Cuproptosis, a novel approach utilizing copper carriers to trigger programmed cell death, exhibits promise for enhancing traditional therapies and activating robust adaptive immune responses. However, the uncontrolled release of Cu ions risks triggering cuproptosis in healthy tissues, potentially causing irreversible damage. To address this, we report on the use of a Cu-MOF (copper metal-organic framework) protective layer to regulate the biodegradation of copper-based nanomaterials. In situ formation of Cu-MOF on Cu2O nanocubes not only stabilizes the material under physiological conditions but also enhances its sonodynamic therapy (SDT) capabilities by establishing a Z-Scheme heterojunction. Upon SDT activation, the targeted Cu ion release at the tumor site triggers a cascade of reactions, generating reactive oxygen species (ROS) via Fenton-like processes and depleting glutathione (GSH). This ROS surge, combined with effective cuproptosis, modulates the immunosuppressive tumor microenvironment, inducing immunogenic cell death to eliminate primary tumors and inhibit metastasis. This study offers a new paradigm for the controlled integration of SDT, chemodynamic therapy (CDT), cuproptosis, and immunotherapy, achieving precise tumor-targeted treatment via controlled copper nanomaterial degradation.

Pancreatic cancer therapies such as chemotherapy and immunotherapy are hindered by the dense extracellular matrix known as physical barriers, leading to heterogeneity impeding the effective penetration of chemotherapeutic agents and activation of antitumor immune responses. To address this challenge, we developed a hybrid nanoassembly with a distinct core-satellite-like heterostructure, PLAF@P/T-PD, which is responsive to both internal pH/redox and external ultrasound stimulations. This heterostructural nanoassembly features a polymersome core encapsulating an ultrasound contrast agent perfluoropentane and a chemotherapeutic agent Taxol (PLAF@P/T) electrostatically coated with satellite-like polyplexes carrying an immune agonist dsDNA (PD), which brings about synergistic functions inside the pancreatic tumor. The PLAF@P/T core functions as an enhancer for intratumor delivery through size enlargement and charge conversion in response to reactive oxygen species (ROS) and low pH, which triggers polyplex release and enables ultrasound-assisted tumor-penetrating Taxol delivery. Meanwhile, the released cationic polyplexes function as nucleic nanomedicine preferentially engulfed by peripheral dendritic cells (DCs) for immune modulation. Animal studies in mouse orthotopic pancreatic tumor model demonstrated exceptional therapeutic efficacy against both primary and metastatic tumors, which underlines the potential of this heterostructural nanoplatform for overcoming the therapeutic challenges associated with the heterogeneous physical barrier hindering intratumor drug delivery in pancreatic cancer treatment.

Ferroptosis is an iron-dependent form of programmed cell death with the potential to reverse traditional cancer therapy resistance. The combination of ferroptosis with chemotherapy, photodynamic therapy and X-ray therapy has demonstrated remarkably improved therapeutic efficiency. Radiopharmaceutical therapy (RPT) is an emerging approach that achieves precise radiation to diseased tissues via radionuclide delivery. However, insufficient accumulation and retention of therapeutic radiopharmaceuticals in tumor region as well as cancer radioresistance impact treatment efficacy. Here, a nanoassembly of renal clearable ultrasmall iron nanoparticles (USINPs) and 131I-aPD-L1 is prepared via the affinity of fluorophenylboronic acid modified on the USINPs with 131I-aPD-L1. The 150 nm USINAs(131I-aPD-L1) nanoassembly is stable in blood circulation, effectively targets to the tumor and disassembles in the presence of ATP in the tumor microenvironment. Both in vitro and in vivo experiments prove that USINPs-induced ferroptosis boosted the tumor radiosensitization to 131I while 131I-mediated RPT further enhanced ferroptosis. Meanwhile, the immunogenic cell death caused by RPT and ferroptosis combined with PD-L1 immune checkpoint blockade therapy exhibits a strong antitumor immunity. This study provides a novel way to improve the tumor accumulation of ferroptosis inducer and radiopharmaceuticals, insights into the interaction between RPT and ferroptosis and an effective SPECT-guided ferroptosis-enhanced radio-immunotherapy.

Cuproptosis that utilizes copper ionophore to induce programmed cell death holds promise for enhancing the effectiveness of conventional anticancer therapies and triggering efficient adaptive immune responses. However, the non-tumor-specific release of Cu ions can induce cuproptosis and cause irreversible damage to normal tissues. To maximize the therapeutic effects of tumor-specific cuproptosis, this work reports for the first time the regulation of degradation behaviors of Cu-based nanomaterials using graphene quantum dots (GQDs) as a protection layer. The deposition of GQDs not only avoids the degradation of Cu2O nanocubes under normal physiological conditions, but also sensitizes their sonodynamic activity due to the formation of Z-scheme heterojunctions. The tumor-specific released Cu ions achieve the cascade amplification of reactive oxygen species (ROS) generation through Cu+-mediated Fenton-like reaction and Cu2+-facilitated GSH depletion. More importantly, the immunosuppressive tumor microenvironment (TME) can be reversed by the greatly enhanced ROS levels and high-efficiency cuproptosis, ultimately inducing immunogenic cell death that promotes robust systemic immune responses for the eradication of primary tumors and suppression of distant tumors. This work provides a novel paradigm for the integration of SDT, CDT, cuproptosis, and immunotherapy in a controlled manner to achieve tumor-specific antitumor therapy by controlling the degradation behaviors of Cu-based nanomaterials.

