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The excessive intracellular Ca2+ can induce oxidative stress, mitochondrial damage and cell apoptosis, which has been extensively explored for tumor therapy. However, the low Ca2+ accumulation originated from Ca2+-based nanosystems substantially weakens the therapeutic effect. Herein, a functional plant polyphenol-appended enzyodynamic nanozyme system CaFe 2 O 4 @BSA-curcumin (abbreviation as CFO-CUR) has been rationally designed and engineered to achieve magnified Ca2+ accumulation process, deleterious reactive oxygen species (ROS) production, as well as mitochondrial dysfunction through enzyodynamic-Ca2+ overload synergistic effect. The exogenous Ca2+ released by CaFe 2 O 4 nanozymes under the weakly acidic tumor microenvironment and Ca2+ efflux inhibition by curcumin boost mitochondria-dominant antineoplastic efficiency. The presence of Fe components with multivalent characteristic depletes endogenous glutathione and outputs the incremental ROS due to the oxidase-, peroxidase-, glutathione peroxidase-mimicking activities. The ROS burst-triggered regulation of Ca2+ channels and pumps strengthens the intracellular Ca2+ accumulation. Especially, the exogenous ultrasound stimulation further amplifies mitochondrial damage. Both in vitro and in vivo experimental results affirm the ultrasound-augmented enzyodynamic-Ca2+ overload synergetic tumor inhibition outcomes. This study highlights the role of ultrasound coupled with functional nanozyme in the homeostasis imbalance and function disorder of mitochondria for highly efficient tumor treatment. [Display omitted] [ABSTRACT FROM AUTHOR]

Reactive oxygen species (ROS) that are overproduced in certain tumors can be considered an indicator of oxidative stress levels in the tissue. Here, we report a magnetic resonance imaging (MRI)-based probe capable of detecting ROS levels in the tumor microenvironment (TME) using ROS-responsive manganese ion (Mn2+)-chelated, biotinylated bilirubin nanoparticles (Mn@bt-BRNPs). These nanoparticles are disrupted in the presence of ROS, resulting in the release of free Mn2+, which induces T1-weighted MRI signal enhancement. Mn@BRNPs show more rapid and greater MRI signal enhancement in high ROS-producing A549 lung carcinoma cells compared with low ROS-producing DU145 prostate cancer cells. A pseudo three-compartment model devised for the ROS-reactive MRI probe enables mapping of the distribution and concentration of ROS within the tumor. Furthermore, doxorubicin-loaded, cancer-targeting ligand biotin-conjugated Dox/Mn@bt-BRNPs show considerable accumulation in A549 tumors and also effectively inhibit tumor growth without causing body weight loss, suggesting their usefulness as a new theranostic agent. Collectively, these findings suggest that Mn@bt-BRNPs could be used as an imaging probe capable of detecting ROS levels and monitoring drug delivery in the TME with potential applicability to other inflammatory diseases. [Display omitted] [ABSTRACT FROM AUTHOR]

We evaluated modulation of the immunosuppressive tumor microenvironment in both local and liver metastatic colorectal cancer (LMCC), focusing on tumor-associated macrophages, which are the predominant immunosuppressive cells in LMCC. We developed an orally administered metronomic chemotherapy regimen, oral CAPOX. This regimen combines capecitabine and a nano-micelle encapsulated, lysine-linked deoxycholate and oxaliplatin complex (OPt/LDC-NM). The treatment effectively modulated immune cells within the tumor microenvironment by activating the cGAS-STING pathway and inducing immunogenic cell death. This therapy modulated immune cells more effectively than did capecitabine monotherapy, the current standard maintenance chemotherapy for colorectal cancer. The macrophage-modifying effect of oral CAPOX was mediated via the cGAS-STING pathway. This is a newly identified mode of immune cell activation induced by metronomic chemotherapy. Moreover, oral CAPOX synergized with anti -PD-1 antibody (αPD-1) to enhance the T-cell–mediated antitumor immune response. In the CT26. CL25 subcutaneous model, combination therapy achieved a 91 % complete response rate with a confirmed memory effect against the tumor. This combination also altered the immunosuppressive tumor microenvironment in LMCC, which αPD-1 monotherapy could not achieve. Oral CAPOX and αPD-1 combination therapy outperformed the maximum tolerated dose for treating LMCC, suggesting metronomic therapy as a promising strategy. [Display omitted] • A self-assembling nano-micelle formulation increased the bioavailability of oxaliplatin. • An oral FOLFOX formulation was developed to modulate the tumor microenvironment. • Oral CAPOX modulated the M2-like anti-inflammatory tumor-associated macrophage in LMCC. • CGAS-STING pathway is suggested for the mechanism of metronomic chemotherapy. • Metronomic chemotherapy more effectively supported immunotherapy than MTD. [ABSTRACT FROM AUTHOR]

Photodynamic therapy (PDT) is a promising modality for cancer treatment. However, limited tissue penetration of external radiation and complicated tumor microenvironments (TMEs) restrict the antitumor efficiency of PDT. Herein, we report an energy-storing DNA-based hydrogel, which enables tumor-selective PDT without external radiation and regulates TMEs to achieve boosted PDT-mediated tumor immunotherapy. The system is constructed with two ultralong single-stranded DNA chains, which programmed partial complementary sequences and repeated G-quadruplex forming AS1411 aptamer for photosensitizer loading via hydrophobic interactions and π-π stacking. Then, energy-storing persistent luminescent nanoparticles are incorporated to sensitize PDT selectively at tumor site without external irradiation, generating tumor antigen to agitate antitumor immune response. The system catalytically generates O 2 to alleviate hypoxia and releases inhibitors to reverse the IDO-related immunosuppression, synergistically remodeling the TMEs. In the mouse model of breast cancer, this hydrogel shows a remarkable tumor suppression rate of 78.3 %. Our study represents a new paradigm of photodynamic immunotherapy against cancer by combining laser-free fashion and TMEs remodeling. [ABSTRACT FROM AUTHOR]

The use of CAR-T cells in treating solid tumors frequently faces significant challenges, mainly due to the heterogeneity of tumor antigens. This study assessed the efficacy of an acidity-targeting transition-aided universal chimeric antigen receptor T (ATT-CAR-T) cell strategy, which is facilitated by an acidity-targeted transition. Specifically, the EGFRvIII peptide was attached to the N-terminus of a pH-low insertion peptide. Triggered by the acidic conditions of the tumor microenvironment, this peptide alters its structure and selectively integrates into the membrane of solid tumor cells. The acidity-targeted transition component effectively relocated the EGFRvIII peptide across various tumor cell membranes; thus, allowing the direct destruction of these cells by EGFRvIII-specific CAR-T cells. This method was efficient even when endogenous antigens were absent. In vivo tests showed marked antigen modification within the acidic tumor microenvironment using this component. Integrating this component with CAR-T cell therapy showed high effectiveness in combating solid tumors. These results highlight the capability of ATT-CAR-T cell therapy to address the challenges presented by tumor heterogeneity and expand the utility of CAR-T cell therapy in the treatment of solid tumors. [ABSTRACT FROM AUTHOR]

One of the hurdles to the development of new anticancer therapies is the lack of in vitro models which faithfully reproduce the in vivo tumor microenvironment (TME). Understanding the dynamic relationships between the components of the TME in a controllable, scalable, and reliable setting would indeed support the discovery of biological targets impacting cancer diagnosis and therapy. Cancer research is increasingly shifting from traditional two-dimensional (2D) cell culture toward three-dimensional (3D) culture models, which have been demonstrated to increase the significance and predictive value of in vitro data. In this scenario, microphysiological systems (also known as organs-on-chip) have emerged as a relevant technological platform enabling more predictive investigation of cell-cell and cell-ECM interplay in cancer, attracting a significant research effort in the last years. This review illustrates one decade of progress in the field of tumor-microenvironment-on-chip (TMOC) approaches, exploiting either cell-laden microfluidic chambers or microfluidic confined tumor spheroids to model the TME. TMOCs have been designed to recapitulate several aspects of the TME, including tumor cells, the tumor-associated stroma, the immune system, and the vascular component. Significantly, the last aspect has emerged for its pivotal role in orchestrating cellular interactions and modulating drug pharmacokinetics on-chip. A further advancement has been represented by integration of TMOCs into multi-organ microphysiological systems, with the final aim to follow the metastatic cascade to target organs and to study the effects of chemotherapies at a systemic level. We highlight that the increased degree of complexity achieved by the most advanced TMOC models has enabled scientists to shed new light on the role of microenvironmental factors in tumor progression, metastatic cascade, and response to drugs. [ABSTRACT FROM AUTHOR]

