Red-Light Triggered H-Abstraction Photoinitiators for the Efficient Oxygen-Independent Therapy of Hypoxic Tumors.

The clinical application of photodynamic therapy (PDT) is limited by oxygen-dependence and side effects caused by photosensitizer residues. Photoinitiators based on the H-abstraction reaction can address these challenges because they can generate alkyl radical-killing cells independently of oxygen and undergo rapid bleaching following H-abstraction. Nonetheless, the development of photoinitiators for PDT has been impeded by the absence of effective design strategies. Herein, we have developed aryl-ketone substituted cyanine (ACy-R), the first red-light triggered H-abstraction photoinitiators for hypoxic cancer therapy. These ACy-R molecules inherited the near-infrared absorption of cyanine dye, and aryl-ketone modification imparted H-abstraction capability. Experimental and quantum calculations revealed that modifying the electron-withdrawing groups of the aryl (e.g., ACy-5F) improved the contribution of the O atom to the photon excitation process promoting intersystem crossing and H-abstraction ability. Particularly, ACy-5F rapidly penetrated cells and enriched in the endoplasmic reticulum. Even under severe hypoxia, ACy-5F initiated red-light induced H-abstraction with intracellular biomolecules, inducing necroptosis and ferroptosis. Moreover, ACy-5F was degraded after H-abstraction, thus avoiding the side effects of long-term phototoxicity after therapy. This study not only provides a crucial molecular tool for hypoxic tumors therapy, but also presents a promising strategy for the development of multifunctional photosensitizers and photoinitiators.

Activating Iterative Revolutions of the Cancer-Immunity Cycle in Hypoxic Tumors with a Smart Nano-Regulator.

The activation of sequential events in the cancer-immunity cycle (CIC) is crucial for achieving effective antitumor immunity. However, formidable challenges, such as innate and adaptive immune resistance, along with the off-target adverse effects of nonselective immunomodulators, persist. In this study, a tumor-selective nano-regulator named PNBJQ has been presented, focusing on targeting two nonredundant immune nodes: inducing immunogenic cancer cell death and abrogating immune resistance to fully activate endogenous tumor immunity. PNBJQ is obtained by encapsulating the immunomodulating agent JQ1 within a self-assembling system formed by linking a Type-I photosensitizer to polyethylene glycol through a hypoxia-sensitive azo bond. Benefiting from the Type-I photosensitive mechanism, PNBJQ triggers the immunogenic cell death of hypoxic tumors under near-infrared (NIR) light irradiation. This process resolves innate immune resistance by stimulating sufficient cytotoxic T-lymphocytes. Simultaneously, PNBJQ smartly responds to the hypoxic tumor microenvironment for precise drug delivery, adeptly addressing adaptive immune resistance by using JQ1 to downregulate programmed death ligand 1 (PD-L1) and sustaining the response of cytotoxic T lymphocytes. The activatable synergic photoimmunotherapy promotes an immune-promoting tumor microenvironment by activating an iterative revolution of the CIC, which remarkably eradicates established hypoxic tumors and suppresses distal lesions under low light dose irradiation.

Gram-negative bacteria recognition and photodynamic elimination by Zn-DPA based sensitizers.

The abuse and overuse of antibiotics let drug-resistant bacteria emerges. Antibacterial photodynamic therapy (APDT) has shown outstanding merits to eliminate the drug-resistant bacteria via cytotoxic reactive oxygen species produced by irradiating photosensitizer. However, most of photosensitizers are not effective for Gram-negative bacteria elimination. Herein conjugates of NBS, a photosensitizer, linked with one (NBS-DPA-Zn) or two (NBS-2DPA-Zn) equivalents of zinc-dipicolylamine (Zn-DPA) have been designed to achieve the functional recognition of different bacteria. Due to the cationic character of NBS and metal transfer channel effect of Zn-DPA, NBS-DPA-Zn exhibited the first regent to distinguish P. aeruginosa from other Gram-negative bacteria. Whereas NBS-2DPA-Zn showed broad-spectrum antibacterial effect because the two arm of double Zn-DPA enhanced interactions with anionic membranes of bacteria, led the bacteria aggregation and thus provided the efficacy of APDT to bacteria and corresponding biofilm. In combination with a hydrogel of Pluronic, NBS-2DPA-Zn@gel shows promising clinical application in mixed bacterial diabetic mouse model infection. This might propose a new method that can realize functional identification and elimination of bacteria through intelligent regulation of Zn-DPA, and shows excellent potential for antibacterial application.

