Intratumor injected gold molecular clusters for NIR-II imaging and cancer therapy.

Surgical resections of solid tumors guided by visual inspection of tumor margins have been performed for over a century to treat cancer. Near-infrared (NIR) fluorescence labeling/imaging of tumor in the NIR-I (800 to 900 nm) range with systemically administrated fluorophore/tumor-targeting antibody conjugates have been introduced to improve tumor margin delineation, tumor removal accuracy, and patient survival. Here, we show Au25 molecular clusters functionalized with phosphorylcholine ligands (AuPC, ~2 nm in size) as a preclinical intratumorally injectable agent for NIR-II/SWIR (1,000 to 3,000 nm) fluorescence imaging-guided tumor resection. The AuPC clusters were found to be uniformly distributed in the 4T1 murine breast cancer tumor upon intratumor (i.t.) injection. The phosphocholine coating afforded highly stealth clusters, allowing a high percentage of AuPC to fill the tumor interstitial fluid space homogeneously. Intra-operative surgical navigation guided by imaging of the NIR-II fluorescence of AuPC allowed for complete and non-excessive tumor resection. The AuPC in tumors were also employed as a photothermal therapy (PTT) agent to uniformly heat up and eradicate tumors. Further, we performed in vivo NIR-IIb (1,500 to 1,700 nm) molecular imaging of the treated tumor using a quantum dot-Annexin V (QD-P3-Anx V) conjugate, revealing cancer cell apoptosis following PTT. The therapeutic functionalities of AuPC clusters combined with rapid renal excretion, high biocompatibility, and safety make them promising for clinical translation.

Salinomycin and IR780-loaded upconversion nanoparticles influence biological behavior of liver cancer stem cells by persistently activating the MAPK signaling pathway.

The combination of chemotherapy and phototherapy has emerged as a promising therapeutic approach for enhancing the efficacy of cancer treatment and mitigating drug resistance. Salinomycin (SAL), a polyether antibiotic, exhibits potent cytotoxicity against chemotherapy-resistant cancer cells. IR780 iodide, a novel photosensitive reagent with excellent near-infrared (NIR) light absorption and photothermal conversion abilities, is suitable for use in photothermal therapy for cancers. However, both SAL and IR780 exhibit hydrophobic properties that limit their clinical applicability. Upconversion nanoparticles (UCNPs) are an emerging class of fluorescent probe materials capable of emitting high-energy photons upon excitation by low-energy NIR light. The UCNPs not only function as nanocarriers for drug delivery but also serve as light transducers to activate photosensitizers for deep-tissue photodynamic therapy. Here, to enhance the targeting and bioavailability of hydrophobic drugs in liver cancer stem cells (LCSCs), we employ distearoyl phosphorethanolamine-polyethylene glycol (DSPE-PEG) to encapsulate SAL and IR780 on the surface of UCNPs. Cell viability was evaluated using the CCK-8 assay. Cell migration was assessed by the Transwell Boyden Chamber. The activation of the mitogen-activated protein kinase (MAPK) signaling pathway was measured via western blot. The results demonstrated successful loading of both IR780 and SAL onto the UCNPs, and the SAL and IR780-loaded UCNPs (UISP) exhibited a robust photothermal effect under NIR light irradiation. The UISP effectively inhibited the viability of HCCLM3 and LCSCs. Under NIR light irradiation, the UISP further suppressed HCCLM3 viability but had no impact on LCSC viability; however, it could further inhibit LCSC migration. Meanwhile, under NIR light irradiation, the UISP persistently activated the MAPK pathway more significantly in LCSCs. These findings suggest that exposure to NIR light results in persistent activation of the MAPK pathway by UISP, thereby influencing the biological behavior of LCSCs and enhancing their therapeutic efficacy against liver cancer.

Au Nanorods Activated the Zn/Ce Composites with Cancer Cell Specific Cytotoxicity for Enhanced Chemodynamic Therapy.

Chemodynamic therapy based on the Fenton reaction has been developed as an extremely promising modality for cancer therapeutics. In this study, a core-shell structure nanoplatform was constructed by a Au nanorod externally encapsulating Ce/Zn-based composites (ACZO). The nanoparticles can catalyze the generation of reactive oxygen species (ROS) under acidic conditions and effectively consume existing glutathione (GSH) to destroy the redox balance within the tumor. Moreover, the decomposition of the nanocomplexes under acidic conditions releases large amounts of zinc ions, leading to zinc overload in cancer cells. The photothermal effect generated by the Au nanorods not only provides photothermal therapy (PTT) but also augments the catalytic reaction and ions action mentioned above. This facile strategy to improve the efficacy of chemodynamic therapy by the photothermal enhancement of catalytic activity and zinc ion release provides a promising perspective for potential tumor treatment.