Hepatocellular carcinoma (HCC) exhibits a low response to immunotherapy due to the dense extracellular matrix (ECM) filled with immunosuppressive cells including dendritic cells (DCs) of blocked maturation. Herein, we develop a nanoprodrug self-assembled from polyethylene glycol-poly-4-borono-l-phenylalanine (mPEG-PBPA) conjugating with quercetin (QUE) via boronic ester bonds. In addition, an immune adjuvant of imiquimod (R837) is incorporated. The nanodrug (denoted as Q&R@NPs) is prepared from a simple mixing means with a high loading content of QUE reaching more than 30%. Owing to the acid and reactive oxygen species (ROS) sensitivities of boronic ester bonds, Q&R@NPs can respond to the tumor microenvironment (TME) and release QUE and R837 to synchronously exert multicellular regulation functions. Specifically, QUE inhibits the activation state of hepatic stellate cells and reduces highly expressed programmed death receptor ligand 1 (PD-L1) on tumor cells, meanwhile R837 exposes calreticulin on tumor cell surface as an "eat me" signal and leads to a large number of DCs maturing for enhanced antigen presentation. Consequently, the cooperative immune regulation results in a remodeled TME with high infiltration of cytotoxic T lymphocytes for enhanced HCC immunotherapy, which demonstrates an effective immunotherapy paradigm for dense ECM characterized solid tumors with high PD-L1 expression.

Localized cancer therapies such as radiotherapy, phototherapy, and chemotherapy are precise cancer treatment strategies aimed at minimizing systemic side effects. However, cancer metastasis remains the primary cause of mortality among cancer patients in clinical settings, and localized cancer treatments have limited efficacy against metastatic cancer. Therefore, researchers are exploring strategies that combine localized therapy with immunotherapy to activate robust anti-tumor immune responses, thereby eradicating metastatic cancer. Biomaterials, as novel materials, exhibit great potential in biomedical applications and have achieved great progress in clinic translation. This review introduces biomaterials and their applications in research focused on enhancing localized cancer treatment activated anti-tumor immunity. Additionally, the current challenges and future directions of biomaterials are also discussed, providing insights and references for related research.

Cancers have become the second leading cause of death worldwide, following cardiovascular diseases.Traditional anti- cancer strategies, including radiotherapy chemotherapy, surgery, and targeted therapies, have been widely used but are often reassessed due to their significant side effects and relatively low cure rate. Recently, the development of novel formulations for anti-tumor drugs has gained considerable attention, marking a pivotal step forward in cancer treatment advancements. These innovative formulations aim to enhance the therapeutic efficacy of anti-tumor drugs by employing advanced drug formulation technologies and delivery systems. In particular, nano-drug delivery systems (NDDS) have emerged as a promising approach to improve drug targeting, reduce side effects, and overcome drug resistance. This review highlights recent progress in NDDS for anti-tumor drug development and explores the future prospects of these advanced formulations in improving cancer treatment outcomes.

Reactive oxygen species (ROS) play a dual role in cancer, acting as both signaling molecules that promote tumour growth and as agents that can inhibit tumour progression through cytotoxic effects. In cancer therapy, ROS-responsive drug delivery systems take advantage of the elevated ROS levels found in tumors compared to healthy tissues. These systems are engineered to release drugs precisely in response to increased ROS levels in tumour cells, allowing targeted and controlled treatment, minimizing side effects, and enhancing therapeutic outcomes. ROS generation in cancer cells is linked to metabolic changes, mitochondrial dysfunction, and oncogenic signaling, leading to increased oxidative stress. Tumour cells manage this by upregulating antioxidant defenses to prevent ROS from reaching harmful levels. This balance between ROS production and neutralization is critical for cancer cell survival, making ROS both a challenge and an opportunity for targeted therapies. ROS also connect inflammation and cancer. Chronic inflammation leads to elevated ROS, which can damage DNA and proteins, promoting mutations and cancer development. Additionally, ROS contribute to protein degradation, affecting essential cellular functions. Therapeutic strategies targeting ROS aim to either increase ROS beyond tolerable levels for cancer cells or inhibit their antioxidant defenses. Nanocarriers responsive to ROS show great potential in improving the precision of cancer treatments by releasing drugs specifically in high ROS environments, like tumors. This review discusses the mechanisms of ROS in cancer, its role in inflammation and protein degradation, and the advances in ROS-targeted nanocarrier therapies across different cancer types.

Cancer immunotherapy has significant potential as a cancer treatment since it boosts the immune system and prevents immune escape to get rid of or fight cancers. However, its clinical applicability is still limited because of the low response rate and immune-related side effects. Recently ultrasound has been shown to alter the tumor immune microenvironment, enhance the effectiveness of other antitumor therapies, and cause tumors to become more sensitive to immunotherapy, thus providing new insights into cancer treatment. Nanomedicines are also anticipated to have a positive impact on improving the immunological effects and enhancing ultrasound effect for cancer therapy. Therefore, designing effective nanomedicines enhanced ultrasound effect for augmenting sono-immunotherapy has been a pivot on anticancer therapy. In this review, the immunological impacts of various ultrasound therapeutic modalities, ultrasound parameters, and their underlying mechanisms are discussed. Moreover, we highlight the recent progress of nanomedicines synergistically enhancing sono-immunotherapy. Finally, we put forward opportunities and challenges on sono-immunotherapy.

This case report highlights the immune-related adverse events (irAEs) that occurred during the treatment of esophageal cancer with Tislelizumab and discusses management strategies, indicating that photodynamic therapy (PDT) may be an optimal adjunctive treatment option. Following Tislelizumab therapy, the patient demonstrated significant tumor reduction; however, subsequent irAEs related to immunotherapy emerged, including eyelid muscle weakness and myocardial and skeletal muscle injury. Methylprednisolone successfully alleviated these symptoms, with early intervention being crucial for controlling irAEs. The patient then underwent PDT, which not only further helped manage irAEs but also inhibited tumor progression. This case underscores the specific adverse reactions, such as eyelid ptosis, skeletal muscle, and myocardial damage associated with Tislelizumab, and the importance of early corticosteroid intervention. It also emphasizes the significance of PDT as an adjunctive treatment for controlling tumors and alleviating immune-related adverse reactions.