The efficacy of radiotherapy has not yet achieved optimal results, partially due to insufficient priming and infiltration of effector immune cells within the tumor microenvironment (TME), which often exhibits suppressive phenotypes. In particular, the infiltration of X–C motif chemokine receptor 1 (XCR1)-expressing conventional type-1 dendritic cells (cDC1s), which are critical in priming CD8+ cytotoxic T cells, within the TME is noticeably restricted. Hence, we present a facile methodology for the efficient fabrication of a calcium phosphate hydrogel loaded with X–C motif chemokine ligand 1 (XCL1) to selectively recruit cDC1s. Manganese phosphate microparticles were also loaded into this hydrogel to reprogram the TME via cGAS-STING activation, thereby facilitating the priming of cDC1s propelled specific CD8+ T cells. They also polarize tumor-associated macrophages towards the M1 phenotype and reduce the proportion of regulatory cells, effectively reversing the immunosuppressive TME into an immune-active one. The yielded XCL1@CaMnP gel exhibits significant efficacy in enhancing the therapeutic outcomes of radiotherapy, particularly when concurrently administered with postoperative radiotherapy, resulting in an impressive 60 % complete response rate. Such XCL1@CaMnP gel, which recruits cDC1s to present tumor antigens generated in situ, holds great potential as a versatile platform for enhanced cancer treatment through modulating the immunosuppressive TME. [ABSTRACT FROM AUTHOR]

The tumor microenvironment (TME), which is mostly composed of tumor cells, immune cells, signaling molecules, stromal tissue, and the vascular system, is an integrated system that is conducive to the formation of tumors. TME heterogeneity makes the response to immunotherapy different in different tumors, such as "immune-cold" and "immune-hot" tumors. Tumor-associated macrophages, myeloid-derived suppressor cells, and regulatory T cells are the major suppressive immune cells and their different phenotypes interact and influence cancer cells by secreting different signaling factors, thus playing a key role in the formation of the TME as well as in the initiation, growth, and metastasis of cancer cells. Nanotechnology development has facilitated overcoming the obstacles that limit the further development of conventional immunotherapy, such as toxic side effects and lack of targeting. In this review, we focus on the role of three major suppressive immune cells in the TME as well as in tumor development, clinical trials of different drugs targeting immune cells, and different attempts to combine drugs with nanomaterials. The aim is to reveal the relationship between immunotherapy, immunosuppressive TME and nanomedicine, thus laying the foundation for further development of immunotherapy. [ABSTRACT FROM AUTHOR]

Tumors are complex materials whose physical properties dictate growth and treatment outcomes. Recent evidence suggests time-dependent physical properties, such as viscoelasticity, are crucial, distinct mechanical regulators of cancer progression and malignancy, yet the genesis and consequences of tumor viscoelasticity are poorly understood. Here, using Wide-bandwidth AFM-based ViscoElastic Spectroscopy (WAVES) coupled with mathematical modeling, we probe the origins of tumor viscoelasticity. From single carcinoma cells to increasingly sized carcinoma spheroids to established tumors, we describe a stepwise evolution of dynamic mechanical properties that create a nanorheological signature of established tumors: increased stiffness, decreased rate-dependent stiffening, and reduced energy dissipation. We dissect this evolution of viscoelasticity by scale, and show established tumors use fluid-solid interactions as the dominant mechanism of mechanical energy dissipation as opposed to fluid-independent intrinsic viscoelasticity. Additionally, we demonstrate the energy dissipation mechanism in spheroids and established tumors is negatively correlated with the cellular density, and this relationship strongly depends on an intact actin cytoskeleton. These findings define an emergent and targetable signature of the physical tumor microenvironment, with potential for deeper understanding of tumor pathophysiology and treatment strategies. [ABSTRACT FROM AUTHOR]

Cancer thrives in a complex environment where interactions between cellular and acellular components, surrounding the tumor, play a crucial role in disease development and progression. Despite significant progress in cancer research, the mechanism driving tumor growth and therapeutic outcomes remains elusive. Two-dimensional (2D) cell culture assays and in vivo animal models are commonly used in cancer research and therapeutic testing. However, these models suffer from numerous shortcomings including lack of key features of the tumor microenvironment (TME) & cellular composition, cost, and ethical clearance. To that end, there is an increased interest in incorporating and elucidating the influence of TME on cancer progression. Advancements in 3D-engineered ex vivo models, leveraging biomaterials and microengineering technologies, have provided an unprecedented ability to reconstruct native-like bioengineered cancer models to study the heterotypic interactions of TME with a spatiotemporal organization. These bioengineered cancer models have shown excellent capabilities to bridge the gap between oversimplified 2D systems and animal models. In this review article, we primarily provide an overview of the immune and stromal cellular components of the TME and then discuss the latest state-of-the-art 3D-engineered ex vivo platforms aiming to recapitulate the complex TME features. The engineered TME model, discussed herein, are categorized into three main sections according to the cellular interactions within TME: (i) Tumor-Stromal interactions, (ii) Tumor-Immune interactions, and (iii) Complex TME interactions. Finally, we will conclude the article with a perspective on how these models can be instrumental for cancer translational studies and therapeutic testing. [ABSTRACT FROM AUTHOR]

Tumor-associated macrophages (TAMs) are abundant in the tumor microenvironment which promotes the formation of the immunosuppressive tumor microenvironment (ITME) through multiple mechanisms, severely counteracting the therapeutic efficacy of immunotherapy. In this study, a novel biomimetic ferroptosis inducer (D@FMN-M) capable of ITME regulation for enhanced cancer ferroptosis immunotherapy is reported. Upon tumor accumulation of D@FMN-M, the intratumoral mild acidity triggers the biodegradation of Fe-enriched nanocarriers and the concurrent co-releases of dihydroartemisinin (DHA) and Fe3+. The released Fe3+ is reduced to Fe2+ by consuming intratumoral glutathione (GSH), which promotes abundant free radical generation via triggering Fenton and Fe2+-DHA reactions, thus inducing ferroptosis of both cancer cells and M2-type TAMs. Resultantly, the anticancer immune response is strongly activated by the massive tumor-associated antigens released by ferroptositic cancer cells. Also importantly, the ferroptosis-sensitive M2-type TAMs will be either damaged or gradually domesticated to ferroptosis-resistant M1 TAMs under the ferroptosis stress, favoring the normalization of ITME and finally amplifying cancer ferroptosis immunotherapeutic efficacy. This work provides a novel strategy for ferroptosis immunotherapy of solid tumors featuring TAMs infiltration and immunosuppression by inducing dual ferroptosis of tumor cells and M2-type TAMs. Herein, we present a novel strategy of ferroptosis immunotherapy for solid tumors by inducing dual ferroptosis of both tumor cells and TAMs with a biomimetic ferroptosis inducer (D@FMN-M). This dual ferroptosis of tumor cells and TAMs-initiated ferroptosis immunotherapeutic methodology featuring negligible side effects, much-amplified immunogenicity of the tumor, and alleviated ITME, has been evidenced to activate the robust anticancer immune response, as well as reprogram TAMs, which offers a promising paradigm for combinational cancer therapy. [Display omitted] [ABSTRACT FROM AUTHOR]

Reactive oxygen species (ROS) play a crucial role in regulating the metabolism of tumor growth, metastasis, death and other biological processes. ROS-based nanodynamic therapies (NDTs) are becoming attractive due to non-invasive, low side effects and tumor-specific advantages. NDTs have rapidly developed into numerous branches, such as photodynamic therapy, chemodynamic therapy, sonodynamic therapy and so on. However, the complexity of the tumor microenvironment and the limitations of existing sensitizers have greatly restricted the therapeutic effects of NDTs, which heavily rely on ROS levels. To address the limitations of NDTs, various strategies have been developed to increase ROS yield, which is an urgent aspect for the positive development of NDTs. In this review, the nanodynamic potentiation strategies in terms of unique properties and universalities of NDTs are comprehensively outlined. We mainly summarize the current dilemmas faced by each NDT and the respective solutions. Meanwhile, the NDTs universalities-based potentiation strategies and NDTs-based combined treatments are elaborated. Finally, we conclude with a discussion of the key issues and challenges faced in the development and clinical transformation of NDTs. [Display omitted] • The dilemmas of each NDTs and the corresponding breakthrough strategies are discussed in this review. • The universal potentiation strategies based on the universalities of NDTs are summarized exhaustively. • The key issues and challenges faced in the development and clinical transformation of NDTs are prospected. [ABSTRACT FROM AUTHOR]

Developing nanoplatforms integrating superior fluorescence imaging ability in second near-infrared (NIR-II) window and tumor microenvironment responsive multi-modal therapy holds great potential for real-time feedback of therapeutic efficacy and optimizing tumor inhibition. Herein, we developed a pH-sensitive pyrrolopyrrole aza-BODIPY-based amphiphilic molecule (PTG), which has a balanced NIR-II fluorescence brightness and photothermal effect. PTG is further co-assembled with a vascular disrupting agent (known as DMXAA) to prepare PTDG nanoparticles for combined anti-vascular/photothermal therapy and real-time monitoring of the tumor vascular disruption. Each PTG molecule has an active PT-3 core which is linked to two PEG chains via pH-sensitive ester bonds. The cleavage of ester bonds in the acidic tumor environment would tricker releases of DMXAA for anti-vascular therapy and further assemble PT-3 cores into micrometer particles for long term monitoring of the tumor progression. Furthermore, benefiting from the high brightness in the NIR-II region (119.61 M−1 cm−1) and long blood circulation time (t 1/2 = 235.6 min) of PTDG nanoparticles, the tumor vascular disrupting process can be in situ visualized in real time during treatment. Overall, this study demonstrates a self-assembly strategy to build a pH-responsive NIR-II nanoplatform for real-time monitoring of tumor vascular disruption, long-term tracking tumor progression and combined anti-vascular/photothermal therapy. [ABSTRACT FROM AUTHOR]