Inhalable Polymeric Microparticles for Phage and Photothermal Synergistic Therapy of Methicillin-Resistant Staphylococcus aureus Pneumonia.

Acute methicillin-resistant Staphylococcus aureus (MRSA) pneumonia is a common and serious lung infection with high morbidity and mortality rates. Due to the increasing antibiotic resistance, toxicity, and pathogenicity of MRSA, there is an urgent need to explore effective antibacterial strategies. In this study, we developed a dry powder inhalable formulation which is composed of porous microspheres prepared from poly(lactic-co-glycolic acid) (PLGA), internally loaded with indocyanine green (ICG)-modified, heat-resistant phages that we screened for their high efficacy against MRSA. This formulation can deliver therapeutic doses of ICG-modified active phages to the deep lung tissue infection sites, avoiding rapid clearance by alveolar macrophages. Combined with the synergistic treatment of phage therapy and photothermal therapy, the formulation demonstrates potent bactericidal effects in acute MRSA pneumonia. With its long-term stability at room temperature and inhalable characteristics, this formulation has the potential to be a promising drug for the clinical treatment of MRSA pneumonia.

An Injectable Photothermal-Fusing Hydrogel: Achieving Temperature-Controllable Mild Photothermal Therapy to Reverse Chemotherapy-Induced Immune Tolerance.

Mild photothermal therapy (M-PTT) can induce immunogenic cell death (ICD) to reverse the immune tolerance caused by low-dose chemotherapy. However, it still needs convenient strategies to control temperature during M-PTT. In this work, the phase change material lauric acid (LA, melting point 43 °C) was introduced to construct nanoparticles loaded with deferoxamine mesylate (DFO) and cisplatin (CDDP), which were mixed into a supramolecular hydrogel formed by polyvinylpyrrolidone (PVP)/tannic acid (TA)/Fe3+ to obtain FeTP@DLD/DLC. When the temperature reached 43 °C under laser irradiation, DFO was released from melted LA and destroyed the interaction between Fe3+ and TA to cut off the temperature increase, achieving a "photothermal fusing effect". Meanwhile, CDDP was released for low-dose chemotherapy, while the resulting immune tolerance was reversed by M-PTT-induced ICD. Finally, through a single administration, FeTP@DLD/DLC-mediated M-PTT synergized with chemotherapy achieved a potent antitumor effect. This work provided a convenient solution for the revitalization of these traditional antitumor therapies.

Scalable Drug-Mimicking Nanoplasmonic Therapy for Bradyarrhythmia in Cardiomyocytes.

Bradyarrhythmia poses a serious threat to human health, with chronic progression causing heart failure and acute onset leading to sudden death. In this study, we develop a scalable drug-mimicking nanoplasmonic therapeutic strategy by introducing gold nanorod (Au NR) mediated near-infrared (NIR) photothermal effects. An integrated sensing and regulation platform is established for in situ synchronized NIR laser regulation and electrophysiological property recording. The Au NR plasmonic regulation enables the restoration of normal cardiomyocyte rhythm from the bradyarrhythmia. By regulating the aspect ratio and concentration of Au NRs, as well as the intensity and time of NIR irradiation, we precisely optimized the plasmonic photothermal effect to explore effective therapeutic strategies. Furthermore, mRNA sequencing revealed a significant increase in the number of differentially expressed genes (DEGs) involved in the electrophysiological activities of cardiomyocytes following photothermal therapy. Au NR-mediated plasmonic photothermal therapy, as an efficient and noninvasive approach to bradyarrhythmia, holds profound implications for cardiology research.

Suitable Isolation Side Chains: A Simple Strategy for Simultaneously Improving the Phototherapy Efficacy and Biodegradation Capacities of Conjugated Polymer Nanoparticles.