Low-intensity ultrasound-mediated sonodynamic therapy (SDT), which, by design, integrates sonosensitizers and molecular oxygen to generate therapeutic substances (e.g., toxic hydroxyl radicals, superoxide anions, or singlet oxygen) at disease sites, has shown enormous potential for the effective treatment of a variety of diseases. Nanoscale sonosensitizers play a crucial role in the SDT process because their structural, compositional, physicochemical, and biological characteristics are key determinants of therapeutic efficacy. In particular, advances in materials science and nanotechnology have invigorated a series of optimization strategies for augmenting the therapeutic efficacy of nanosonosensitizers. This comprehensive review systematically summarizes, discusses, and highlights state-of-the-art studies on the current achievements of nanosonosensitizer optimization in enhanced sonodynamic disease treatment, with an emphasis on the general design principles of nanosonosensitizers and their optimization strategies, mainly including organic and inorganic nanosonosensitizers. Additionally, recent advancements in optimized nanosonosensitizers for therapeutic applications aimed at treating various diseases, such as cancer, bacterial infections, atherosclerosis, and autoimmune diseases, are clarified in detail. Furthermore, the biological effects of the improved nanosonosensitizers for versatile SDT applications are thoroughly discussed. The review concludes by highlighting the current challenges and future opportunities in this rapidly evolving research field to expedite its practical clinical translation and application.

Cold exposure (CE) therapy can quickly induce tumor starvation by brown adipose tissue (BAT) thermogenesis. Exploring the combined antitumor mechanism of CE and traditional therapies (such as radiotherapy (RT)) is exciting and promising. In this study, we investigated the effect of CE in combination with nitric oxide (NO) gas therapy on sensitizing tumors to RT and promoting tumor radio-immunotherapy. We first constructed a liposome (SL) loaded with the NO prodrug S-nitroso-N-acetylpenicillamine (SNAP). When SL is injected, the glutathione (GSH) within the tumor region promotes the release of NO from SNAP. Subsequently, the superoxide anion produced by RT reacts with NO to generate peroxynitrite (ONOO-), which has strong oxidative properties and induces cell death. Meanwhile, the mice were exposed to a CE environment of 4 °C. CE-mediated BAT thermogenesis induced tumor starvation, which led to a decrease in ATP and GSH content within the tumor as well as an improvement in the hypoxic microenvironment and a decrease in myeloid-derived suppressor cells. All of the above have promoted the effectiveness of RT and activated the systemic antitumor immunity. In the bilateral tumor experiment, treatment of the primary tumor inhibited the growth of the distant tumor and promoted the infiltration of CD8+ T cells into the tumor. These findings reveal that the synergy of CE, NO gas therapy, and RT could confer high effective anticancer effects, providing possibilities in personalized cancer treatment.

Solid tumors create a hypoxic microenvironment and this character can be utilized for cancer therapy, but the hypoxia levels are insufficient to achieve satisfactory therapeutic benefits. Some tactics have been used to improve hypoxia, which however will cause side effects due to the uncontrolled drug release. We herein report near-infrared (NIR) photoactivatable three-in-one nanoagents (PCT) to aggravate tumor hypoxia and enable amplified photo-combinational chemotherapy. PCT are formed based on a thermal-responsive liposome nanoparticle containing three therapeutic agents: a hypoxia responsive prodrug tirapazamine (TPZ) for chemotherapy, a vascular targeting agent combretastatin A-4 (CA4) for vascular disturbance and a semiconducting polymer for both photodynamic therapy (PDT) and photothermal therapy (PTT). With NIR laser irradiation, PCT generate heat for PTT and destructing thermal-responsive liposomes to achieve activatable releases of TPZ and CA4. Moreover, PCT produce singlet oxygen (1O2) for PDT via consuming tumor oxygen. CA4 can disturb the blood vessels in tumor microenvironment to aggravate the hypoxic microenvironment, which results in the activation of TPZ for amplified chemotherapy. PCT thus enable PTT, PDT and hypoxia-amplified chemotherapy to afford a high therapeutic efficacy to almost absolutely eradicate subcutaneous 4 T1 tumors and effectively inhibit tumor metastases in lung and liver. This work presents an activatable three-in-one therapeutic nanoplatform with remotely controllable and efficient therapeutic actions to treat cancer.

Cold exposure therapy (CE), as an inexpensive method, has shown great potential in cancer therapy. Exploring the combined anti-tumor mechanism of CE and traditional therapies (such as photodynamic therapy (PDT)) is exciting and promising. Here, a bionic aggregation-induced emission photosensitizer system (named THL) is designed for combined CE to enhance anti-tumor immunotherapy. THL inherits the homologous targeting ability of tumor derived exosomes, promoting the enrichment of THL at the tumor site. Under external illumination, THL generates hydroxyl radicals and superoxide anions through type I PDT. In addition, mice are pretreated with cold exposure, which promotes THL mediated PDT and reactive oxygen species (ROS) generation by reducing the production of ATP and GSH in tumor tissue. This combination therapy increases production of ROS within the tumor, inhibits the growth of distant tumors, recurrent and rechallenged tumors and increases the number of cytotoxic CD8+T cells and memory T cells. Compared to PDT alone, combination therapy shows greater advantages in tumor immunotherapy. The combination therapy strategy provides new ideas for cancer immunotherapy.

Tumor microenvironment is formed by various cellular and non-cellular components which interact with one another and form a complex network of interactions. Some of these cellular components also attain a secretory phenotype and release growth factors, cytokines, chemokines etc. in the surroundings which are capable of inducing even greater number of signalling networks. All these interactions play a decisive role in determining the course of tumorigenesis. The treatment strategies against cancer also exert their impact on the local microenvironment. Such interactions and anticancer therapies have been found to induce more deleterious outcomes like immunosuppression and chemoresistance in the process of tumor progression. Hence, understanding the tumor microenvironment is crucial for dealing with cancer and chemoresistance. This review is an attempt to develop some understanding about the tumor microenvironment and different factors which modulate it, thereby contributing to tumorigenesis. Along with summarising the major components of tumor microenvironment and various interactions taking place between them, it also throws some light on how the existing and potential therapies exert their impact on these dynamics.

