Gel-mediated recruitment of conventional type 1 dendritic cells potentiates the therapeutic effects of radiotherapy.

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.

An Injectable Puerarin Depot Can Potentiate Chimeric Antigen Receptor Natural Killer Cell Immunotherapy Against Targeted Solid Tumors by Reversing Tumor Immunosuppression.

Chimeric antigen receptor natural killer (CAR-NK) cell therapy represents a potent approach to suppressing tumor growth because it has simultaneously inherited the specificity of CAR and the intrinsic generality of NK cells in recognizing cancer cells. However, its therapeutic potency against solid tumors is still restricted by insufficient tumor infiltration, immunosuppressive tumor microenvironments, and many other biological barriers. Motivated by the high potency of puerarin, a traditional Chinese medicine extract, in dilating tumor blood vessels, an injectable puerarin depot based on a hydrogen peroxide-responsive hydrogel comprising poly(ethylene glycol) dimethacrylate and ferrous chloride is concisely developed. Upon intratumoral fixation, the as-prepared puerarin depot (abbreviated as puerarin@PEGel) can activate nitrogen oxide production inside endothelial cells and thus dilate tumor blood vessels to relieve tumor hypoxia and reverse tumor immunosuppression. Such treatment can thus promote tumor infiltration, survival, and effector functions of customized epidermal growth factor receptor (HER1)-targeted HER1-CAR-NK cells after intravenous administration. Consequently, such puerarin@PEGel-assisted HER1-CAR-NK cell treatment exhibits superior tumor suppression efficacy toward both HER1-overexpressing MDA-MB-468 and NCI-H23 human tumor xenografts in mice without inducing obvious side effects. This study highlights a potent strategy to activate CAR-NK cells for augmented treatment of targeted solid tumors through reprogramming tumor immunosuppression.

Tumor Microenvironment Modulating CaCO3 -Based Colloidosomal Microreactors Can Generally Reinforce Cancer Immunotherapy.

Tumor hypoxia and acidity, two general features of solid tumors, are known to have negative effect on cancer immunotherapy by directly causing dysfunction of effector immune cells and promoting suppressive immune cells inside tumors. Herein, a multifunctional colloidosomal microreactor is constructed by encapsulating catalase within calcium carbonate (CaCO3 ) nanoparticle-assembled colloidosomes (abbreviated as CaP CSs) via the classic double emulsion method. The yielded CCaP CSs exhibit well-retained proton-scavenging and hydrogen peroxide decomposition performances and can thus neutralize tumor acidity, attenuate tumor hypoxia, and suppress lactate production upon intratumoral administration. Consequently, CCaP CSs treatment can activate potent antitumor immunity and thus significantly enhance the therapeutic potency of coloaded anti-programmed death-1 (anti-PD-1) antibodies in both murine subcutaneous CT26 and orthotopic 4T1 tumor xenografts. In addition, such CCaP CSs treatment also markedly reinforces the therapeutic potency of epidermal growth factor receptor expressing chimeric antigen receptor T (EGFR-CAR-T) cells toward a human triple-negative breast cancer xenograft by promoting their tumor infiltration and effector cytokine secretion. Therefore, this study highlights that chemical modulation of tumor acidity and hypoxia can collectively reverse tumor immunosuppression and thus significantly potentiate both immune checkpoint blockade and CAR-T cell immunotherapies toward solid tumors.

Self-fueling ferroptosis-inducing microreactors based on pH-responsive Lipiodol Pickering emulsions enable transarterial ferro-embolization therapy.