A PROTAC Augmenter for Photo-Driven Pyroptosis in Breast Cancer.

Proteolysis targeting chimera (PROTAC) has recently emerged as a promising strategy for inducing post-translational knockdown of target proteins in disease treatment. The degradation of bromodomain-containing protein 4 (BRD4), an essential nuclear protein for gene transcription, induced by PROTAC is proposed as an epigenetic approach to treat breast cancer. However, the poor membrane permeability and indiscriminate distribution of PROTAC in vivo results in low bioavailability, limiting its development and application. Herein, a nano "targeting chimera" (abbreviated as L@NBMZ) consisting of BRD4-PROTAC combined with a photosensitizer, to serve as the first augmenter for photo-driven pyroptosis in breast cancer, is developed. With excellent BRD4 degradation ability, high biosafety, and biocompatibility, L@NBMZ blocks gene transcription by degrading BRD4 through proteasomes in vivo, and surprisingly, induces the cleavage of caspase-3. This type of caspase-3 cleavage is synergistically amplified by light irradiation in the presence of photosensitizers, leading to efficient photo-driven pyroptosis. Both in vitro and in vivo outcomes demonstrate the remarkable anti-cancer efficacy of this augmenter, which significantly inhibits the lung metastasis of breast cancer in vivo. Thus, the photo-PROTAC "targeting chimera" augmenter construction strategy may pave a new way for expanding PROTAC applications within anti-cancer paradigms.

Lipid Droplet Targeting Type I Photosensitizer for Ferroptosis via Lipid Peroxidation Accumulation.

As an iron-dependent lipid peroxidation (LPO) mediated cell death pathway, ferroptosis offers promises for anti-tumor treatment. Photodynamic therapy (PDT) is an ideal way to generate reactive oxygen species (ROS) for LPO. However, the conventional PDT normally functions on subcellular organelles, such as endoplasmic reticulum, mitochondria, and lysosome, causing rapid cell death before triggering ferroptosis. Herein, the first lipid droplet (Ld)-targeting type I photosensitizer (PS) with enhanced superoxide anion (O2 -· ) production, termed MNBS, is reported. The newly designed PS selectively localizes at Ld in cells, and causes cellular LPO accumulation by generating sufficient O2 -· upon irradiation, and subsequently induces ferroptosis mediated chronical PDT, achieving high-efficient anti-tumor PDT in hypoxia and normoxia. Theoretical calculations and comprehensive characterizations indicate that the Ld targeting property and enhanced O2 -· generation of MNBS originate from the elevated H-aggregation tendency owing to dispersed molecular electrostatic distribution. Further in vivo studies using MNBS-encapsulated liposomes demonstrate the excellent anti-cancer efficacy as well as anti-metastatic activity. This study offers a paradigm of H-aggregation reinforced type I PS to achieve ferroptosis-mediated PDT.

Aryl-Modified Pentamethyl Cyanine Dyes at the C2' Position: A Tunable Platform for Activatable Photosensitizers.