Exosome-nanoparticle hybrid nanoplatforms, can be prepared by combining exosomes with different types of nanoparticles. The main purpose of combining exosomes with nanoparticles is to overcome the limitations of using each of them as drug delivery systems. Using nanoparticles for drug delivery has some limitations, such as high immunogenicity, poor cellular uptake, low biocompatibility, cytotoxicity, low stability, and rapid clearance by immune cells. However, using exosomes as drug delivery systems also has its own drawbacks, such as poor encapsulation efficiency, low production yield, and the inability to load large molecules. These limitations can be addressed by utilizing hybrid nanoplatforms. Additionally, the use of exosomes allows for targeted delivery within the hybrid system. Exosome-inorganic/organic hybrid nanoparticles may be used for both therapy and diagnosis in the future. This may lead to the development of personalized medicine using hybrid nanoparticles. However, there are a few challenges associated with this. Surface modifications, adding functional groups, surface charge adjustments, and preparing nanoparticles with the desired size are crucial to the possibility of preparing exosome-nanoparticle hybrids. Additional challenges for the successful implementation of hybrid platforms in medical treatments and diagnostics include scaling up the manufacturing process and ensuring consistent quality and reproducibility across various batches. This review focuses on various types of exosome-nanoparticle hybrid systems and also discusses the preparation and loading methods for these hybrid nanoplatforms. Furthermore, the potential applications of these hybrid nanocarriers in drug/gene delivery, disease treatment and diagnosis, and cell/tissue imaging are explained.

Traditional cancer treatment strategies often have severe toxic side effects and poor therapeutic efficacy. To address the long-standing problems related to overcoming the complexity of tumors, we develop a novel nanozyme based on the in situ oxidation of 2D Ti3C2 structure to perform simultaneous phototherapy and sonodynamic therapy on tumors. Ti3C2 nanozymes exhibit multi-enzyme activity, including intrinsic peroxidase (POD) activities, which can react with H2O2 in the tumor microenvironment. This new material can construct Ti3C2/TiO2 heterostructures in vivo.

Photothermal (PTT), sonodynamic (SDT) effects, and photoacoustic (PA) image-guided synergy therapy can be achieved. Finally, anticancer immune responses occur with this nanozyme. In vivo experiments revealed that the Ti3C2/TiO2 heterostructure inhibited tumor growth.

Complementarily, our results showed that the Ti3C2/TiO2 heterostructure enhanced the immunogenic activity of tumors by recruiting cytotoxic T cells, thereby enhancing the tumor ablation effect. Mechanistic studies consistently indicated that Reactive Oxygen Species (ROS) regulates apoptosis of HCC cells by modulating NRF2/OSGIN1 signaling both in vitro and in vivo. As a result, Ti3C2 nanozyme effectively inhibited tumor through its synergistic ability to modulate ROS and enhance immune infiltration of cytotoxic T cells in the tumor microenvironment.

These findings open up new avenues for enhancing 2D Ti3C2 nanosheets and suggest a new way to develop more effective sonosensitizers for the treatment of cancer.

Phototherapy promotes anti-tumor immunity by inducing immunogenic cell death (ICD), However, the accompanying inflammatory responses also trigger immunosuppression, attenuating the efficacy of photo-immunotherapy. Herein, they co-assembled a cell-membrane targeting chimeric peptide C16-Cypate-RRKK-PEG8-COOH (CCP) and anti-inflammatory diclofenac (DA) to develop a nanodrug (CCP@DA) that both enhances the immune effect of phototherapy and weakens the inflammation-mediated immunosuppression. CCP@DA achieves cell membrane-targeting photodynamic and photothermal synergistic therapies to damage programmed death ligand 1 (PD-L1) and induce a strong ICD to activate anti-tumor response. Simultaneously, the released DA inhibits the cycoperoxidase-2 (COX-2)/prostaglandin E2 (PGE2) pathway in tumor cells to inhibit pro-tumor inflammation and further down-regulate PD-L1 expression to relieve the immunosuppressive microenvironment. CCP@DA significantly inhibited tumor growth and inflammation both in vitro and in vivo, while maintaining a potent anti-tumor immune response. Additionally, it exhibits excellent anti-metastatic capabilities and prolongs mouse survival time with a single dose and low levels of near-infrared (NIR) light exposure. This work provides a valuable strategy to control the therapy-induced inflammation for high-efficiency photoimmunotherapy.

Autophagy could play suppressing role in cancer therapy by facilitating release of tumor antigens from dying cells and inducing immunogenic cell death (ICD). Therefore, discovery and rational design of more effective inducers of cytotoxic autophagy is expected to develop new strategies for finding innovative drugs for precise and successful cancer treatment. Herein, we develop MoO3-x nanowires (MoO3-x NWs) with high oxygen vacancy and strong photothermal responsivity to ablate tumors through hyperthermia, thus promote the induction of cytotoxic autophagy and severe ICD. As expected, the combination of MoO3-x NWs and photothermal therapy (PTT) effectively induces autophagy to promote the release of tumor antigens from the ablated cells, and induces the maturation and antigen presentation of dendritic cells (DCs), subsequently activates cytotoxic T lymphocytes (CTLs)-mediated adaptive immunity. Furthermore, the combination treatment of MoO3-x NWs with immune checkpoint blockade of PD-1 could promote the tumor-associated macrophages (TAMs) polarization into tumor-killing M1 macrophages, inhibit infiltration of Treg cells at tumor sites, and alleviate immunosuppression in the tumor microenvironment, finally intensify the anti-tumor activity in vivo. This study provides a strategy and preliminary elucidation of the mechanism of using MoO3-x nanowires with high oxygen vacancy to induce autophagy and thus enhance photothermal immunotherapy.