Utilizing one molecule to realize combinational photodynamic and photothermal therapy upon single-wavelength laser excitation, which relies on a multifunctional phototherapy agent, is one of the most cutting-edge research directions in tumor therapy owing to the high efficacy achieved over a short course of treatment. Herein, a simple strategy of "suitable isolation side chains" is proposed to collectively improve the fluorescence intensity, reactive oxygen species production, photothermal conversion efficiency, and biodegradation capacity. Both in vitro and in vivo results reveal the practical value and huge potential of the designed biodegradable conjugated polymer PTD-C16 with suitable isolation side chains in fluorescence image-guided combinational photodynamic and photothermal therapy. These improvements are achieved through manipulation of aggregated states by only side chain modification without changing any conjugated structure, providing new insight into the design of biodegradable high-performance phototherapy agents.

Biological Applications of Thermoplasmonics.

Thermoplasmonics has emerged as an extraordinarily versatile tool with profound applications across various biological domains ranging from medical science to cell biology and biophysics. The key feature of nanoscale plasmonic heating involves remote activation of heating by applying laser irradiation to plasmonic nanostructures that are designed to optimally convert light into heat. This unique capability paves the way for a diverse array of applications, facilitating the exploration of critical biological processes such as cell differentiation, repair, signaling, and protein functionality, and the advancement of biosensing techniques. Of particular significance is the rapid heat cycling that can be achieved through thermoplasmonics, which has ushered in remarkable technical innovations such as accelerated amplification of DNA through quantitative reverse transcription polymerase chain reaction. Finally, medical applications of photothermal therapy have recently completed clinical trials with remarkable results in prostate cancer, which will inevitably lead to the implementation of photothermal therapy for a number of diseases in the future. Within this review, we offer a survey of the latest advancements in the burgeoning field of thermoplasmonics, with a keen emphasis on its transformative applications within the realm of biosciences.

Temperature Self-Limited Intelligent Thermo-chemotherapeutic Lipid Nanosystem for P-gp Reversal Time Window Matched Pulse Treatment of MDR Tumor.

Mild photothermal therapy (PTT) shows the potential for chemosensitization by tumor-localized P-glycoprotein (P-gp) modulation. However, conventional mild PTT struggles with real-time uniform temperature control, obscuring the temperature-performance relationship and resulting in thermal damage. Besides, the time-performance relationship and the underlying mechanism of mild PTT-mediated P-gp reversal remains elusive. Herein, we developed a temperature self-limiting lipid nanosystem (RFE@PD) that integrated a reversible organic heat generator (metal-phenolic complexes) and metal chelator (deferiprone, DFP) encapsulated phase change material. Upon NIR irradiation, RFE@PD released DFP for blocking ligand-metal charge transfer to self-limit temperature below 45 °C, and rapidly reduced P-gp within 3 h via Ubiquitin-proteasome degradation. Consequently, the DOX·HCl-loaded thermo-chemotherapeutic lipid nanosystem (RFE@PD-DOX) led to dramatically improved drug accumulation and 5-fold chemosensitization in MCF-7/ADR tumor models by synchronizing P-gp reversal and drug pulse liberation, achieving a tumor inhibition ratio of 82.42%. This lipid nanosystem integrated with "intrinsic temperature-control" and "temperature-responsive pulse release" casts new light on MDR tumor therapy.

A targeting nanoplatform for chemo-photothermal synergistic therapy of small-cell lung cancer.

The precise delivery of drugs to tumor sites and the thermoresistance of tumors remain major challenges in photothermal therapy (PTT). Somatostatin receptor 2 (SSTR2) is proposed as an ideal target for the precise treatment of SCLC. We developed a targeting nano-drug delivery system comprising anti-SSTR2 monoclonal antibody (MAb) surface-modified nanoparticles co-encapsulating Cypate and gambogic acid (GA). The formed SGCPNs demonstrated excellent monodispersity, physiological stability, preferable biocompatibility, and resultant efficient photothermal conversion efficacy. SGCPNs were quickly internalized by SSTR2-overexpressing SCLC cells, triggering the release of GA under acidic and near-infrared (NIR) laser irradiation environments, leading to their escape from lysosomes to the cytosol and then diffusion into the nucleus. SGCPNs can not only decrease the cell survival rate but also inhibit the activity of heat shock protein 90 (HSP90). SGCPNs can be precisely delivered to xenograft tumors of SSTR2-positive SCLC in vivo. Upon NIR laser irradiation, therapy of SGCPNs showed significant tumor regression. In conclusion, SGCPNs provide a new chemo-photothermal synergistic treatment strategy for targeting SCLC.

Prussian blue nanoparticles coated with tumor cell membranes for precise photothermal therapy and subsequent inflammation reduction.