Pentamethyl cyanine dyes are promising fluorophores for fluorescence sensing and imaging. However, advanced biomedical applications require enhanced control of their excited-state properties. Herein, a synthetic approach for attaching aryl substituents at the C2' position of the thio-pentamethine cyanine (TCy5) dye structure is reported for the first time. C2'-aryl substitution enables the regulation of both the twisted intramolecular charge transfer (TICT) and photoinduced electron transfer (PET) mechanisms to be regulated in the excited state. Modulation of these mechanisms allows the design of a nitroreductase-activatable TCy5 fluorophore for hypoxic tumor photodynamic therapy and fluorescence imaging. These C2'-aryl TCy5 dyes provide a tunable platform for engineering cyanine dyes tailored to sophisticated biological applications, such as photodynamic therapy.

Photoinduced Cuproptosis with Tumor-Specific for Metastasis-Inhibited Cancer Therapy.

Cuproptosis is a novel form of regulated cell death which guarantees to increase the efficacy of existing anticancer treatments that employ traditional apoptotic therapeutics. However, reducing the amount of undesirable Cu ions released in normal tissue and maximizing Cu-induced cuproptosis therapeutic effects at tumor sites are the major challenges. In this study, exploiting the chemical properties of copper ionophores and the tumor microenvironment, a novel method is developed for controlling the valence of copper ions that cause photoinduced cuproptosis in tumor cells. CJS-Cu nanoparticles (NPs) can selectively induce cuproptosis after cascade reactions through H2 O2 -triggered Cu2+ release, photoirradiation-induced superoxide radical (∙O2 - ) generation, and reduction of Cu2+ to Cu+ by ∙O2 - . The generated reactive oxygen species can result in glutathione depletion and iron-sulfur cluster protein damage and further augmented cuproptosis. CJS-Cu NPs effectively suppressed tumor growth and downregulated the expression of metastasis-related proteins, contributing to the complete inhibition of lung metastasis. Ultimately, this study suggests novel avenues for the manipulation of cellular cuproptosis through photochemical reactions.

Dipicolylamine-Zn Induced Targeting and Photo-Eliminating of Pseudomonas aeruginosa and Drug-Resistance Gram-Positive Bacteria.

The emergence of drug-resistant bacteria, particularly resistant strains of Gram-negative bacteria, such as Pseudomonas aeruginosa, poses a significant threat to public health. Although antibacterial photodynamic therapy (APDT) is a promising strategy for combating drug-resistant bacteria, actively targeted photosensitizers (PSs) remain unknown. In this study, a PS based on dipicolylamine (DPA), known as WZK-DPA-Zn, is designed for the selective identification of P. aeruginosa and drug-resistant Gram-positive bacteria. WZK-DPA-Zn exploits the synergistic effects of DPA-Zn2+ coordination and cellular uptake, which could effectively anchor P. aeruginosa within a brief period (10 min) without interference from other Gram-negative bacteria. Simultaneously, the cationic nature of WZK-DPA-Zn enhances its interaction with Gram-positive bacteria via electrostatic forces. Compared to traditional clinical antibiotics, WZK-DPA-Zn shows exceptional antibacterial activity without inducing drug resistance. This effectiveness is achieved using the APDT strategy when irradiated with white light or sunlight. The combination of WZK-DPA-Zn with Pluronic-based thermosensitive hydrogel dressings (WZK-DPA-Zn@Gel) effectively eliminates mixed bacterial infections and accelerates wound healing, thereby achieving a synergistic effect where "1+1>2." In summary, this study proposes a precise strategy employing DPA-Zn as the targeting moiety of a PS, facilitating the rapid elimination of P. aeruginosa and drug-resistant Gram-positive bacteria using APDT.

An Activatable Prodrug Nanosystem for Ultrasound-Driven Multimodal Tumor Therapy and Metastasis Inhibition.