Ultrasound is widely used in the diagnosis and therapy of cancer. Tumors can be treated by thermal or mechanical tissue ablation. Furthermore, tumors can be manipulated by hyperthermia, sonodynamic therapy and sonoporation, e.g., by increasing tumor perfusion or the permeability of biological barriers to enhance drug delivery. These treatments induce various immune responses in tumors. However, conflicting data and high heterogeneity between experimental settings make it difficult to generalize the effects of ultrasound on tumor immunity. Therefore, we performed a systematic review to answer the question: "Does ultrasound alter the immune reaction of peripheral solid tumors in humans and animals compared to control conditions without ultrasound?" A systematic literature search was performed in PubMed, EMBASE, and Web of Science and 24,401 potentially relevant publications were identified. Of these, 96 publications were eligible for inclusion in the systematic review. Experiments were performed in humans, rats, and mice and focused on different tumor types, primarily breast and melanoma. We collected data on thermal and non-thermal ultrasound settings, the use of sono-sensitizers or sono-enhancers, and anti-tumor therapies. Six meta-analyses were performed to quantify the effect of ultrasound on tumor infiltration by T cells (cytotoxic, helper, and regulatory T cells) and on blood cytokines (interleukin-6, interferon-γ, tumor necrosis factor-α). We provide robust scientific evidence that ultrasound alters T cell infiltration into tumors and increases blood cytokine concentrations. Furthermore, we identified significant differences in immune cell infiltration based on tumor type, ultrasound settings, and mouse age. Stronger effects were observed using hyperthermia in combination with sono-sensitizers and in young mice. The latter may impair the translational impact of study results as most cancer patients are older. Thus, our results may help refining ultrasound parameters to enhance anti-tumor immune responses for therapeutic use and to minimize immune effects in diagnostic applications.

Cuproptosis, a newly discovered mechanism of inducing tumor cell death, primarily relies on the intracellular accumulation of copper ions. The utilization of Cu-based nanomaterials to induce cuproptosis holds promising prospects in future biomedical applications. However, the presence of high levels of glutathione (GSH) within tumor cells hinders the efficacy of cuproptosis. In this study, we have developed a BPTES-loaded biomimetic Cu-doped polypyrrole nanoparticles (CuP) nanosystem (PCB) for enhanced cuproptosis and immune modulation. PCB comprises an internal BPTES and CuP core and an external platelet membrane (PM) that facilitates active targeting to tumor sites following intravenous administration. Subsequently, PCB effectively suppresses glutaminase (GLS1) activity, thereby reducing GSH content. Moreover, CuP catalyze intracellular H2O2, amplifying oxidative stress while simultaneously inducing dihydrolipoyl transacetylase (DLAT) oligomerization through released Cu2+, resulting in cuproptosis. PCB not only inhibits primary tumors but also exhibits inhibitory effects on abscopal tumors. This work represents the first instance where GLS inhibition has been employed to enhance cuproptosis and immunotherapy. It also provides valuable insights into further investigations on cuproptosis.

The applications of hydrogels have expanded significantly due to their versatile, highly tunable properties and breakthroughs in biomaterial technologies. In this review, we cover the major achievements and the potential of hydrogels in therapeutic applications, focusing primarily on two areas: emerging cell-based therapies and promising non-cell therapeutic modalities. Within the context of cell therapy, we discuss the capacity of hydrogels to overcome the existing translational challenges faced by mainstream cell therapy paradigms, provide a detailed discussion on the advantages and principal design considerations of hydrogels for boosting the efficacy of cell therapy, as well as list specific examples of their applications in different disease scenarios. We then explore the potential of hydrogels in drug delivery, physical intervention therapies, and other non-cell therapeutic areas (e.g., bioadhesives, artificial tissues, and biosensors), emphasizing their utility beyond mere delivery vehicles. Additionally, we complement our discussion on the latest progress and challenges in the clinical application of hydrogels and outline future research directions, particularly in terms of integration with advanced biomanufacturing technologies. This review aims to present a comprehensive view and critical insights into the design and selection of hydrogels for both cell therapy and non-cell therapies, tailored to meet the therapeutic requirements of diverse diseases and situations.

Immune checkpoint blockade (ICB) has achieved unprecedented progress in tumor immunotherapy by blocking specific immune checkpoint molecules. However, the high biodistribution of the drug prevents it from specifically targeting tumor tissues, leading to immune-related adverse events. Biomimetic nanodrug delivery systems (BNDSs) readily applicable to ICB therapy have been widely developed at the preclinical stage to avoid immune-related adverse events. By exploiting or mimicking complex biological structures, the constructed BNDS as a novel drug delivery system has good biocompatibility and certain tumor-targeting properties. Herein, the latest findings regarding the aforementioned therapies associated with ICB therapy are highlighted. Simultaneously, prospective bioinspired engineering strategies can be designed to overcome the four-level barriers to drug entry into lesion sites. In future clinical translation, BNDS-based ICB combination therapy represents a promising avenue for cancer treatment.

Glioblastoma (GBM) as one of the most lethal brain tumours, remains poor therapeutic index due to its typical characters including heterogeneous, severe immune suppression as well as the existence of blood brain barrier (BBB). Immune sonodynamic (ISD) therapy combines noninvasive sonodynamic therapy with immunotherapy, which has great prospects for the combinational treatment of GBM. Herein, we develop macrophage cell membrane cloaked reactive oxygen species (ROS) responsive biomimetic nanoparticles, co-delivering of sonosensitizer Ce6 and JQ1 (a bromo-domain protein 4 (BRD4) inhibitor which can down-regulate PD-L1) and realizing potent GBM ISD therapy. The ApoE peptide decorated macrophage membrane coating endows these biomimetic nanoparticles with low immunogenicity, efficient BBB permeability, prolonged blood circulation half-live and good biocompatibility. The ROS responsive polymeric inner core could be readily degraded as triggered by excessive ROS under the ultrasound once they accumulated in tumour cells, fast release encapsulated drugs. The generation of ROS not only killed tumour cells via sonodynamic therapy, but also induced immunogenic cell death (ICD) and further activated the anti-tumour immune response. The released JQ1 inhibited tumour cell proliferation and augmented the immune activities by inhibiting the PD-L1 expression on the surface of tumour cells. The cascade sonodynamic and immune therapy resulted in significantly improved median survival time in both orthotopic GL261 and PTEN deficient immunosuppressive CT2A GBM mice models. Therefore, our developed biomimetic nanoparticle platform provides a promising combinational therapy strategy to treat immune suppressive GBM.

