23 residues encoded. Pf-ghC1q was clustered with some C1qDCs from other invertebrates in the phylogenetic tree analysis, rather than vertebrates. Pf-ghC1q was detected in all tested tissues, including the mantle, hemocyte, digestive gland, gill, and adductor muscle. Moreover, the expression levels of Pf-ghC1q were up-regulated in all tested tissues after the challenge with Vibrio alginolyticus 4 h later. The expression level of Pf-ghC1q was inhibited by specific si-276, and the low level of Pf-ghC1q affected the phagocytosis efficiency of V. alginolyticus by hemocytes. These results indicated that Pf-ghC1q may participate in the target recognition of V. alginolyticus and the phagocytosis process in the immune response of P. fucata.

First comprehensive proteome analysis of lysine crotonylation in Streptococcus agalactiae, a pathogen causing meningoencephalitis in teleosts.

BACKGROUD: Streptococcus agalactiae is a common colonizer of the rectovaginal tract and lead to infectious diseases of neonatal and non-pregnant adults, which also causes infectious disease in fish and a zoonotic risk as well. Lysine crotonylation (Kcr) is a kind of histone post-translational modifications discovered in 2011. In yeast and mammals, Kcr function as potential enhancers and promote gene expression. However, lysine crotonylation in S. agalactiae has not been studied yet. METHODS: In this study, the crotonylation profiling of fish pathogen, S. agalactiae was investigated by combining affinity enrichment with LC MS/MS. The Kcr modification of several selected proteins were further validated by Western blotting. RESULTS: In the present study, we conducted the proteome-wide profiling of Kcr in S. agalactiae and identified 241 Kcr sites from 675 screened proteins for the first time. Bioinformatics analysis showed that 164 sequences were matched to a total of six definitively conserved motifs, and many of them were significantly enriched in metabolic processes, cellular process, and single-organism processes. Moreover, four crotonylation modified proteins were predicted as virulence factors or to being part of the quorum sensing system PTMs on bacteria. The data are available via ProteomeXchange with identifier PXD026445. CONCLUSIONS: These data provide a promising starting point for further functional research of crotonylation in bacterial virulence in S. agalactiae.

Retrospective analysis of traumatic triradiate cartilage injury in children.

BACKGROUND: To summarize and analyze the epidemiological characteristics, treatment and corresponding curative effect of triradiate cartilage injury(TCI) in children after trauma, to provide a theoretical basis for early diagnosis and improvement of treatment. METHODS: The TCI was classified according to Bucholz classification, and the final curative effect was evaluated with Harris Hip Score and imaging examination during follow-up. Finally, a comprehensive analysis was made by reviewing the cases in the literature combined with the patients in our hospital. RESULTS: A total of 15 cases (18 hips) of triradiate cartilage injuries were collected in our hospital. There was 1 hip with type I injury, nine hips with type II injury, two hips with type IV injury, one hip with type V injury and five hips with type VI injury. Among the 12 cases with complete follow-up, the bone bridge was found in or around the triradiate cartilage in 8 cases, early fusion of triradiate cartilage occurred in 5 patients, 3 cases had hip dysplasia, 4 cases had a subluxation of the femoral head, and HHS was excellent in 8 cases and good in 4 cases. CONCLUSION: The early diagnosis of TCI is still a difficult problem. Conservative treatment is often the first choice. The overall prognosis of acetabular fractures involving triradiate cartilage is poor. The formation of the bone bridge in triradiate cartilage usually indicates the possibility of premature closure, which may lead to severe complications of post-traumatic acetabular dysplasia and subluxation of the femoral head.

Identification, characterization, and expressions profile analysis of growth hormone receptors (GHR1 and GHR2) in Hybrid grouper (Epinephelus fuscoguttatus ♀ × Epinephelus polyphekadion ♂).

Growth hormone is an essential hormone that plays essential roles in growth, metabolism, cellular differentiation, immunity and reproduction in fish, by means of the growth hormone receptors. The encoding cDNA growth hormone receptors (GHR1 and GHR2) were cloned and characterized from Hybrid grouper (Epinephelus fuscoguttatus♀ × Epinephelus polyphekadion♂). Sequence analysis of the cloned GHR1 was observed as containing 2176, which comprised an ORF of 1842 bp, 5 UTR of 6 bp and 3 UTR of 328 bp, with 612 amino acids encoding proteins, while GHR2 was observed as containing 1824 bp that encompassed an ORF of 708 bp, 5 UTR of 48 bp and 3 UTR of 1068 bp with 235 amino acids encoding proteins. Relative mRNA expression of GHR1 and GHR2 in the liver and muscle was found to be highest respectively. Our findings provide vital statistics of GHRs likely to play a significant role in the growth of the fish.

Identification and expression analysis of cobia (Rachycentron canadum) liver-related miRNAs under hypoxia stress.

At present, due to the influence of global warming, seasonal change, diurnal variation, and eutrophication of the water body, hypoxia has become one of the major factors limiting the stable development of cobia (Rachycentron canadum) culture. In this study, the miRNAs involved in hypoxia stress were screened, and the target genes of miRNAs were annotated and analyzed. The results showed that a total of 184 conservative microRNA (miRNA) and 121 newly predicted miRNA were obtained by sequencing the liver of control (C) and hypoxic (dissolved oxygen, DO (2.64 ± 0.25) mg/L; 3 h) (S) groups. The pathways involved in energy metabolism included starch and sucrose metabolism (ko00500), glycosaminoglycan degradation (ko00531), and galactose metabolism (ko00052). The results indicate that the body maintains physiological activities by regulating some important pathways at the transcriptional level under hypoxia stress, such as the conversion of aerobic metabolism and anaerobic metabolism, the reduction of energy consumption, and the promotion of red blood cell proliferation to maintain the homeostasis of the body.

Harnessing Hypoxia-Dependent Cyanine Photocages for In†Vivo Precision Drug Release.

Photocaging holds promise for the precise manipulation of biological events in space and time. However, current near-infrared (NIR) photocages are oxygen-dependent for their photolysis and lack of timely feedback regulation, which has proven to be the major bottleneck for targeted therapy. Herein, we present a hypoxia-dependent photo-activation mechanism of dialkylamine-substituted cyanine (Cy-NH) accompanied by emissive fragments generation, which was validated with retrosynthesis and spectral analysis. For the first time, we have realized the orthogonal manipulation of this hypoxia-dependent photocaging and dual-modal optical signals in living cells and tumor-bearing mice, making a breakthrough in the direct spatiotemporal control and in vivo feedback regulation. This unique photoactivation mechanism overcomes the limitation of hypoxia, which allows site-specific remote control for targeted therapy, and expands the photo-trigger toolbox for on-demand drug release, especially in a physiological context with dual-mode optical imaging under hypoxia.