Ultrasound, featuring deep tissue penetration and noninvasiveness, offers a new opportunity to activate functional materials in a tumor-selective manner. However, very few direct ultrasound-responsive redox systems are applicable under therapeutic ultrasound (1 MHz). Herein, the investigations on nanoprodrug of DHE@PEG-SS-DSPE are reported, which exhibit glutathione-activated release of dihydroethidium (DHE) in tumor cells. DHE is stable with good biosafety and is transformed into cytotoxic ethidium to induce DNA damage under medical ultrasound irradiation, accompanied by the generation of reactive oxygen species. Further, DHE@PEG-SS-DSPE could effectively induce ferroptosis through glutathione depletion, lipid peroxide accumulation, and downregulation of glutathione peroxidase 4. In vivo studies confirmed that DHE@PEG-SS-DSPE nanoparticles effectively inhibit both the growth of solid tumors and the expression of metastasis-related proteins in mice, thus effectively inhibiting lung metastasis. This DHE-based prodrug nanosystem could lay a foundation for the design of ultrasound-driven therapeutic agents.

Synchronized activating therapeutic nano-agent: Enhancement and tracing for hypoxia-induced chemotherapy.

Prodrug is a potential regime to overcome serious adverse events and off-target effects of chemotherapy agents. Among various prodrug activators, hypoxia stands out owing to the generalizability and prominence in tumor micro-environment. However, existing hypoxia activating prodrugs generally face the limitations of stringent structural requirements, the lack of feedback and the singularity of therapeutic modality, which is imputed to the traditional paradigm that recognition groups must be located at the terminus of prodrugs. Herein, a multifunctional nano-prodrug Mal@Cy-NTR-CB has been designed. In this nano-prodrug, a self-destructive tether is introduced to break the mindset, and achieves the activation by hypoxia of chemotherapy based on Chlorambucil (CB), whose efficacy can be augmented and traced by photodynamic therapy (PDT) and fluorescence from Cyanine dyes (Cy). In addition, Maleimide (Mal) carried by the nano-shells can regulate glutathione (GSH) content, preventing 1O2 scavenging, so as to realize PDT sensitization. Experiments demonstrate that Mal@Cy-NTR-CB specifically responds to hypoxic tumors, and achieve synchronous activation, enhancement and feedback of chemotherapy and PDT, inhibiting the tumor growth effectively. This study broadens the design ideas of activatable prodrugs and provides the possibility of multifunctional nano-prodrugs to improve the generalization and prognosis in precision oncology.

A GPX4-targeted photosensitizer to reverse hypoxia-induced inhibition of ferroptosis for non-small cell lung cancer therapy.

Ferroptosis therapy is gradually becoming a new strategy for the treatment of non-small cell lung cancer (NSCLC) because of its active iron metabolism. Because the hypoxic microenvironment in NSCLC inhibits ferroptosis heavily, the therapeutic effect of some ferroptosis inducers is severely limited. To address this issue, this work describes a promising photosensitizer ENBS-ML210 and its application against hypoxia of NSCLC treatment based on type I photodynamic therapy and glutathione peroxidase 4 (GPX4)-targeted ferroptosis. ENBS-ML210 can promote lipid peroxidation and reduce GPX4 expression by generating superoxide anion radicals under 660 nm light irradiation, which reverses the hypoxia-induced resistance of ferroptosis and effectively kills H1299 tumor cells. Finally, the excellent synergistic antitumor effects are confirmed both in vitro and in vivo. We firmly believe that this method will provide a new direction for the clinical treatment of NSCLC in the future.

Highly Efficient Photosensitizers with Molecular Vibrational Torsion for Cancer Photodynamic Therapy.