Breaking the poor permeability of immune checkpoint inhibitors (ICIs) caused by the stromal barrier and reversing the immunosuppressive microenvironment are significant challenges in pancreatic cancer immunotherapy. In this study, we synthesized core-shell Fe3O4@TiO2 nanoparticles to act as carriers for loading VISTA monoclonal antibodies to form Fe3O4@TiO2@VISTAmAb (FTV). The nanoparticles are designed to target the overexpressed ICIs VISTA in pancreatic cancer, aiming to improve magnetic resonance imaging-guided sonodynamic therapy (SDT)-facilitated immunotherapy. Laser confocal microscopy and flow cytometry results demonstrate that FTV nanoparticles are specifically recognized and phagocytosed by Panc-2 cells. In vivo experiments reveal that ultrasound-triggered TiO2 SDT can induce tumor immunogenic cell death (ICD) and recruit T-cell infiltration within the tumor microenvironment by releasing damage-associated molecular patterns (DAMPs). Furthermore, ultrasound loosens the dense fibrous stroma surrounding the pancreatic tumor and increases vascular density, facilitating immune therapeutic efficiency. In summary, our study demonstrates that FTV nanoparticles hold great promise for synergistic SDT and immunotherapy in pancreatic cancer.

Copper plays vital roles in numerous cellular processes and its imbalance can lead to oxidative stress and dysfunction. Recent research has unveiled a unique form of copper-induced cell death, termed cuproptosis, which differs from known cell death mechanisms. This process involves the interaction of copper with lipoylated tricarboxylic acid cycle enzymes, causing protein aggregation and cell death. Recently, a growing number of studies have explored the link between cuproptosis and cancer development. This review comprehensively examines the systemic and cellular metabolism of copper, including tumor-related signaling pathways influenced by copper. It delves into the discovery and mechanisms of cuproptosis and its connection to various cancers. Additionally, the review suggests potential cancer treatments using copper ionophores that induce cuproptosis, in combination with small molecule drugs, for precision therapy in specific cancer types.

Cancer has become one of the most important factors threatening human health, and the global cancer burden has been increasing rapidly. Immunotherapy has become another clinical research hotspot after surgery, chemotherapy, and radiotherapy because of its high efficiency and tumor metastasis prevention. However, problems such as lower immune response rate and immune-related adverse reaction in the clinical application of immunotherapy need to be urgently solved. With the development of nanodrug delivery systems, various nanocarrier materials have been used in the research of antitumor immunotherapy with encouraging therapeutic results. In this review, we mainly summarized the combination of nanodrug delivery systems and immunotherapy from the following 4 aspects: (a) nanodrug delivery systems combined with cytokine therapy to improve cytokines delivery in vivo; (b) nanodrug delivery systems provided a suitable platform for the combination of immune checkpoint blockade therapy with other tumor treatments; (c) nanodrug delivery systems helped deliver antigens and adjuvants for tumor vaccines to enhance immune effects; and (d) nanodrug delivery systems improved tumor treatment efficiency and reduced toxicity for adoptive cell therapy. Nanomaterials chosen by researchers to construct nanodrug delivery systems and their function were also introduced in detail. Finally, we discussed the current challenges and future prospects in combining nanodrug delivery systems with immunotherapy.

Cancer is a growing worldwide health problem with the most broadly studied treatments, in which immunotherapy has made notable advancements in recent years. However, innumerable patients have presented a poor response to immunotherapy and simultaneously experienced immune-related adverse events, with failed therapeutic results and increased mortality rates. Consequently, it is crucial to develop alternate tactics to boost therapeutic effects without producing negative side effects. Ultrasound is considered to possess significant therapeutic potential in the antitumor field because of its inherent characteristics, including cavitation, pyrolysis, and sonoporation. Herein, this timely review presents the comprehensive and systematic research progress of ultrasound-enhanced cancer immunotherapy, focusing on the various ultrasound-related mechanisms and strategies. Moreover, this review summarizes the design and application of current sonosensitizers based on sonodynamic therapy, with an attempt to provide guidance on new directions for future cancer therapy.

Sonodynamic therapy (SDT) is an emerging approach for malignant tumor treatment, offering high precision, deep tissue penetration, and minimal side effects. The rapid advancements in nanotechnology, particularly in cancer treatment, have enhanced the efficacy and targeting specificity of SDT. Combining sonodynamic therapy with nanotechnology offers a promising direction for future cancer treatments. In this review, we first systematically discussed the anti-tumor mechanism of SDT and then summarized the common nanotechnology-related sonosensitizers and their recent applications. Subsequently, nanotechnology-related therapies derived using the SDT mechanism were elaborated. Finally, the role of nanomaterials in SDT combined therapy was also introduced.

Photodynamic therapy (PDT) exhibits great application prospects in future clinical oncology due to its spatiotemporal controllability and good biosafety. However, the antitumor efficacy of PDT is seriously hindered by many factors, including tumor hypoxia, limited light penetration ability, and strong defense mechanisms of tumors. Considering that it is difficult to completely solve the first two problems, enhancing the lethality of antitumor PDT has become a good idea to extend its clinical application. Herein, we summarize the nanoplatform-involved strategies to effectively amplify the tumoricidal capability of current PDT and then discuss the present bottlenecks and prospects of the nanoplatform-based PDT sensitization strategies in tumor therapy. We hope this review will provide some references for others to design high-performance PDT nanoplatforms for tumor therapy.

Sonodynamic therapy (SDT), an emerging cancer treatment with significant potential, offers the advantages of non-invasiveness and deep tissue penetrability. The method involves activating sonosensitizers with ultrasound to generate reactive oxygen species (ROS) capable of eradicating cancer cells, addressing the challenge faced by photodynamic therapy (PDT) where conventional light sources struggle to penetrate deep tissues, impacting treatment efficacy. This study addresses prevalent challenges in numerous nanodiagnostic and therapeutic agents, such as intricate synthesis, poor repeatability, low stability, and high cost, by introducing a streamlined one-step assembly method for nanoparticle preparation. Specifically, the sonosensitizer Chlorin e6 (Ce6) and the chemotherapy drug erlotinib are effortlessly combined and self-assembled under sonication, yielding carrier-free nanoparticles (EC-NPs) for non-small cell lung cancer (NSCLC) treatment. The resulting EC-NPs exhibit optimal drug loading capacity, a simplified preparation process, and robust stability both in vitro and in vivo, owing to their carrier-free characteristics. Under the synergistic treatment of sonodynamic therapy and chemotherapy, EC-NPs induce an excess of reactive oxygen in tumor tissue, prompting apoptosis of cancer cells and reducing their proliferative capacity. Both in vitro and in vivo experiments demonstrate superior therapeutic effects of EC-NPs under ultrasound conditions compared to free Ce6. In summary, our research findings highlight that the innovatively designed carrier-free sonosensitizer EC-NPs present a therapeutic option with commendable efficacy and minimal side effects.