The utilization of photothermal agents (PTAs) in photothermal therapy (PTT) is faced with challenges such as immune clearance and inadequate concentration, which consequently result in residual tumors and an increased risk of recurrence and metastasis. Conversely, excessive treatment can lead to heightened inflammation and inevitable harm to adjacent healthy tissues. To address these issues, we developed a nanosystem (M@PB) consisting of Prussian blue coated with tumor cell membrane for precise photothermal therapy (PTT) and subsequent reduction of inflammation. This system not only evades immune attack due to the homologous biological characteristics of the encapsulating cell membrane but also exhibits active targeting capabilities towards homologous tumors. Furthermore, it effectively reduces excessive phototoxicity by leveraging the distinctive photothermal and anti-inflammatory characteristics of PB nanoparticles. The resulting M@PB nanosystem demonstrates effective photothermal ablation under 808 nm laser irradiation while mitigating the inflammatory response through inhibiting of local production of inflammatory mediators. Our study provides valuable insights into achieving targeted PTT with high efficiency while minimizing post-treatment inflammatory responses.

Photothermal/photodynamic synergistic antibacterial study of MOF nanoplatform with SnFe2O4 as the core.

Drug-resistant bacterial infections cause significant harm to public life, health, and property. Biofilm is characterized by overexpression of glutathione (GSH), hypoxia, and slight acidity, which is one of the main factors for the formation of bacterial resistance. Traditional antibiotic therapy gradually loses its efficacy against multi-drug-resistant (MDR) bacteria. Therefore, synergistic therapy, which regulates the biofilm microenvironment, is a promising strategy. A multifunctional nanoplatform, SnFe2O4-PBA/Ce6@ZIF-8 (SBC@ZIF-8), in which tin ferrite (SnFe2O4, denoted as SFO) as the core, loaded with 3-aminobenzeneboronic acid (PBA) and dihydroporphyrin e6 (Ce6), and finally coated with zeolite imidazole salt skeleton 8 (ZIF-8). The platform has a synergistic photothermal therapy (PTT)/photodynamic therapy (PDT) effect, which can effectively remove overexpressed GSH by glutathione peroxidase-like activity, reduce the antioxidant capacity of biofilm, and enhance PDT. The platform had excellent photothermal performance (photothermal conversion efficiency was 55.7 %) and photothermal stability. The inhibition rate of two MDR bacteria was more than 96 %, and the biofilm clearance rate was more than 90 % (150 µg/mL). In the animal model of MDR S. aureus infected wound, after 100 µL SBC@ZIF-8+NIR (150 µg/mL) treatment, the wound area of mice was reduced by 95 % and nearly healed. The serum biochemical indexes and H&E staining results were within the normal range, indicating that the platform could promote wound healing and had good biosafety. In this study, we designed and synthesized multifunctional nanoplatforms with good anti-drug-resistant bacteria effect and elucidated the molecular mechanism of its anti-drug-resistant bacteria. It lays a foundation for clinical application in treating wound infection and promoting wound healing.

Pulsed Photothermal Therapy of Solid Tumors as a Precondition for Immunotherapy.

Photothermal therapy (PTT) refers to the use of plasmonic nanoparticles to convert electromagnetic radiation in the near infrared region to heat and kill tumor cells. Continuous wave lasers have been used clinically to induce PTT, but the treatment is associated with heat-induced tissue damage that limits usability. Here, the engineering and validation of a novel long-pulsed laser device able to induce selective and localized mild hyperthermia in tumors while reducing the heat affected zone and unwanted damage to surrounding tissue are reported. Long-pulsed PTT induces acute necrotic cell death in heat affected areas and the release of tumor associated antigens. This antigen release triggers maturation and stimulation of CD80/CD86 in dendritic cells in vivo that primes a cytotoxic T cell response. Accordingly, long-pulsed PTT enhances the therapeutic effects of immune checkpoint inhibition and increases survival of mice with bladder cancer. Combined, the data promote long-pulsed PTT as a safe and effective strategy for enhancing therapeutic responses to immune checkpoint inhibitors while minimizing unwanted tissue damage.

Light-Driven Biomimetic Nanomotors for Enhanced Photothermal Therapy.