Lipiodol chemotherapeutic emulsions remain one of the main choices for the treatment of unresectable hepatocellular carcinoma (HCC) via transarterial chemoembolization (TACE). However, the limited stability of Lipiodol chemotherapeutic emulsions would lead to rapid drug diffusion, which would reduce the therapeutic benefit and cause systemic toxicity of administrated chemotherapeutics. Therefore, the development of enhanced Lipiodol-based formulations is of great significance to enable effective and safe TACE treatment. Herein, a stable water-in-oil Lipiodol Pickering emulsion (LPE) stabilized by pH-dissociable calcium carbonate nanoparticles and hemin is prepared and utilized for efficient encapsulation of lipoxygenase (LOX). The obtained LOX-loaded CaCO3&hemin-stabilized LPE (LHCa-LPE) showing greatly improved emulsion stability could work as a pH-responsive and self-fueling microreactor to convert polyunsaturated fatty acids (PUFAs), a main component of Lipiodol, to cytotoxic lipid radicals through the cascading catalytic reaction driven by LOX and hemin, thus inducing ferroptosis of cancer cells. As a result, such LHCa-LPE upon transcatheter embolization can effectively suppress the progression of orthotopic N1S1 HCC in rats. This study highlights a concise strategy to prepare pH-responsive and stable LPE-based self-fueling microreactors, which could serve as bifunctional embolic and ferroptosis-inducing agents to enable proof-of-concept transarterial ferro-embolization therapy of HCC.

Efferocytosis Nanoinhibitors to Promote Secondary Necrosis and Potentiate the Immunogenicity of Conventional Cancer Therapies for Improved Therapeutic Benefits.

Efferocytosis of apoptotic cancer cells by tumor-associated macrophages or other phagocytes is reported to promote tumor immunosuppression by preventing them from secondary necrosis, which would lead to the release of intracellular components and thus enhanced immunogenicity. Therefore, current apoptosis-inducing cancer treatments (e.g., chemotherapy and radiotherapy) are less satisfactory in eliciting antitumor immunity. Herein, a nanoparticulate inhibitor of efferocytosis is prepared by encapsulating BMS777607, a hydrophobic inhibitor of receptors in macrophages responsible for phosphatidylserine-dependent efferocytosis, with biocompatible poly(lactic-co-glycolic acid) and its amphiphilic derivatives. The yielded nano-BMS can inhibit the efferocytosis of apoptotic cancer cells, thus redirecting them to immunogenic secondary necrosis. As a result, intratumorally injected nano-BMS is capable of activating both innate and adaptive antitumor immunity to achieve greatly improved therapeutic responses, when synergized with nonimmunogenic chemotherapy by cisplatin, immunogenic chemotherapy by oxaliplatin, or radiotherapy by external beams. Moreover, we further demonstrate that the inhalation of nano-BMS could significantly promote the efficacy of cisplatin chemotherapy to suppress tumor lung metastases. Therefore, this study highlights a general strategy to potentiate the immunogenicity of different cancer treatments by suppressing efferocytosis-propelled tumor immunosuppression, showing tremendous clinical potential in rescuing existing cancer therapies for more effective treatment.

Nanomedicine sheds new light on cancer immunotherapy.

Cancer immunotherapy comprising of immune checkpoint blockade (ICB) therapy, immune cell therapies, cancer vaccines and many others represents a profound arsenal in the fight against different types of cancers. However, their overall clinical objective response rates, particularly against most solid tumors, are still not sufficient owing to a variety of reasons including the heterogenous expression of tumor antigens, limited tumor infiltration of effector immune cells, acquired tumor immunosuppression and some other factors. In recent years, various nanomedicine strategies have been proposed to assist cancer immunotherapy via distinct mechanisms, presenting new promises in many published studies. This perspective will thus provide a brief overview regarding the development of nanomedicine platforms for improving cancer immunotherapy.

Microbubbles-assisted ultrasonication to promote tumor accumulation of therapeutics and modulation of tumor microenvironment for enhanced cancer treatments.

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.

A General Biomineralization Strategy to Synthesize Autologous Cancer Vaccines with cGAS-STING Activating Capacity for Postsurgical Immunotherapy.