Prostate cancer (PCa) poses a significant global health threaten. Immunotherapy has emerged as a novel strategy to augment the inhibition of tumor proliferation. However, the sole use of anti-PD-L1 Ab for PCa has not yielded improvements, mirroring outcomes observed in other tumor types.

This study employed the thin film hydration method to develop lipid nanobubbles (NBs) encapsulating chlorin e6 (Ce6) and anti-PD-L1 Ab (Ce6@aPD-L1 NBs). Our experimental approach included cellular assays and mouse immunization, providing a comprehensive evaluation of Ce6@aPD-L1 NBs' impact.

The Ce6@aPD-L1 NBs effectively induced reactive oxygen species generation, leading to tumor cells death. In mice, they demonstrated a remarkable enhancement of immune responses compared to control groups. These immune responses encompassed immunogenic cell death induced by sonodynamic therapy and PD-1/PD-L1 blockade, activating dendritic cells maturation and effectively stimulating CD8+T cells.

Ce6@aPD-L1 NBs facilitate tumor-targeted delivery, activating anti-tumor effects through direct sonodynamic therapy action and immune system reactivation in the tumor microenvironment. Ce6@aPD-L1 NBs exhibit substantial potential for achieving synergistic anti-cancer effects in PCa.

The anti-Programmed Death-Ligand 1 (termed aPD-L1) immune checkpoint blockade therapy has emerged as a promising treatment approach for various advanced solid tumors. However, the effect of aPD-L1 inhibitors limited by the tumor microenvironment makes most patients exhibit immunotherapy resistance.

We conjugated the Sialyl Lewis X with a polyethylene glycol-coated ultrasmall superparamagnetic iron oxide (USPIO-PEG) to form UPS nanoparticles (USPIO-PEG-SLex, termed UPS). The physicochemical properties of UPS were tested and characterized. Transmission electron microscopy and ICP-OES were used to observe the cellular uptake and targeting ability of UPS. Flow cytometry, mitochondrial membrane potential staining, live-dead staining and scratch assay were used to verify the in vitro photothermal effect of UPS, and the stimulation of UPS on immune-related pathways at the gene level was analyzed by sequencing. Biological safety analysis and pharmacokinetic analysis of UPS were performed. Finally, the amplification effect of UPS-mediated photothermal therapy on aPD-L1-mediated immunotherapy and the corresponding mechanism were studied.

In vitro experiments showed that UPS had strong photothermal therapy ability and was able to stimulate 5 immune-related pathways. In vivo, when the PTT assisted aPD-L1 treatment, it exhibited a significant increase in CD4+ T cell infiltration by 14.46-fold and CD8+ T cell infiltration by 14.79-fold, along with elevated secretion of tumor necrosis factor-alpha and interferon-gamma, comparing with alone aPD-L1. This PTT assisted aPD-L1 therapy achieved a significant inhibition of both primary tumors and distant tumors compared to the alone aPD-L1, demonstrating a significant difference.

The nanotheranostic agent UPS has been introduced into immunotherapy, which has effectively broadened its application in biomedicine. This photothermal therapeutic approach of the UPS nanotheranostic agent enhancing the efficacy of aPD-L1 immune checkpoint blockade therapy, can be instructive to address the challenges associated with immunotherapy resistance, thereby offering potential for clinical translation.

The advent of numerous treatment modalities with desirable therapeutic efficacy has been made possible by the fast development of nanomedicine and materdicine, among which the ultrasound (US)-triggered sonocatalytic process as minimal or non-invasive method has been frequently employed for diagnostic and therapeutic purposes. In comparison to phototherapeutic approaches with inherent penetration depth limitations, sonocatalytic therapy shatters the depth limit of photoactivation and offers numerous remarkable prospects and advantages, including mitigated side effects and appropriate tissue-penetration depth. Nevertheless, the optimization of sonosensitizers and therapies remains a significant issue in terms of precision, intelligence and efficiency. In light of the fact that nanomedicine and materdicine can effectively enhance the theranostic efficiency, we herein aim to furnish a cutting-edge review on the latest progress and development of nanomedicine/materdicine-enabled sonocatalytic therapy. The design methodologies and biological features of nanomedicine/materdicine-based sonosensitizers are initially introduced to reveal the underlying relationship between composition/structure, sonocatalytic function and biological effect, in accompany with a thorough discussion of nanomedicine/materdicine-enabled synergistic therapy. Ultimately, the facing challenges and future perspectives of this intriguing sonocatalytic therapy are highlighted and outlined to promote technological advancements and clinical translation in efficient disease treatment.

Immunotherapy as a milestone in cancer treatment has made great strides in the past decade, but it is still limited by low immune response rates and immune-related adverse events. Utilizing bioeffects of ultrasound to enhance tumor immunotherapy has attracted more and more attention, including sonothermal, sonomechanical, sonodynamic and sonopiezoelectric immunotherapy. Moreover, the emergence of nanomaterials has further improved the efficacy of ultrasound mediated immunotherapy. However, most of the summaries in this field are about a single aspect of the biological effects of ultrasound, which is not comprehensive and complete currently. This review proposes the recent progress of nanomaterials augmented bioeffects of ultrasound in cancer immunotherapy. The concept of immunotherapy and the application of bioeffects of ultrasound in cancer immunotherapy are initially introduced. Then, according to different bioeffects of ultrasound, the representative paradigms of nanomaterial augmented sono-immunotherapy are described, and their mechanisms are discussed. Finally, the challenges and application prospects of nanomaterial augmented ultrasound mediated cancer immunotherapy are discussed in depth, hoping to pave the way for cancer immunotherapy and promote the clinical translation of ultrasound mediated cancer immunotherapy through the reasonable combination of nanomaterials augmented ultrasonic bioeffects.