Nanotechnology-based strategy has recently drawn extensive attention for the therapy of malignant tumors due to its distinct strengths in cancer diagnosis and treatment. However, the limited intratumoral permeability of nanoparticles is a major hurdle to achieving the desired effect of cancer treatment. Due to their superior cargo towing and reliable penetrating property, micro-/nanomotors (MNMs) are considered as one of the most potential candidates for the coming generation of drug delivery platforms. Here, near-infrared (NIR)-actuated biomimetic nanomotors (4T1-JPGSs-IND) are fabricated successfully and we demonstrate that 4T1-JPGSs-IND selectively accumulate in homologous tumor regions due to the effective homing ability. Upon laser irradiation, hyperthermia generated by 4T1-JPGSs-IND leads to self-thermophoretic motion and photothermal therapy (PTT) to ablate tumors with a deep depth, thereby improving the photothermal therapeutic effect for cancer management. The developed nanomotor system with multifunctionalities exhibits promising potential in biomedical applications to fight against various diseases.

Gene and Photothermal Combination Therapy: Principle, Materials, and Amplified Anticancer Intervention.

Gene therapy (GT) and photothermal therapy (PTT) have emerged as promising alternatives to chemotherapy and radiotherapy for cancer treatment, offering noninvasiveness and reduced side effects. However, their efficacy as standalone treatments is limited. GT exhibits slow response rates, while PTT is confined to local tumor ablation. The convergence of GT and PTT, known as GT-PTT, facilitated by photothermal gene nanocarriers, has attracted considerable attention across various disciplines. In this integrated approach, GT reciprocates PTT by sensitizing cellular response to heat, while PTT benefits GT by improving gene translocation, unpacking, and expression. Consequently, this integration presents a unique opportunity for cancer therapy with rapid response and improved effectiveness. Extensive efforts over the past few years have been dedicated to the development of GT-PTT, resulting in notable achievements and rapid progress from the laboratory to potential clinical applications. This comprehensive review outlines recent advances in GT-PTT, including synergistic mechanisms, material systems, imaging-guided therapy, and anticancer applications. It also explores the challenges and future prospects in this nascent field. By presenting innovative ideas and insights into the implementation of GT-PTT for enhanced cancer therapy, this review aims to inspire further progress in this promising area of research.

Propelling Multi-Modal Therapeutics of PEEK Implants through the Power of NO evolving Covalent Organic Frameworks (COFs).

The design and fabrication of NO-evolving core-shell nanoparticles (denoted as NC@Fe), comprised of BNN6-laden COF@Fe3 O4 nanoparticles, are reported. This innovation extends to the modification of 3D printed polyetheretherketone scaffolds with NC@Fe, establishing a pioneering approach to multi-modal bone therapy tailored to address complications such as device-associated infections and osteomyelitis. This work stands out prominently from previous research, particularly those relying on the use of antibiotics, by introducing a bone implant capable of simultaneous NO gas therapy and photothermal therapy (PPT). Under NIR laser irradiation, the Fe3 O4 NP core (photothermal conversion agent) within NC@Fe absorbs photoenergy and initiates electron transfer to the loaded NO donor (BNN6), resulting in controlled NO release. The additional heat generated through photothermal conversion further propels the NC@Fe nanoparticles, amplifying the therapeutic reach. The combined effect of NO release and PPT enhances the efficacy in eradicating bacteria over a more extensive area around the implant, presenting a distinctive solution to conventional challenges. Thorough in vitro and in vivo investigations validate the robust potential of the scaffold in infection control, osteogenesis, and angiogenesis, emphasizing the timeliness of this unique solution in managing complicated bone related infectious diseases.

Nanomaterial-Enabled Photothermal Heating and Its Use for Cancer Therapy via Localized Hyperthermia.

Photothermal therapy (PTT), which employs nanoscale transducers delivered into a tumor to locally generate heat upon irradiation with near-infrared light, shows great potential in killing cancer cells through hyperthermia. The efficacy of such a treatment is determined by a number of factors, including the amount, distribution, and dissipation of the generated heat, as well as the type of cancer cell involved. The amount of heat generated is largely controlled by the number of transducers accumulated inside the tumor, the absorption coefficient and photothermal conversion efficiency of the transducer, and the irradiance of the light. The efficacy of treatment depends on the distribution of the transducers in the tumor and the penetration depth of the light. The vascularity and tissue thermal conduction both affect the dissipation of heat and thereby the distribution of temperature. The successful implementation of PTT in the clinic setting critically depends on techniques for real-time monitoring and management of temperature.