Ion homeostasis distortion through exogenous overload or underload of intracellular ion species has become an arresting therapeutic approach against malignant tumor. Nevertheless, treatment outcomes of such ion interference are always compromised by the intrinsic ion homeostasis maintenance systems in cancer cells. Herein, an ion homeostasis perturbator (CTC) is facilely designed by co-encapsulation of carvacrol (CAR) and meso-tetra-(4-carboxyphenyl)porphine (TCPP) into pH-sensitive nano-CaCO 3 , aiming to disrupt the self-defense mechanism during the process of ion imbalance. Upon the endocytosis of CTC into tumor cells, lysosomal acidity can render the decomposition of CaCO 3 , resulting in the instant Ca2+ overload and CO 2 generation in cytoplasm. Simultaneously, CaCO 3 disintegration triggers the release of CAR and TCPP, which are devoted to TRPM7 inhibition and sonosensitization, respectively. The malfunction of TRPM7 can impede the influx of Mg2+ and allow unrestricted influx of Ca2+ based on the antagonism relationship between Mg2+ and Ca2+, leading to an aggravated Ca2+/Mg2+ dyshomeostasis through ion channel deactivation. In another aspect, US-triggered cavitation can be significantly enhanced by the presence of inert CO 2 microbubbles, further amplifying the generation of reactive oxygen species. Such oxidative damage-augmented Ca2+/Mg2+ interference therapy effectively impairs the mitochondrial function of tumor, which may provide useful insights in cancer therapy. [ABSTRACT FROM AUTHOR]

Radiosensitization efficacy of conventional tumor radiosensitizers has been frequently limited by insufficient competence for tumor microenvironment (TME) regulation and unfavorable cellular uptake at biological barriers. Here, we reported an ultra-efficient radiotherapy (RT) strategy by synthesizing an extracellular vesicles (EVs)-encapsulated hollow MnO 2 to load metformin (Met@HMnER). It demonstrated significant RT enhancement by morphological control of catalyst and cellular respiratory depression against conventional solid MnO 2. Furthermore, the target-modified EVs clothing retains outstanding metformin loading capacity while endowing enhanced biological barrier penetration. A noticeably durable innate immune activation of NK cells was triggered with this nanoplatform via the cGAS-STING pathway. The enhanced immunocompetence was verified on distal metastasis and in-situ recurrence model in vivo , This work paved a new path for synergistic and robust innate immunity in clinical cancer treatment. [Display omitted] [ABSTRACT FROM AUTHOR]

Radiotherapy is an important therapeutic modality in the treatment of cancers. Nevertheless, the characteristics of the tumor microenvironment (TME), such as hypoxia and high glutathione (GSH), limit the efficacy of radiotherapy. Manganese-based (Mn-based) nanomaterials offer a promising prospect for sensitizing radiotherapy due to their good responsiveness to the TME. In this review, we focus on the mechanisms of radiosensitization of Mn-based nanosystems, including alleviating tumor hypoxia, increasing reactive oxygen species production, increasing GSH conversion, and promoting antitumor immunity. We further illustrate the applications of these mechanisms in cancer radiotherapy, including the development and delivery of radiosensitizers, as well as their combination with other therapeutic modalities. Finally, we summarize the application of Mn-based nanosystems as contrast agents in realizing precision therapy. Hopefully, the present review will provide new insights into the biological mechanisms of Mn-based nanosystems, as well as their applications in radiotherapy, in order to address the difficulties and challenges that remain in their clinical application in the future. [ABSTRACT FROM AUTHOR]

The therapeutic effect of cancer immunotherapy is restrained by limited patient response rate caused by 'cold' tumors with an intrinsically immunosuppressive tumor microenvironment (TME). Activating stimulator of interferon genes (STING) confers promising antitumor immunity even in 'cold' tumors, but the further promotion of STING agonists is hindered by undesirable toxicity, low specificity and lack of controllability. Herein, an ultrasound-controllable cGAS-STING amplifying nanoagonist was constructed by coordinating mitochondria-targeting ligand triphenylphosphonium (TPP) to sonodynamic cobalt organic framework nanosheets (TPP@CoTCPP). The Co ions specifically amplify STING activation only when cytosolic mitochondrial DNA leakage is caused by sonocatalysis-induced ROS production and sensed by cGAS. A series of downstream innate immune proinflammatory responses induced by local cGAS-STING pathway activation under spatiotemporal ultrasound stimulation efficiently prime the antitumor T-cell response against bone metastatic tumor, a typical immunosuppressive tumor. We also found that the coordination of TPP augments the sonodynamic effect of CoTCPP nanosheets by reducing the band gap, improving O 2 adsorption and enhancing electron transfer. Overall, our study demonstrates that the targeted and amplified cGAS-STING activation in cancer cell controlled by spatiotemporal ultrasound irradiation boosts high-efficiency sonodynamic-ionicimmunotherapy against immunosuppressive tumor. [ABSTRACT FROM AUTHOR]

It is the challenging goal in cancer biomedicine to search novel cancer-therapeutic modality with concurrent high therapeutic efficiency on combating cancer and low side effects to normal cells/tissues. The recently developed nanocatalytic cancer therapy based on catalytic Fenton reaction represents one of the promising paradigms for potential clinical translation, which has got fast progress very recently. This progress report discusses the rational design and fabrication of Fenton reaction-based nanocatalysts for triggering the in-situ Fenton chemical reaction within tumor microenvironment to generate highly toxic hydroxyl radicals (•OH), which is highly efficient for killing the cancer cells and suppressing the tumor growth. Several strategies for optimizing the nanocatalytic cancer-therapeutic efficiency of Fenton reaction have been highlighted, including screening high-performance Fenton nanocatalysts, increasing peroxide-hydrogen amounts as the reactants, changing the Fenton-reaction conditions (e.g., temperature, acidity and photo-triggering), and Fenton reaction-based synergistic cancer therapy such as some sequential nanocatalytic reactions with improved therapeutic outcome. The facing challenges and future developments of Fenton reaction-based nanocatalytic cancer therapy are also discussed for further promoting the clinical translation of this emerging cancer-therapeutic modality to benefit the cancer patients. Image 1 [ABSTRACT FROM AUTHOR]

Succinate is an important metabolite that modulates metabolism of immune cells and cancer cells in the tumor microenvironment (TME). Herein, we report that polyethylene succinate (PES) microparticles (MPs) biomaterial mediated controlled delivery of succinate in the TME modulates macrophage responses. Administering PES MPs locally with or without a BRAF inhibitor systemically in an immune-defective aging mice with clinically relevant BRAFV600E mutated YUMM1.1 melanoma decreased tumor volume three-fold. PES MPs in the TME also led to maintenance of M1 macrophages with up-regulation of TSLP and type 1 interferon pathway. Impressively, this led to generation of pro-inflammatory adaptive immune responses in the form of increased T helper type 1 and T helper type 17 cells in the TME. Overall, our findings from this challenging tumor model suggest that immunometabolism-modifying PES MP strategies provide an approach for developing robust cancer immunotherapies. [ABSTRACT FROM AUTHOR]

Taking advantage of endogenous Ca2+ to upregulate intramitochondrial Ca2+ level has become a powerful mean for mitochondrial dysfunction-mediated tumor therapy. However, the Ca2+ entered into mitochondria is limited ascribing to the uncontrollability and non-selectivity of endogenous Ca2+ transport. It remains a great challenge to make the maximum use of endogenous Ca2+ to ensure sufficient Ca2+ overloading in mitochondria. Herein, we smartly fabricate an intracellular Ca2+ directional transport channel to selectively transport endogenous Ca2+ from endoplasmic reticulum (ER) to mitochondria based on cascade release nanoplatform ABT-199@liposomes/doxorubicin@FeIII-tannic acid (ABT@Lip/DOX@Fe-TA). In tumor acidic microenvironment, Fe3+ ions are firstly released and reduced by tannic acid (TA) to Fe2+ for ROS generation. Subsequently, under the NIR light irradiation, the released ABT-199 molecules combine with ROS contribute to the formation of IP3R-Grp75-VDAC1 channel between ER and mitochondria, thus Ca2+ ions are directionally delivered and intramitochondrial Ca2+ level is significantly upregulated. The synergetic ROS generation and mitochondrial Ca2+ overloading effectively intensifies mitochondrial dysfunction, thereby achieving efficient tumor inhibition. This work presents a new insight and promising avenue for endogenous Ca2+-involved tumor therapies. [ABSTRACT FROM AUTHOR]