The development of highly effective photosensitizers (PSs) for photodynamic therapy remains a great challenge at present. Most PSs rely on the heavy-atom effect or the spin-orbit charge-transfer intersystem crossing (SOCT-ISC) effect to promote ISC, which brings about additional cytotoxicity, and the latter is susceptible to the interference of solvent environment. Herein, an immanent universal property named photoinduced molecular vibrational torsion (PVT)-enhanced spin-orbit coupling (PVT-SOC) in PSs has been first revealed. PVT is verified to be a widespread intrinsic property of quinoid cyanine (QCy) dyes that occurs on an extremely short time scale (10-10 s) and can be captured by transient spectra. The PVT property can provide reinforced SOC as the occurrence of ISC predicted by the El Sayed rules (1ππ*-3nπ*), which ensures efficient photosensitization ability for QCy dyes. Hence, QTCy7-Ac exhibited the highest singlet oxygen yield (13-fold higher than that of TCy7) and lossless fluorescence quantum yield (ΦF) under near-infrared (NIR) irradiation. The preeminent photochemical properties accompanied by high biosecurity enable it to effectively perform photoablation in solid tumors. The revelation of this property supplies a new route for constructing high-performance PSs for achieving enhanced cancer phototherapy.

Photo-Induced Electron Transfer-Triggered Structure Deformation Promoting Near-Infrared Photothermal Conversion for Tumor Therapy.

Photothermal therapy (PTT) is a promising approach to cancer treatment. Heptamethine cyanine (Cy7) is an attractive photothermal reagent because of its large molar absorption coefficient, good biocompatibility, and absorption of near-infrared irradiation. However, the photothermal conversion efficiency (PCE) of Cy7 is limited without ingenious excitation-state regulation. In this study, the photothermal conversion ability of Cy7 is efficiently enhanced based on photo-induced electron transfer (PET)-triggered structural deformation. Three Cy7 derivatives, whose Cl is replaced by carbazole, phenoxazine, and phenothiazine at the meso-position (CZ-Cy7, PXZ-Cy7, and PTZ-Cy7), are presented as examples to demonstrate the regulation of the energy release of the excited states. Because the phenothiazine moiety exhibits an obvious PET-induced structural deformation in the excited state, which quenches the fluorescence and inhibits intersystem crossing of S1 →T1 , PTZ-Cy7 exhibits a PCE as high as 77.5%. As a control, only PET occurs in PXZ-Cy7, with a PCE of 43.5%. Furthermore, the PCE of CZ-Cy7 is only 13.0% because there is no PET process. Interestingly, PTZ-Cy7 self-assembles into homogeneous nanoparticles exhibiting passive tumor-targeting properties. This study provides a new strategy for excited-state regulation for photoacoustic imaging-guided PTT with high efficiency.

Piezoelectric Metal-Organic Frameworks Based Sonosensitizer for Enhanced Nanozyme Catalytic and Sonodynamic Therapies.

The regulation of electrostatic electric fields through electrical stimulation is an efficient method to increase the catalytic activity of nanozymes and improve the therapeutic effect of nanozyme catalytic therapy. Piezoelectric materials, which are capable of generating a built-in electric field under ultrasound (US), not only improve the activity of nanozymes but also enable piezoelectric sonodynamic therapy (SDT). In this study, a sonosensitizer based on a Hf-based metal-organic framework (UIO-66) and Au nanoparticles (NPs) was produced. Under US irradiation, UIO-66 can generate a built-in electric field inside the materials, which promotes electron-hole separation and produces reactive oxygen species (ROS). The introduction of Au NPs facilitated the electron transfer, which inhibited the recombination of the electron-hole pairs and improved the piezoelectric properties of UIO-66. The value of the piezoelectric constant (d33) increased from 71 to 122 pmV-1 after the deposition of Au NPs. In addition, the intrinsic catalase and peroxidase activities of the Au NPs were increased 2-fold after the stimulation from the built-in electric field induced through US exposure. In vivo and in vitro experiments revealed that the proposed sonosensitizer can kill cancer cells and inhibit tumor growth in mice through the enhanced piezoelectric SDT and nanozyme catalytic therapy. The piezoelectric sensitizer proposed in this work proved to be an efficient candidate that can be used for multiple therapeutic modalities in tumor therapy.

Photothermal "nano-dot" reactivate "immune-hot" for tumor treatment via reprogramming cancer cells metabolism.