Surface Engineering Enhances Vanadium Carbide MXene-Based Nanoplatform Triggered by NIR-II for Cancer Theranostics.

Despite the advantages of high tissue penetration depth, selectivity, and non-invasiveness of photothermal therapy for cancer treatment, developing NIR-II photothermal agents with desirable photothermal performance and advanced theranostics ability remains a key challenge. Herein, a universal surface modification strategy is proposed to effectively improve the photothermal performance of vanadium carbide MXene nanosheets (L-V2C) with the removal of surface impurity ions and generation of mesopores. Subsequently, MnOx coating capable of T1-weighted magnetic resonance imaging can be in situ formed through surface redox reaction on L-V2C, and then, stable nanoplatforms (LVM-PEG) under physiological conditions can be obtained after further PEGylation. In the tumor microenvironment irradiated by NIR-II laser, multivalent Mn ions released from LVM-PEG, as a reversible electronic station, can consume the overexpression of glutathione and catalyze a Fenton-like reaction to produce ·OH, resulting in synchronous cellular oxidative damage. Efficient synergistic therapy promotes immunogenic cell death, improving tumor-related immune microenvironment and immunomodulation, and thus, LVM-PEG can demonstrate high accuracy and excellent anticancer efficiency guided by multimodal imaging. As a result, this study provides a new approach for the customization of 2D surface strategies and the study of synergistic therapy mechanisms, highlighting the application of MXene-based materials in the biomedical field.

Image-Guided Photothermal and Immune Therapy of Tumors via Melanin-Producing Genetically Engineered Bacteria.

Photothermal therapy (PTT) is a new treatment modality for tumors. However, the efficient delivery of photothermal agents into tumors remains difficult, especially in hypoxic tumor regions. In this study, an approach to deliver melanin, a natural photothermal agent, into tumors using genetically engineered bacteria for image-guided photothermal and immune therapy is developed. An Escherichia coli MG1655 is transformed with a recombinant plasmid harboring a tyrosinase gene to produce melanin nanoparticles. Melanin-producing genetically engineered bacteria (MG1655-M) are systemically administered to 4T1 tumor-bearing mice. The tumor-targeting properties of MG1655-M in the hypoxic environment integrate the properties of hypoxia targeting, photoacoustic imaging, and photothermal therapeutic agents in an "all-in-one" manner. This eliminates the need for post-modification to achieve image-guided hypoxia-targeted cancer photothermal therapy. Tumor growth is significantly suppressed by irradiating the tumor with an 808 nm laser. Furthermore, strong antitumor immunity is triggered by PTT, thereby producing long-term immune memory effects that effectively inhibit tumor metastasis and recurrence. This work proposes a new photothermal and immune therapy guided by an "all-in-one" melanin-producing genetically engineered bacteria, which can offer broad potential applications in cancer treatment.

Reprogramming the Tumor Immune Microenvironment Through Activatable Photothermal Therapy and GSH depletion Using Liposomal Gold Nanocages to Potentiate Anti-Metastatic Immunotherapy.

Cancer immunotherapy offers significant clinical benefits for patients with advanced or metastatic tumors. However, immunotherapeutic efficacy is often hindered by the tumor microenvironment's high redox levels, leading to variable patient outcomes. Herein, a therapeutic liposomal gold nanocage (MGL) is innovatively developed based on photo-triggered hyperthermia and a releasable strategy by combining a glutathione (GSH) depletion to remodel the tumor immune microenvironment, fostering a more robust anti-tumor immune response. MGL comprises a thermosensitive liposome shell and a gold nanocage core loaded with maleimide. The flexible shell promotes efficient uptake by cancer cells, enabling targeted destruction through photothermal therapy while triggering immunogenic cell death and the maturation of antigen-presenting cells. The photoactivated release of maleimide depletes intracellular GSH, increasing tumor cell sensitivity to oxidative stress and thermal damage. Conversely, GSH reduction also diminishes immunosuppressive cell activity, enhances antigen presentation, and activates T cells. Moreover, photothermal immunotherapy decreases elevated levels of heat shock proteins in tumor cells, further increasing their sensitivity to hyperthermia. In summary, MGL elicited a robust systemic antitumor immune response through GSH depletion, facilitating an effective photothermal immunotherapeutic strategy that reprograms the tumor microenvironment and significantly inhibits primary and metastatic tumors. This approach demonstrates considerable translational potential and clinical applicability.