Modifying biological agents with polymers such as polyethylene glycol (PEG) has demonstrated clinical benefits; however, post-market surveillance of PEGylated derivatives has revealed PEG-associated toxicity issues, prompting the search for alternatives. We explore how conjugating a poly- l -glutamic acid (PGA) to an anti-insulin growth factor 1 receptor antibody (AVE1642) modulates the bio-nano interface and anti-tumor activity in preclinical prostate cancer models. Native and PGA-modified AVE1642 display similar anti-tumor activity in vitro ; however, AVE1642 prompts IGF-1R internalization while PGA conjugation prompts higher affinity IGF-1R binding, thereby inhibiting IGF-1R internalization and altering cell trafficking. AVE1642 attenuates phosphoinositide 3-kinase signaling, while PGA-AVE1642 inhibits phosphoinositide 3-kinase and mitogen-activated protein kinase signaling. PGA conjugation also enhances AVE1642's anti-tumor activity in an orthotopic prostate cancer mouse model, while PGA-AVE1642 induces more significant suppression of cancer cell proliferation/angiogenesis than AVE1642. These findings demonstrate that PGA conjugation modulates an antibody's bio-nano interface, mechanism of action, and therapeutic activity. Poly- l -glutamic acid (PGA) conjugation alters the biological properties of a human monoclonal antibody against IGFR (AVE1642), increasing its antitumoral activity due to the capability to alter the bio-nano interaction between PGA-AVE1642 conjugate and IGF-1R in aggressive prostate cancer. These differential bio-nano interactions result in differential effects on critical cellular signaling pathways and the tumor microenvironment. [Display omitted] [ABSTRACT FROM AUTHOR]

The efficacy of photodynamic therapy (PDT) is severely limited by the hypoxic tumor microenvironment (TME), while the performance of PDT-aroused antitumor immunity is frustrated by the immunosuppressive TME and deficient immunogenic cell death (ICD) induction. To simultaneously tackle these pivotal problems, we herein create an albumin-based nanoplatform co-delivering IR780, NLG919 dimer and a hypoxia-activated prodrug tirapazamine (TPZ) as the dual enhancer for synergistic cancer therapy. Under NIR irradiation, IR780 generates 1O 2 for PDT, which simultaneously cleaves the ROS-sensitive linker for triggered TPZ release, and activates its chemotherapy via exacerbated tumor hypoxia. Meanwhile, firstly found by us, TPZ-mediated chemotherapy boosts PDT-induced tumor ICD to evoke stronger antitumor immunity including the development of tumor-specific cytotoxic T lymphocytes (CTLs). Eventually, enriched intratumoral GSH triggers the activation of NLG919 to mitigate the immunosuppressive TME via specific indoleamine 2,3-dioxygenase 1 (IDO-1) inhibition, consequently promoting the intratumoral infiltration of CTLs and the killing of both primary and distant tumors, while the resultant memory T cells allows nearly 100% suppression of tumor recurrence and metastasis. This nanoplatform sets up an example for dully enhanced photodynamic immunotherapy of breast cancer via hypoxia-activated chemotherapy, and paves a solid way for the treatment of other hypoxic and immunosuppressive malignant tumors. [Display omitted] [ABSTRACT FROM AUTHOR]

The poor permeability of therapeutic drugs, limited T-cell infiltration, and strong immunosuppressive tumor microenvironment of triple-negative breast cancer (TNBC) acts as a prominent barrier to the delivery of drugs and immunotherapy including programmed cell death ligand-1 antibody (anti-PD-L1). Transforming growth factor (TGF)- β , an important cytokine produced by cancer-associated fibroblasts (CAFs) and tumor cells contributes to the pathological vasculature, dense tumor stroma and strong immunosuppressive tumor microenvironment (TME). Herein, a nanomedicine platform (HA-LSL/siTGF- β) employing dual-targeting, alongside hyaluronidase (HAase) and glutathione (GSH) triggered release was elaborately constructed to efficiently deliver TGF- β small interference RNA (siTGF- β). It was determined that this system was able to improve the efficacy of anti-PD-L1. The siTGF- β nanosystem efficiently silenced TGF- β -related signaling pathways in both activated NIH 3T3 cells and 4T1 cells in vitro and in vivo. This occurred firstly, through CD44-mediated uptake, followed by rapid escape mediated by HAase in endo/lysosomes and release of siRNA mediated by high GSH concentrations in the cytoplasm. By simultaneous silencing of TGF- β in stromal and tumor cells, HA-LSL/siTGF- β dramatically reduced stroma deposition, promoted the penetration of nanomedicines for deep remodeling of the TME, improved oxygenation, T cells infiltration and subsequent anti-PD-L1 deep penetration. The double suppression of TGF- β has been demonstrated to promote blood vessel normalization, inhibit an epithelial-to-mesenchymal transition (EMT), and further modify the immunosuppressive TME, which was supported by an overall increase in the proportion of dendritic cells and cytotoxic T cells. Further, a reduction in the proportion of immunosuppression cells such as regulatory T cells and myeloid-derived suppressor cells was also observed in the TME. Based on the comprehensive remodeling of the tumor microenvironment by this nanosystem, subsequent anti-PD-L1 therapy elicited robust antitumor immunity. Specifically, this system was able to suppress the growth of both primary and distant tumor while preventing tumor metastasis to the lung. Therefore, the combination of the dual-targeted siTGF- β nanosystem, alongside anti-PD-L1 may serve as a novel method to enhance antitumor immunotherapy against stroma-rich TNBC. [ABSTRACT FROM AUTHOR]

The heterogeneous cell population in the stromal microenvironment is considered to be attributed to the multiple sources from which the cells originate. Tumor associated myoepithelial cells (TAMEs) are one of the most important populations in the tumor microenvironment (TME) especially in breast cancer. On the other hand, cancer stem cells (CSCs) have previously been described to be the origin of tumor-associated cellular components in the TME. We prepared a cancer stem cell model converting mouse-induced pluripotent stem cells (miPSCs) in the presence of conditioned medium of breast cancer cell line MDA-MB-231 cells. The converted cells developed tumors progressing into invasive carcinoma with ductal carcinoma in situ (DCIS) like structure when transplanted into mouse mammary fat pads. The primary cultured cells from the tumor further exhibited markers of CSC such as Sox2, Oct3/4, - CD133 and EpCAM, and mammary gland-related TAME markers such as α-smooth muscle actin, cytokeratin 8, whey acidic protein, prolactin receptor and progesterone receptor as well. These results indicated that the CSCs could be an origin of TAMEs contributing to mammary gland epithelial cell differentiation and the progression to invasive carcinoma during tumor development. The gene expression profiles confirmed the enhanced signaling pathways of PI3K/AKT and MAPK, which have been demonstrated to be enriched in the CSC models, together with the estrogen receptor signaling which was peculiar to mammary gland-derived character. [Display omitted] [ABSTRACT FROM AUTHOR]

The use of overwhelming reactive oxygen species (ROS) attack has shown great potential for treating aggressive malignancies; however, targeting this process for further applications is greatly hindered by inefficiency and low selectivity. Here, a novel strategy for ROS explosion induced by tumor microenvironment-initiated lipid redox cycling was proposed, which was developed by using soybean phosphatidylcholine (SPC) to encapsulate lactate oxidase (LOX) and sorafenib (SRF) self-assembled nanoparticles (NPs), named LOX/SRF@Lip. SPC is not only the delivery carrier but an unsaturated lipid supplement for ROS explosion. And LOX catalyzes excessive intratumoral lactate to promote the accumulation of large amounts of H 2 O 2. Then, H 2 O 2 reacts with excessive endogenous iron ions to generate amounts of hydroxyl radical for the initiation of SPC peroxidation. Once started, the reaction will proceed via propagation to form new lipid peroxides (LPO), resulting to devastating LPO explosion and widespread oxidative damage in tumor cells. Furthermore, SRF makes contribution to mass LPO accumulation by inhibiting LPO elimination. Compared to normal tissue, tumor tissue has higher levels of lactate and iron ions. Therefore, LOX/SRF@Lip shows low toxicity in normal tissues, but generates efficient inhibition on tumor proliferation and metastasis , enabling excellent and safe tumor-specific therapy. This work offers new ideas on how to magnify anticancer effect of ROS through rational nanosystem design and tumor-specific microenvironment utilization. [ABSTRACT FROM AUTHOR]