Cancer immunotherapy, despite its enormous application prospect, is trapped in the abnormal lactic acid metabolism of tumor cells that usually causes an immunosuppressive tumor microenvironment (ITM). Inducing immunogenic cell death (ICD) not only sensitizes cancer cells to carcer immunity, but also leads to a great increase in tumor-specific antigens. It improves tumor condition from "immune-cold" to "immune-hot". Herein, a near-infrared photothermal agent NR840 was developed and encapsulated into tumor-targeted polymer DSPE-PEG-cRGD and carried lactate oxidase (LOX) by electrostatic interaction, forming self-assembling "nano-dot" PLNR840 with high loading capacity for synergistic antitumor photo-immunotherapy. In this strategy, PLNR840 was swallowed by cancer cells, then dye NR840 was excited at 808 nm to generate heat inducing tumor cell necrosis, which further caused ICD. LOX could serve as a catalyst, reducing lactic acid efflux via regulation of cell metabolism. More importantly, the consumption of intratumoral lactic acid could substantially reverse ITM, including promoting the polarization of tumor-associated macrophages from M2 to M1 type, inhibiting the viability of regulatory T cells for sensitizing photothermal therapy (PTT). After the combination of αPD-L1 (programmed cell death protein ligand 1), PLNR840 restored CD8+ T-cell activity that thoroughly cleaned the pulmonary metastasis of breast cancer in 4T1 mouse model and cured hepatocellular carcinoma in Hepa1-6 mouse model. This study provided an effective PTT strategy to boost "immune-hot" and reprogrammed tumor metabolism for antitumor immunotherapy.

A near-infrared GPX4 fluorescent probe for non-small cell lung cancer imaging.

Glutathione peroxidase 4 (GPX4) is overexpressed in non-small cell lung cancer (H1299) cells. In this work, a near-infrared fluorescent probe ENBO-ML210 was developed. In vitro and in vivo imaging results showed that ENBO-ML210 could target and visualize GPX4 in H1299 cells, exhibiting potential for the diagnosis of non-small lung cancer.

Urea-Bond Scission Induced by Therapeutic Ultrasound for Biofunctional Molecule Release.

Ultrasound-triggered remote control of biomolecular functions in cells provides unique advantages for us to interrogate nature. However, strategies to design therapeutic ultrasound-responsive functional molecules remain elusive, and rare ultrasound-cleavable chemical bonds have been developed to date. Herein, therapeutic ultrasound (1 MHz)-induced scission of urea bonds for drug release is demonstrated for the first time. Such a transformation has been verified to be initiated by hydroxyl radicals generated in the interior of cavitation bubbles, occurring specifically at the cavitation bubble-liquid interface. A series of urea-bond-containing prodrugs based on methylene blue (MB), namely MBUs, are designed. Upon sonication with low-intensity therapeutic ultrasound, the urea bonds linked with primary amines can be selectively cleaved, and free MB is released in a physiologically relevant environment, accompanied by recovered absorbance, fluorescence, and photosensitivity. Moreover, an FDA-approved alkylating agent (i.e., melphalan) bearing urea bond is also developed (MBU-Mel), successfully achieving ultrasound-triggered drug release in deep-seated cancer cells (mimic with 1 cm pigskin), showing the scalability of our ultrasound-responsive molecule platform in bioactive molecules release. This may set the starting point for therapeutic ultrasound-induced drug release, making a forward step in "sonopharmacology".

Precise gliomas therapy: Hypoxia-activated prodrugs sensitized by nano-photosensitizers.