Oral administration is the most preferred approach for treating colon diseases, and in situ vaccination has emerged as a promising cancer therapeutic strategy. However, the lack of effective drug delivery platforms hampered the application of in situ vaccination strategy in oral treatment of colorectal cancer (CRC). Here, we construct an oral core-shell nanomedicine by preparing a silk fibroin-based dual sonosensitizer (chlorin e6, Ce6)- and immunoadjuvant (imiquimod, R837)-loaded nanoparticle as the core, with its surface coated with plant-extracted lipids and pluronic F127 (p127). The resultant nanomedicines (Ce6/R837@Lp127NPs) maintain stability during their passage through the gastrointestinal tract and exert improved locomotor activities under ultrasound irradiation, achieving efficient colonic mucus infiltration and specific tumor penetration. Thereafter, Ce6/R837@Lp127NPs induce immunogenic death of colorectal tumor cells by sonodynamic treatment, and the generated neoantigens in the presence of R837 serve as a potent in situ vaccine. By integrating with immune checkpoint blockades, the combined treatment modality inhibits orthotopic tumors, eradicates distant tumors, and modulates intestinal microbiota. As the first oral in situ vaccination, this work spotlights a robust oral nanoplatform for producing a personalized vaccine against CRC.

Infection by Helicobacter pylori, a prevalent global pathogen, currently requires antibiotic-based treatments, which often lead to antimicrobial resistance and gut microbiota dysbiosis. Here, we develop a non-antibiotic approach using sonodynamic therapy mediated by a lecithin bilayer-coated poly(lactic-co-glycolic) nanoparticle preloaded with verteporfin, Ver-PLGA@Lecithin, in conjunction with localized ultrasound exposure of a dosage permissible for ultrasound medical devices. This study reveals dual functionality of Ver-PLGA@Lecithin. It effectively neutralizes vacuolating cytotoxin A, a key virulence factor secreted by H. pylori, even in the absence of ultrasound. When coupled with ultrasound exposure, it inactivates H. pylori by generating reactive oxygen species, offering a potential solution to overcome antimicrobial resistance. In female mouse models bearing H. pylori infection, this sonodynamic therapy performs comparably to the standard triple therapy in reducing gastric infection. Significantly, unlike the antibiotic treatments, the sonodynamic therapy does not negatively disrupt gut microbiota, with the only major impact being upregulation of Lactobacillus, which is a bacterium widely used in yogurt products and probiotics. This study presents a promising alternative to the current antibiotic-based therapies for H. pylori infection, offering a reduced risk of antimicrobial resistance and minimal disturbance to the gut microbiota.

Functional nanomaterial graphene and its derivatives have attracted considerable attention in many fields because of their unique physical and chemical properties. Most notably, graphene has become a research hotspot in the biomedical field, especially in relation to malignant tumors. In this study, we briefly review relevant research from recent years on graphene and its derivatives in tumor diagnosis and antitumor therapy. The main contents of the study include the graphene-derivative diagnosis of tumors in the early stage, graphene quantum dots, photodynamics, MRI contrast agent, acoustic dynamics, and the effects of ultrasonic cavitation and graphene on tumor therapy. Moreover, the biocompatibility of graphene is briefly described. This review provides a broad overview of the applications of graphene and its derivatives in tumors. Conclusion, graphene and its derivatives play an important role in tumor diagnosis and treatment.

Currently, immune checkpoint blockade (ICB) therapies that target the programmed cell death ligand-1 (PD-L1) have been used as revolutionary cancer treatments in the clinic. Apart from restoring the antitumor response of cytotoxic T cells by blocking the interaction between PD-L1 on tumor cells and programmed cell death-1 (PD-1) on T cells, PD-L1 proteins were also newly revealed to possess the capacity to accelerate DNA damage repair (DDR) and enhance tumor growth through multiple mechanisms, leading to the impaired efficacy of tumor therapies. Nevertheless, current free anti-PD-1/PD-L1 therapy still suffered from poor therapeutic outcomes in most solid tumors due to the non-selective tumor accumulation, ineludible severe cytotoxic effects, as well as the common occurrence of immune resistance. Recently, nanoparticles with efficient tumor-targeting capacity, tumor-responsive prosperity, and versatility for combination therapy were identified as new avenues for PD-L1 targeting cancer immunotherapies. In this review, we first summarized the multiple functions of PD-L1 protein in promoting tumor growth, accelerating DDR, as well as depressing immunotherapy efficacy. Following this, the effects and mechanisms of current clinically widespread tumor therapies on tumor PD-L1 expression were discussed. Then, we reviewed the recent advances in nanoparticles for anti-PD-L1 therapy via using PD-L1 antibodies, small interfering RNA (siRNA), microRNA (miRNA), clustered, regularly interspaced, short palindromic repeats (CRISPR), peptide, and small molecular drugs. At last, we discussed the challenges and perspectives to promote the clinical application of nanoparticles-based PD-L1-targeting therapy.

Burgeoning is an evolution from conventional photodynamic therapy (PDT). Thus, sonodynamic therapy (SDT) regulated by nanoparticles (NPs) possesses multiple advantages, including stronger penetration ability, better biological safety, and not reactive oxygen species (ROS)-dependent tumor-killing effect. However, the limitation to tumor inhibition instead of shrinkage and the incapability of eliminating metastatic tumors hinder the clinical potential for SDT. Fortunately, immune checkpoint blockade (ICB) can revive immunological function and induce a long-term immune memory against tumor rechallenges. Hence, synergizing NPs-based SDT with ICB can provide a promising therapeutic outcome for solid tumors. Herein, we briefly reviewed the progress in NPs-based SDT and ICB therapy. We highlighted the synergistic anti-tumor mechanisms and summarized the representative preclinical trials on SDT-assisted immunotherapy. Compared to other reviews, we provided comprehensive and unique perspectives on the innovative sonosensitizers in each trial. Moreover, we also discussed the current challenges and future corresponding solutions.