Immuno-oncology therapies have been of great interest with the goal of inducing sustained tumor regression, but clinical results have demonstrated the need for improved and widely applicable methods. An antigen-free method of cancer immunotherapy can stimulate the immune system to recruit lymphocytes and produce immunostimulatory factors without prior knowledge of neoantigens, while local delivery reduces the risk of systemic toxicity. To improve the interactions between tumor cells and cytotoxic lymphocytes, a gene delivery nanoparticle platform was engineered to reprogram the tumor microenvironment (TME) in situ to be more immunostimulatory by inducing tumor-associated antigen-presenting cells (tAPCs) to activate cytotoxic lymphocytes against the tumor. Biodegradable, lipophilic poly (beta-amino ester) (PBAE) nanoparticles were synthesized and used to co-deliver mRNA constructs encoding a signal 2 co-stimulatory molecule (4-1BBL) and a signal 3 immuno-stimulatory cytokine (IL-12), along with a nucleic acid-based immunomodulatory adjuvant. Nanoparticles are combined with a thermoresponsive block copolymer for gelation at the injection site for local NP retention at the tumor. The reprogramming nanoparticle gel synergizes with immune checkpoint blockade (ICB) to induce tumor regression and clearance in addition to resistance to tumor rechallenge at a distant site. In vitro and in vivo studies reveal increases in immunostimulatory cytokine production and recruitment of immune cells as a result of the nanoparticles. Intratumoral injection of nanoparticles encapsulating mRNA encoding immunostimulatory agents and adjuvants via an injectable thermoresponsive gel has great translational potential as an immuno-oncology therapy that can be accessible to a wide range of patients. [ABSTRACT FROM AUTHOR]

Abnormal tumor vasculature is reported to severely hinder the therapeutic potency of diverse cancer therapeutics by restricting their intratumoral accumulation and/or causing therapeutic resistance. Herein, a microbubble-assisted ultrasonication technology (MAUT) of systemic administration of octafluoropropane-filled microbubbles together with tumor localized ultrasound (US) exposure is developed to generally promote intratumoral accumulation efficacy of three kinds of anti-tumor drugs with varying sizes through the cavitation effect-induced disruption of tumor blood vessels. MAUT was further shown to enable selective tumor hypoxia attenuation by filling microbubbles with high-purity oxygen and thus reducing the production of immunosuppressive lactic acids by suppressing glycolysis in cancer cells. Resultantly, MAUT markedly enhanced the therapeutic outcome of systemically administered anti-programmed death-1 (anti -PD-1) and chemotherapeutic doxorubicin (DOX) with and without using nanoscale liposomes as delivery vehicles. This work highlights that MAUT is a biocompatible yet versatile strategy to effectively reinforce the therapeutic potency of a broad range of cancer therapeutics, promising for future clinical usage. [ABSTRACT FROM AUTHOR]

Although immunotherapy has recently emerged as a promising anti-tumor approach, it remains limited by the immunosuppressive tumor microenvironment. Cold atmospheric plasma irradiation can generate reactive oxygen species and trigger the presentation of tumor-associated antigens. Here, we exploited cold atmospheric plasma for on-site hydrogel application in the tumor environment, aiming to facilitate the sustainable uptake of tumor-associated antigens and nanoadjuvants by dendritic cells. Hyaluronic acid-tyramine conjugate was intratumorally injected as a liquid and formed an on-site hydrogel under irradiation with cold atmospheric plasma. Intratumoral delivery of hyaluronic acid-tyramine conjugate with transforming growth factor β-blocking nanoadjuvant (TLN) followed by cold atmospheric plasma irradiation yielded a micro-network of TLN-loaded hydrogel (TLN@CHG). In vivo intratumoral injection of TLN@CHG promoted the activation of dendritic cells and more effectively increased the proportion of CD4 T cells and CD8 T cells in the tumor microenvironment, compared to the groups receiving TLN or hydrogel alone. Moreover, in CT26 tumor model mice, cold atmospheric plasma-induced TLN@CHG therapy ablated the primary tumor and provided 100% survival among mice rechallenged with CT26 cells. Taken together, our findings suggest that an on-site hydrogel-based micro-network of TLN has the potential to remodel the tumor immune microenvironment. Although we used TLN in this study, the concept could be extended to support the sustained action of other nanoadjuvants in a hydrogel micro-network. [ABSTRACT FROM AUTHOR]

Cancer is a complex pathological phenomenon that needs to be treated from different aspects. Herein, we developed a size/charge dually transformable nanoplatform (PDR NP) with multiple therapeutic and immunostimulatory properties to effectively treat advanced cancers. The PDR NPs exhibit three different therapeutic modalities (chemotherapy, phototherapy and immunotherapy) that can be used to effectively treat primary and distant tumors, and reduce recurrent tumors; the immunotherapy is simultaneously activated by three major pathways, including toll-like receptor, stimulator of interferon genes and immunogenic cell death, effectively suppresses the tumor development in combination with an immune checkpoint inhibitor. In addition, PDR NPs show size and charge responsive transformability in the tumor microenvironment, which overcomes various biological barriers and efficiently delivers the payloads into tumor cells. Taking these unique characteristics together, PDR NPs effectively ablate primary tumors, activate strong anti-tumor immunity to suppress distant tumors and reduce tumor recurrence in bladder tumor-bearing mice. Our versatile nanoplatform shows great potential for multimodal treatments against metastatic cancers. [ABSTRACT FROM AUTHOR]

Pancreatic cancer is a complex disease accounting for fibrotic tumors and an aggressive phenotype. Gemcitabine (GEM) is used as a standard therapy, which develops chemoresistance leading to poor patient outcome. We have recently developed a superparamagnetic iron oxide nanoparticle (SPION) formulation of curcumin (SP-CUR), which is a nontoxic, bioactive anti-inflammatory/anti-cancer agent for its enhanced delivery in tumors. In this study, we demonstrate that SP-CUR effectively delivers bioactive curcumin to pancreatic tumors, simultaneously enhances GEM uptake and its efficacy. Mechanistic revelations suggest that SP-CUR targets tumor microenvironment via suppression of sonic hedgehog (SHH) pathway and an oncogenic CXCR4/CXCL12 signaling axis that inhibits bidirectional tumor-stromal cells interaction. Increased GEM uptake was observed due to upregulation of the human nucleoside transporter genes (DCK, hCNT) and blocking ribonucleotide reductase subunits (RRM1/RRM2). Additionally, co-treatment of SP-CUR and GEM targets cancer stem cells by regulating pluripotency maintaining stemness factors (Nanog, Sox2, c-Myc and Oct-4), and restricting tumor sphere formation. In an orthotopic mouse model, an enhanced accumulation of SP-CUR was found in pancreas, which potentiated GEM to reduce tumor growth and metastasis. Analysis of tumor tissues suggest that the treatment inhibits tumor stroma (α-SMA, Desmin and Hyluronic Acid) and induces changes in cell stiffness, as measured via Atomic Force Microscopy. This was accompanied by alteration of key cellular proteins of SHH signaling such as SHH, Gli-1, Gli-2, Sufu, and NFĸB-65 as indicated by Immunoblotting and Immunohistochemistry. These results suggest that SP-CUR has a great potential for future clinical use in the management of pancreatic cancer. [ABSTRACT FROM AUTHOR]

Reactive oxygen species (ROS)-mediated nanocatalytic therapy, as conducted by the tumor microenvironment to generate toxic hydroxyl (OH) radicals with the assistant of Fenton nanocatalysts, exhibits high tumor-therapeutic promise due to its high therapeutic selectivity and desirable therapeutic outcome. The mostly explored Fe-based Fenton nanocatalysts-enabled nanocatalytic cancer therapy substantially suffers from lowed pH condition and the corresponding therapeutic effect is still far from satisfactory for further clinic application. In this work, we report, for the first time, that copper (Cu)-based nanocatalysts have the intrinsic capability to catalyze hydrogen peroxide (H 2 O 2) into hydroxyl radicals in a wide range pH condition with the comparable and even better performance as compared to mostly explored Fe-based nanocatalysts. Especially, ultrasmall (≤5 nm) PEGylated Cu 2-x S nanodots (Cu 2-x S-PEG) were fabricated to serve as the novel Fenton nanocatalysts for nanocatalytic tumor therapy. Importantly, taking the unique advantage of high near infrared (NIR) light absorbance at NIR-II biowindow (1000–1350 nm), light-activated photonic theranostic modality, i.e. photoacoustic imaging and photothermal therapy at both NIR-II biowindows was introduced, which could efficiently delineate/monitor the tumor regions and synergistically enhance Fenton-mediated therapeutic efficacy by photonic hyperthermia, respectively. Both systematic in vitro and in vivo experiments have demonstrated the high therapeutic efficacy of Cu 2-x S-enabled synergistic photothermal hyperthermia-enhanced nanocatalytic therapy. This work not only provides a nanoparticle-augmented synergistic cancer-therapeutic modality, but also enriches the totally new nanocatalyst types for catalytic Fenton reaction-based nanocatalytic tumor therapy. Image 1 [ABSTRACT FROM AUTHOR]