Hypoxia is one of the prominent features of solid tumors. Hypoxia activated prodrugs (HAPs), selectively killing hypoxic cells, possess the potential to transform hypoxia from a nuisance to an advantage in precision therapy. Exhibiting a more significant hypoxic microenvironment, gliomas, as the most frequent and incurable neurological tumors, provide HAPs a more attractive therapeutic prospect. However, the insufficient hypoxia and the obstruction of the blood-brain barrier (BBB) severely limit the activation and bio-availability of HAPs. Herein, a novel nanoparticle iRGD@ZnPc + TPZ was designed and synthesized to achieve gliomas inhibition by encapsulating tirapazamine (TPZ) as a HAP and zinc phthalocyanine (ZnPc) as a photosensitizer to enhance hypoxia. iRGD@ZnPc + TPZ can realize breakthrough BBB, deep penetration, and significant retention in gliomas, which is attributed to the iRGD-mediated receptor targeting and active transport. After being internalized by tumor cells and radiated, ZnPc efficiently consumes intratumoral O2 to produce reactive oxygen species, which not only implements tumor suppression, but also intensify hypoxia to activate TPZ for amplifying chemotherapy. The photosensitizer-enhanced activation of HAPs inhibits gliomas growth. This study provides a new strategy with sensitizing and activating HAPs for gliomas treatment in clinical.

Photoredox catalysis may be a general mechanism in photodynamic therapy.

Elucidating the underlying photochemical mechanisms of action (MoA) of photodynamic therapy (PDT) may allow its efficacy to be improved and could set the stage for the development of new classes of PDT photosensitizers. Here, we provide evidence that "photoredox catalysis in cells," wherein key electron transport pathways are disrupted, could constitute a general MoA associated with PDT. Taking the cellular electron donor nicotinamide adenine dinucleotide as an example, we have found that well-known photosensitizers, such as Rose Bengal, BODIPY, phenoselenazinium, phthalocyanine, and porphyrin derivatives, are able to catalyze its conversion to NAD+. This MoA stands in contrast to conventional type I and type II photoactivation mechanisms involving electron and energy transfer, respectively. A newly designed molecular targeting photocatalyst (termed CatER) was designed to test the utility of this mechanism-based approach to photosensitizer development. Photoexcitation of CatER induces cell pyroptosis via the caspase 3/GSDME pathway. Specific epidermal growth factor receptor positive cancer cell recognition, high signal-to-background ratio tumor imaging (SBRTI = 12.2), and good tumor growth inhibition (TGI = 77.1%) are all hallmarks of CatER. CatER thus constitutes an effective near-infrared pyroptotic cell death photo-inducer. We believe the present results will provide the foundation for the synthesis of yet-improved phototherapeutic agents that incorporate photocatalytic chemistry into their molecular design.

ER-Targeting Cyanine Dye as an NIR Photoinducer to Efficiently Trigger Photoimmunogenic Cancer Cell Death.

Endoplasmic reticulum (ER) stress, caused by overproduction of reactive oxygen species (ROS), has been shown to be responsible for immunogenic cell death (ICD). Seeking ROS generator targeting ER is an optimal solution to efficiently induce ER stress. Despite clear indications of demand for ER-targeting photosensitizer, the alternative chemical tools remain limited. Herein, the first ER-localizable ICD photoinducer using thio-pentamethine cyanine dye (TCy5) to induce ER stress under mild near-infrared (NIR) irradiation has been developed. Within the ICD photoinducer design, polyfluorinated TCy5-Ph-3F possesses a selective tropism to ER accumulation and superior ROS generation capability in both normoxia and hypoxia conditions, which benefit from its low singlet-triplet gaps. Under NIR irradiation, cancer cells stained by TCy5-Ph-3F will lead to ER stress and induce massive emission of damage-associated molecular patterns, including calreticulin and heat-shock protein 70 exposure, high mobility group box 1 efflux, and adenosine triphosphate secretion. Dendritic cells maturation and CD8+ T cells activation in vivo also highlight the effectiveness. Therefore, the growth of abscopal tumors was substantially suppressed by the primary tumor treated with TCy5-Ph-3F and NIR irradiation. These results confer practical applicability that could provide a guideline for designing efficient ICD photoinducers, which will enable expanding organic molecular applications for cancer immunotherapy.