Abstract Developing new strategies to alleviate tumor hypoxia and enhance the therapeutic efficacy towards solid tumors is of great significance to tumor therapy. Herein, to overcome tumor hypoxia, specifically designed aza-BODIPY photosensitizer is co-loaded with anti-cancer drug (doxorubicin, DOX) onto the hydrangea-structured MnO 2 nanoparticles, and a tumor microenvironment (TME) responsive degradable nanoplatform (MDSP NP) is established. MDSP NPs (∼54 nm), with near infrared absorption (∼853 nm), can be rapidly dissociated to generate oxygen in response to TME, whereby improving tumor hypoxia, in favor of effective drugs release and enhanced chemo/photodynamic therapy. Revealed by in vivo fluorescence and photoaccoustic imaging, MDSP NPs are preferential accumulated at tumor site. Confirmed by photothermal imaging, MDSP NPs can induce hyperthermia to relieve hypoxia, promote the uptake of therapeutic nanoparticles, and further reduce the resistance and improve the therapeutic efficiency. As a result, a remarkable synergistic tumor chemo/photodynamic/photothermal therapy with hydrangea-structured TME responsive oxygen-self-generation nanoplatform is confirmed by both in vitro and in vivo studies, testifying its great potential for hypoxic tumor treatment in clinical application. [ABSTRACT FROM AUTHOR]

Abstract Glioblastoma (GBM) is the most common primary malignant brain tumor, with patients exhibiting poor survival (median survival time: 15 months). Difficulties in treating GBM include not only the inability to resect the diffusively-invading tumor cells, but also therapeutic resistance. The perivascular niche (PVN) within the GBM tumor microenvironment contributes significantly to tumor cell invasion, cancer stem cell maintenance, and has been shown to protect tumor cells from radiation and chemotherapy. In this study, we examine how the inclusion of non-tumor cells in culture with tumor cells within a hydrogel impacts the overall gene expression profile of an in vitro artificial perivascular niche (PVN) comprised of endothelial and stromal cells directly cultured with GBM tumor cells within a methacrylamide-functionalized gelatin hydrogel. Using RNA-seq, we demonstrate that genes related to angiogenesis and extracellular matrix remodeling are upregulated in the PVN model compared to hydrogels containing only tumor or perivascular niche cells, while downregulated genes are related to cell cycle and DNA damage repair. Signaling pathways and genes commonly implicated in GBM malignancy, such as MGMT, EGFR , PI3K-Akt signaling, and Ras/MAPK signaling are also upregulated in the PVN model. We describe the kinetics of gene expression within the PVN hydrogels over a course of 14 days, observing the patterns associated with tumor cell-mediated endothelial network co-option and regression. We finally examine the effect of temozolomide, a frontline chemotherapy used clinically against GBM, on the PVN culture. Notably, the PVN model is less responsive to TMZ compared to hydrogels containing only tumor cells. Overall, these results demonstrate that inclusion of cellular and matrix-associated elements of the PVN within an in vitro model of GBM allows for the development of gene expression patterns and therapeutic response relevant to GBM. Graphical abstract Image 1 [ABSTRACT FROM AUTHOR]

Abstract Mitochondria, which are a major source of adenosine triphosphate (ATP) and apoptosis regulators, are the key organelles that promote tumor cell proliferation, and their dysfunction affects tumor cell behavior. Additionally, mitochondria have been shown to play a central role in the biosynthesis of protoporphyrin IX (PpIX), which is a widely used photosensitizer that has been used for tumor detection, monitoring and photodynamic therapy. Nevertheless, photosensitizers administrated exogenously are often restricted by limited bioavailability.δ-Aminolevulinic acid (δ-ALA) is a naturally occurring delta amino acid that can be converted in situ to PpIX via the heme biosynthetic pathway in mitochondria. Because δ-ALA is the precursor for PpIX, δ-ALA-based photodynamic therapy (PDT) shows promise in treating cancer. However, the accumulation of δ-ALA within endosomal system limits the production of PpIX and eventually impedes its effectiveness. Theranostic nanoparticles (NPs) capable of endosomal escape are expected to optimize the endogenous biosynthetic yield. In this study, δ-ALA was improved with triphenylphosphoniumcation (TPP+), a high net position cation that functions in endosomal escape and as a mitochondria-targeting ligand, and was further modified with bovine serum albumin stabilized manganese dioxide (MnO 2). The tumor microenvironment (TME) responsive MnO 2 in this system can elevate oxygen content to relieve hypoxia. Both enhanced photosensitizer yield and elevated oxygen contributing to the final therapeutic effect. Moreover, the enhancement of magnetic resonance imaging (MRI) (r 1 = 5.410 s−1mM−1) stemming from the degradation of MnO 2 by the TME could serve as a guide prior to treatment for accurate location, while in situ hysteretic photoluminescence imaging derived from PpIX can be utilize as a supervisor for prognosis evaluation. This systematic design could broaden the biomedical application and highlight the considerable therapeutic promise of PDT. [ABSTRACT FROM AUTHOR]

Abstract Anticancer immunotherapy is emerging as a promising tumor treatment that can replace the conventional tumor treatment such as surgery, radiation and chemo drug, but its therapeutic effect against solid tumor is limited due to the tumor microenvironment (TME). Herein, to overcome this limitation, the biocompatibility controllable immuno-sensitizer (BCI) based on polyethylene imine that can be applied to solid tumors is developed. BCI accumulates in the tumors by EPR effect and induces in situ tumor destruction that convert tumors into antigen source by biocompatibility change through surface charge switching in response to the acidic TME. Generated tumor antigens promote the maturation of dendritic cells and recruitment of cytotoxic T cells in tumors. Results from in vitro and in vivo experiments reveal that the BCI effectively induces tumor destruction and antitumor immune response. In consequence, the synergic effect of in situ tumor destruction and antitumor immune response induced by BCI's biocompatibility conversion remarkably enhances immunotherapeutic effect. This study may provide a way to improve immunotherapeutic effect on solid tumors by demonstrating the therapeutic effect of BCI against solid tumor and suggest a platform to control the toxicity of cationic polymer for the its extended biomedical application. [ABSTRACT FROM AUTHOR]

Abstract The tumour microenvironment plays a vital role in the development of solid malignancies. Here we describe an in vitro human prostate cancer microtissue model that facilitates the incorporation and interrogation of key elements of the local prostatic tumour microenvironment. Primary patient-derived cancer-associated fibroblasts (CAFs) were cultured in three-dimensional (3D) melt electrowritten scaffolds where they deposited extensive extracellular matrix (ECM) and promoted significant changes in prostate epithelial morphology, when compared to matched non-malignant prostatic fibroblasts (NPFs). The addition of mast cells, a resident prostatic immune population that is expanded during early malignancy, enhanced the morphometric transition of benign epithelia via a tryptase-mediated mechanism. Our patient-specific 3D microtissues reveal a cascade of interactions between prostatic CAFs, their native ECM and mast cell-derived tryptase, rendering them important microenvironmental drivers of prostate cancer progression. [ABSTRACT FROM AUTHOR]

Abstract The effective design of a targeted drug delivery system could improve the therapeutic efficacy of anticancer drugs by reducing their undesirable adsorption and toxic side effects. Here, an RGD-peptide functionalized and bioresponsive ruthenium prodrug (Ru-RGD) was designed for both cancer therapy and clinical diagnosis. This prodrug can be selectively delivered to cervical tumor sites to enhance theranostic efficacy. The benzimidazole-based ligand of the complex is susceptible to acidic conditions so, after reaching the tumor microenvironment, ligand substitution occurs and the therapeutic drug is released. The deep-red emissions produced by both one-photon and two-photon excitation increases the potential of Ru-RGD for use in the deep tissue imaging of 3D tumor spheroids. The specific accumulation of the Ru prodrug in tumor sites allows for precise tumor diagnosis and therapy in vivo. Luminescence staining of 38 clinical patient specimens shows that Ru-RGD exhibits differences in binding capability between cervical cancer and normal tissue, with a sensitivity of 95% and a specificity of 100%. This study thus provides an approach for the effective design and application of targeted metal complexes in cancer therapy and clinical diagnosis. Graphical abstract A bioresponsive prodrug was designed to realize precise cancer therapy and rapid clinical diagnosis. The RGD-peptide functionalized Ru prodrug (Ru-RGD) could be selectively delivered to the tumor microenvironment, where it is designed to release the therapeutic drug. The deep-red luminescence of this complex makes it suitable for in vivo tumor imaging and specific luminescence staining of clinical specimens from patients, demonstrating the theranostic potential of these complexes. Image 1 [ABSTRACT FROM AUTHOR]

Abstract Polyrotaxane (PRX) is a promising supramolecular carrier for gene delivery. Classic PRX exhibits a linear structure in which the amine-functionalized α-cyclodextrin (CD) is threaded along the entire polyethylene glycol (PEG) backbone. While promising in vitro , the absence of free PEG moieties after CD threading compromised the in vivo implementation, due to the unfavorable pharmacokinetics (PK) and biodistribution profile. Herein, we developed a multi-arm PRX nanocarrier platform, which has been designed for protective nucleic acid encapsulation, augmented biodistribution and PK, and suitable for intravenous (IV) administration. A key design was to introduce cationic CD rings onto a multi-arm PEG backbone in a spatially selective fashion. The optimal structural design was obtained through iterative rounds of experimentation to determine the appropriate type and density of cationic charge on CD ring, the degree of PEGylation, the size and structure of polymer backbone, etc. This allowed us to effectively deliver large size reporter and therapeutic plasmids in cancer mouse models. Post IV injection, we demonstrated that our multi-arm polymer design significantly enhanced circulatory half-life and PK profile compared to the linear PRX. We continued to use the multi-arm PRX to formulate a therapeutic plasmid encoding an immunomodulatory cytokine, IL-12. When tested in a colon cancer syngeneic mouse model with same background, the IL-12 plasmid was protected by the multi-arm PRX and delivered through the tail vein to the tumor site, leading to a significant tumor inhibition effect. Moreover, our delivery system was devoid of major systemic toxicity. [ABSTRACT FROM AUTHOR]

Abstract Peritoneal invasion through the mesothelial cell layer is a hallmark of ovarian cancer metastasis. Using tissue engineering technologies, we recreated an ovarian tumor microenvironment replicating this aspect of disease progression. Ovarian cancer cell-laden hydrogels were combined with mesothelial cell-layered melt electrospun written scaffolds and characterized with proliferation and transcriptomic analyses and used as intraperitoneal xenografts. Here we show increased cancer cell proliferation in these 3D co-cultures, which we validated using patient-derived cells and linked to peritoneal tumor growth in vivo. Transcriptome-wide expression analysis identified IGFBP7, PTGS2, VEGFC and FGF2 as bidirectional factors deregulated in 3D co-cultures compared to 3D mono-cultures, which we confirmed by immunohistochemistry of xenograft and patient-derived tumor tissues and correlated with overall and progression-free survival. These factors were further increased upon expression of kallikrein-related proteases. This clinically predictive model allows us to mimic the complexity and processes of the metastatic disease that may lead to therapies that protect from peritoneal invasion or delay the development of metastasis. Graphical abstract Image 1 [ABSTRACT FROM AUTHOR]

Abstract Myeloid-derived suppressor cells (MDSCs) promote tumor-mediated immunosuppression and cancer progression. Gemcitabine (Gem) is a MDSC-depleting chemotherapeutic agent; however, its clinical use is hampered by its drug resistance and inefficient in vivo delivery. Here we describe a strategy to formulate a Gem analogue gemcitabine monophosphate (GMP) into a lipid-coated calcium phosphate (LCP) nanoparticle, and investigate its antitumor immunity and therapeutic effects after systemic administrations. In the syngeneic mouse model of B16F10 melanoma, compared with free Gem, the LCP-formulated GMP (LCP-GMP) significantly induced apoptosis and reduced immunosuppression in the tumor microenvironment (TME). LCP-GMP effectively depleted MDSCs and regulatory T cells, and skewed macrophage polarization towards the antitumor M1 phenotype in the TME, leading to enhanced CD8+ T-cell immune response and profound tumor growth inhibition. Thus, engineering the in vivo delivery of MDSC-depleting agents using nanotechnology could substantially modulate immunosuppressive TME and boost T-cell immune response for enhanced antitumor efficacy. [ABSTRACT FROM AUTHOR]

Abstract Radioresistance resulted from the intrinsic features of tumors often gives rise to unsatisfied therapeutic outcome. In particular, the tumor microenvironment (TME) with abundant antioxidants, elevated hydrogen peroxide (H 2 O 2) and hypoxia has been believed as a tremendous obstacle for radiotherapy. Therefore, developing an effective radiosensitizer in response to both X-ray and the TME is highly imperative but remains a challenge so far. Here, we for the first time explore bismuth heteropolytungstate (BiP 5 W 30) nanoclusters as radiosensitizers for the TME-manipulated enhancement of radiotherapy. On the one hand, BiP 5 W 30 nanoclusters can increase radiation dose deposition within tumors by high-Z elements like Bi and W. On the other hand, in virtue of the unique electron structure and multi-electron property, they have the capability of depleting glutathione (GSH) via redox reaction and catalyzing the decomposition of H 2 O 2 to HO to enhance ROS generation upon X-ray radiation. Moreover, reduced graphene oxide (rGO) coupled with BiP 5 W 30 can further improve radiocatalytic activity through promoting electron-hole separation. Simultaneously, due to the considerable near-infrared absorption of rGO, photothermal therapy can overcome the tumor hypoxia microenvironment and thus synergize with radiotherapy. In addition to providing a promising radiosensitizer, this finding is expected to extend the application of polyoxometalates used in the biomedical field. Graphical abstract The tumor microenvironment-manipulated bismuth heteropolytungstate nanoclusters could serve as a simple yet powerful radiocatalytic sensitizer for achieving tumor-specific radiotherapy by simultaneously increasing X-ray dose deposition and reversing the radio-resistance through the improvement of hypoxia environment, depletion of glutathione, and radiocatalytic conversion of overproduced hydrogen peroxide into highly toxic hydroxyl radical. Image 1 [ABSTRACT FROM AUTHOR]

Abstract Mild acidity matrix, rich blood vessels and special biomarkers constitute the primary tumor microenvironment. Nanoparticles could change their physicochemical characteristics by functionalizing a series of moieties which is responsive towards pH or specific markers. So precise regulation of nanocarrier-based drug delivery systems by the tumor microenvironment has showed great potential for theranostics. Herein, we developed a smart nano delivery system STD-NM, showing tumor microenvironment responsive targeting, efficient drug delivery and precise evaluation of therapeutic effect in vivo. STD-NM kept in 'stealth' state in normal environment while 'activated' in the tumor acidic environment, which could show stability in blood circulation while deeply penetrate into tumor tissues. Additionally, STD-NM was designed with aggregation-induced emission (AIE) characteristic, of which the fluorescence 'switch on' when apoptosis taken place. Gene analysis by RNA-seq also confirmed a superior therapeutic effect of drug loaded STD-NM treatment. We envisioned the well-designed smart nano materials for drug delivery could open a new avenue in precisely tumor imaging and specific cancer therapeutics. [ABSTRACT FROM AUTHOR]

Abstract The intrinsic characteristics of the tumor microenvironment (TME), including acidic pH and overexpression of hydrolytic enzymes, offer an exciting opportunity for the rational design of TME-drug delivery systems (DDS). We developed and characterized a pH-responsive biodegradable poly-L-glutamic acid (PGA)-based combination conjugate family with the aim of optimizing anticancer effects. We obtained combination conjugates bearing Doxorubicin (Dox) and aminoglutethimide (AGM) with two Dox loadings and two different hydrazone pH-sensitive linkers that promote the specific release of Dox from the polymeric backbone within the TME. Low Dox loading coupled with a short hydrazone linker yielded optimal effects on primary tumor growth, lung metastasis (∼90% reduction), and toxicological profile in a preclinical metastatic triple-negative breast cancer (TNBC) murine model. The use of transcriptomic analysis helped us to identify the molecular mechanisms responsible for such results including a differential immunomodulation and cell death pathways among the conjugates. This data highlights the advantages of targeting the TME, the therapeutic value of polymer-based combination approaches, and the utility of –omics-based analysis to accelerate anticancer DDS. Graphical abstract Image 1 [ABSTRACT FROM AUTHOR]

Abstract Given that vascular endothelial growth factor (VEGF) and placental growth factor (PIGF), over-expressed in breast cancer cells and M2-like tumor-associated macrophages (M2-TAMs) within tumor microenvironment (TME), work synergistically and independently in mediating tumor progression and immunosuppression, combinatorial immune-based approaches targeting them are expected to be a potent therapeutic modality for patients. Here, polyethylene glycol (PEG) and mannose doubly modified trimethyl chitosan (PEG = MT) along with citraconic anhydride grafted poly (allylamine hydrochloride) (PC)-based nanoparticles (NPs) (PEG = MT/PC NPs) with dual pH-responsiveness were developed to deliver VEGF siRNA (siVEGF)/PIGF siRNA (siPIGF) to both M2-TAMs and breast cancer cells for antitumor immunotherapy. With prolonged blood circulation and intelligent pH-sensitivity, PEG = MT/PC NPs were highly accumulated in tumor tissues and then internalized in M2-TAMs and breast cancer cells via mannose-mediated active targeting and passive targeting, respectively. With the charge-reversal of PC, PEG = MT/PC NPs presented effective endosomal/lysosomal escape and intracellular siRNA release, resulting in efficient gene silencing. Due to the synergism between siVEGF and siPIGF in anti-proliferation of tumor cells and reversal of the TME from pro-oncogenic to anti-tumoral, PEG = MT/PC/siVEGF/siPIGF NPs (PEG = MT/PC/siV-P NPs) exerted robust suppression of breast tumor growth and lung metastasis. This combination strategy may provide a promising alternative for breast cancer therapy. [ABSTRACT FROM AUTHOR]

Abstract 3D multicellular tumor spheroids (3D-MCTS) that closely mimic in vitro the complex lung tumor microenvironment (TME) are highly desirable for screening innovative anti-cancer therapeutics. Despite significant improvements in mimicking lung TME, few models have combined tumor-infiltrating mesenchymal stem cells from bone marrow (hBM-MSCs) with heterotypic 3D tumor spheroid models containing ECM mimetic components. Herein, we engineered hybrid 3D-MCTS that combine, for the first time, A549:fibroblasts:hBM-MSCs in heterotypic tri-culture, with bioinstructive hyaluronan microparticles that act as tumor-ECM mimetics and as cell-anchoring hotspots. The obtained results indicated that 3D microspheres provided proper support for cells to self-assemble into compact 3D microtissues and promoted an increase in CD44 expression, emulating the presence of native-ECM hyaluronan. 3D-MCTS size and sphere-like morphology was reproducible and tri-culture models presented the characteristic solid tumors necrotic core. Mesenchymal stem cells tracking demonstrated that hBM-MSCs migrate to different regions in 3D microtumors mass exhibiting dynamic interactions with cancer cells and stromal fibroblasts, alike in human tumors. Importantly, doxorubicin administration revealed hBM-MSCs effect on cytotoxic responses in 3D tri-culture models and in dual cultures of hBM-MSCs:A549 at 10:1 ratio. Such findings evidence the relevance of including hBM-MSCs in combination with cancer-stromal fibroblasts in 3D in vitro tumor models and the importance to test different cell-to-cell ratios to mimic tumor heterogeneity. In addition, bioinstructive hyaluronan-microparticles were also effective as cell-agglomerating scaffolds and showed potential to be used as an enabling technology for including different ECM components in 3D in vitro models in the future. [ABSTRACT FROM AUTHOR]

Glioblastoma (GBM) is the deadliest and most common type of primary brain tumor in adults with a grim prognosis despite multimodal treatments. Dendritic cell (DC)-based immunotherapy has emerged as a promising therapeutic modality for GBM, whose efficacy is nonetheless fundamentally undermined by GBM-induced immunosuppression. Inducing emission of damage associated molecular patterns (DAMPs) is a highly effective strategy to subvert tumor-associated immunosuppression. The present work was carried out to explore the idea of subverting the GBM immunosuppressive microenvironment through DC-mediated delivery of doxorubicin-polyglycerol-nanodiamond composites (Nano-DOX), a potent DAMPs inducer demonstrated by our previous study, and thereby eliciting enhanced DC-driven anti-GBM immune response. In the in-vitro work on human cell models, Nano-DOX-loaded DC were shown to be functionally viable and release cargo drug to co-cultured GBM cells (GC). Nano-DOX-treated GC displayed not only profuse DAMPs emission but also antigen release. Enhanced activation and acquisition and presentation of GC-derived antigen were then demonstrated in DC in co-culture with GC and Nano-DOX. Consistently, co-culture with GC and Nano-DOX also activated mouse bone marrow-derived DC (mDC) which in turn stimulated mouse spleen-derived lymphocytes which ultimately suppressed co-cultured GC. Next, athymic mice bearing orthotopic human GBM xenografts were intravenously injected with Nano-DOX-loaded mDC and, 48 h later, spleen-derived lymphocytes. The presence of Nano-DOX, DAMPs emission and enhanced infiltration and activation of mDC and lymphocytes were detected in the GBM xenografts. Taken together, our results demonstrate the efficacy of DC-mediated delivery of Nano-DOX to stimulate GC immunogenicity and elicit anti-cancer immune response in the GBM. By this work, we present a novel approach with great application potential to subverting the GBM immunosuppressive microenvironment and to anti-GBM immunotherapy. Investigation has also been conducted probing the mechanisms by which Nano-DOX stimulates GC immunogenicity, which is described in a follow-up paper. [ABSTRACT FROM AUTHOR]

Breast cancer cell invasion is influenced by growth factor concentration gradients in the tumor microenvironment. However, studying the influence of growth factor gradients on breast cancer cell invasion is challenging due to both the complexities of in vivo models and the difficulties in recapitulating the tumor microenvironment with defined gradients using in vitro models. A defined hyaluronic acid (HA)-based hydrogel crosslinked with matrix metalloproteinase (MMP) cleavable peptides and modified with multiphoton labile nitrodibenzofuran (NDBF) was synthesized to photochemically immobilize epidermal growth factor (EGF) gradients. We demonstrate that EGF gradients can differentially influence breast cancer cell invasion and drug response in cell lines with different EGF receptor (EGFR) expression levels. Photopatterned EGF gradients increase the invasion of moderate EGFR expressing MDA-MB-231 cells, reduce invasion of high EGFR expressing MDA-MB-468 cells, and have no effect on invasion of low EGFR-expressing MCF-7 cells. We evaluate MDA-MB-231 and MDA-MB-468 cell response to the clinically tested EGFR inhibitor, cetuximab. Interestingly, the cellular response to cetuximab is completely different on the EGF gradient hydrogels: cetuximab decreases MDA-MB-231 cell invasion but increases MDA-MB-468 cell invasion and cell number, thus demonstrating the importance of including cell-microenvironment interactions when evaluating drug targets. [ABSTRACT FROM AUTHOR]

Cancer immunotherapy has been emerging in recent years, due to the inherent nature of the immune system. Although recent successes of immunotherapeutics in clinical application have attracted development of a novel immunotherapeutics, the off-target side effect and low immunogenicity of them remain challenges for the effective cancer immunotherapy. Theranostic nanoparticle system may one of key technology to address these issues by offering targeted delivery of various types of immunotherapeutics, resulting in significant improvements in the tumor immunotherapy. However, appropriate design or engineering of nanoparticles will be needed to improve delivery efficiency of antigen, adjuvant and therapeutics, resulting in eliciting antitumor immunity. Here, we review the current state of the art of cancer immunotherapeutic strategies, mainly based on nanoparticles (NPs). This includes NP-based antigen/adjuvant delivery vehicles to draining lymph nodes, and tumor antigen-specific T-lymphocytes for cancer immunotherapy. Several NP-based examples are shown for immune checkpoint modulation and immunogenic cell death. These overall studies demonstrate the great potential of NPs in cancer immunotherapy. Finally, engineering NP strategies will provide great opportunities to improve therapeutic effects as well as optimization of treatment processes, allowing to meet the individual needs in the cancer immunotherapy. [ABSTRACT FROM AUTHOR]

Non-invasive imaging-guided tumor therapy requires new-generation bio-nanomaterials to sensitively respond to the unique tumor microenvironment for precise diagnosis and efficient treatment. Here, we report such a theranostic nanoplatform by engineering defect-rich multifunctional Cu-doped layered double hydroxide (Cu-LDH) nanoparticles, which integrates pH-sensitive T 1 -magnetic resonance imaging (MRI), acid-enhanced photothermal therapy and heat-facilitated chemotherapy. As characterized with EXAFS and XPS, smaller Cu-LDH nanoparticles possess a considerable amount of defects around Cu cations, an advantageous microstructure that enables a high photothermal conversion of 808 nm NIR laser (53.1%). The exposure of Cu OH octahedra on the LDH surface makes the photothermal conversion significantly acid-enhanced (53.1% at pH 7.0 vs. 81.9% at pH 5.0). This Cu peculiar microstructure also makes T 1 -MRI very pH-sensitive, a desirable guide for subsequent tumor photothermal therapy. Combined photothermal therapy and chemotherapy lead to nearly complete elimination of tumor tissues in vivo with a low injection dose of agents. Therefore, this novel defect-rich Cu-LDH nanoplatform is one of promising tumor-specific nanotheranostic agents for non-invasive imaging-guided combinational therapy. [ABSTRACT FROM AUTHOR]

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) can induce apoptosis in cancer cells without toxicity to normal cells. However, the efficiency is greatly limited by its short half-life and wild resistance in various cancer cells. In this study, we reported a micellar hybrid nanoparticle to carry TRAIL ligand (denoted as IPN@TRAIL) for a novel photo-excited TRAIL therapy. These IPN@TRAIL offered increased TRAIL stability, prolonged half-life and enhanced tumor accumulation, monitored by dual mode imaging. Furthermore, IPN@TRAIL nanocomposites enhanced wrapped TRAIL therapeutic efficiency greatly towards resistant cancer cells by TRAIL nanovectorization. More importantly, when upon external laser, these nanocomposites not only triggered tumor photothermal therapy (PTT), but also upregulated the expression of death receptors (DR4 and DR5), resulting in a greater apoptosis mediated by co-delivered TRAIL ligand. Such photo/TRAIL synergistic effect showed its great killing effects in a controllable manner on TRAIL-resistant A549 tumor model bearing mice. Finally, these nanocomposites exhibited rapid clearance without obvious systemic toxicity. All these features rendered our nanocomposites a promising theranostic platform in cancer therapy. [ABSTRACT FROM AUTHOR]