Autologous cancer vaccines constructed by nonproliferative whole tumor cells or tumor lysates together with appropriate adjuvants represent a promising strategy to suppress postsurgical tumor recurrence. Inspired by the potency of cytosolic double-stranded DNA (dsDNA) in initiating anticancer immunity by activating the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway, we herein report the concise synthesis of a cGAS-STING agonist through dsDNA-templated biomineralization growth of calcium carbonate (CaCO3) microparticles. The yielded DNA@CaCO3 can activate the intracellular cGAS-STING pathway of dendritic cells (DCs) by promoting endosomal escape of dsDNA, triggering their maturation and activation as a potent immune stimulator. Upon intratumoral injection, DNA@CaCO3 can reverse the immunosuppressive tumor microenvironment by simultaneously provoking innate and adaptive antitumor immunity, thereby effectively suppressing the growth of murine CT26 and B16-F10 tumors in mice. Furthermore, via CaCO3-based biomineralization of complete tumor lysates, we constructed a personalized autologous cancer vaccine with intrinsic cGAS-STING activation capacity that could provoke tumor-specific immune responses to not only delay the growth of challenged tumors but also synergize with anti-PD-1 immunotherapy to suppress postsurgical tumor recurrence. This study highlights a CaCO3-based biomineralization method to prepare autologous cancer vaccines in a concise manner, which is promising for personalized immunotherapy and clinical translation.

Rational Design of Biomaterials to Potentiate Cancer Thermal Therapy.

Cancer thermal therapy, also known as hyperthermia therapy, has long been exploited to eradicate mass lesions that are now defined as cancer. With the development of corresponding technologies and equipment, local hyperthermia therapies such as radiofrequency ablation, microwave ablation, and high-intensity focused ultrasound, have has been validated to effectively ablate tumors in modern clinical practice. However, they still face many shortcomings, including nonspecific damages to adjacent normal tissues and incomplete ablation particularly for large tumors, restricting their wide clinical usage. Attributed to their versatile physiochemical properties, biomaterials have been specially designed to potentiate local hyperthermia treatments according to their unique working principles. Meanwhile, biomaterial-based delivery systems are able to bridge hyperthermia therapies with other types of treatment strategies such as chemotherapy, radiotherapy and immunotherapy. Therefore, in this review, we discuss recent progress in the development of functional biomaterials to reinforce local hyperthermia by functioning as thermal sensitizers to endow more efficient tumor-localized thermal ablation and/or as delivery vehicles to synergize with other therapeutic modalities for combined cancer treatments. Thereafter, we provide a critical perspective on the further development of biomaterial-assisted local hyperthermia toward clinical applications.

Biomaterials-assisted construction of neoantigen vaccines for personalized cancer immunotherapy.

INTRODUCTION: Cancer vaccine represents a promising strategy toward personalized immunotherapy, and its therapeutic potency highly relies on the specificity of tumor antigens. Among these extensively studied tumor antigens, neoantigens, a type of short synthetic peptides derived from random somatic mutations, have been shown to be able to elicit tumor-specific antitumor immune response for tumor suppression. However, challenges remain in the efficient and safe delivery of neoantigens to antigen-presenting cells inside lymph nodes for eliciting potent and sustained antitumor immune responses. The rapid advance of biomaterials including various nanomaterials, injectable hydrogels, and macroscopic scaffolds has been found to hold great promises to facilitate the construction of efficient cancer vaccines attributing to their high loading and controllable release capacities. AREAS COVERED: In this review, we will summarize and discuss the recent advances in the utilization of different types of biomaterials to construct neoantigen-based cancer vaccines, followed by a simple perspective on the future development of such biomaterial-assisted cancer neoantigen vaccination and personalized immunotherapy. EXPERT OPINION: These latest progresses in biomaterial-assisted cancer vaccinations have shown great promises in boosting substantially potentiated tumor-specific antitumor immunity to suppress tumor growth, thus preventing tumor metastasis and recurrence.

Chemical Modulation of Glucose Metabolism with a Fluorinated CaCO3 Nanoregulator Can Potentiate Radiotherapy by Programming Antitumor Immunity.

Tumor hypoxia and acidity are well-known features in solid tumors that cause immunosuppression and therapeutic resistance. Herein, we rationally synthesized a multifunctional fluorinated calcium carbonate (fCaCO3) nanoregulator by coating CaCO3 nanoparticles with dopamine-grafted perfluorosebacic acid (DA2-PFSEA) and ferric ions by utilizing their coordination interaction. After PEGylation, the obtained fCaCO3-PEG showed high loading efficacy to perfluoro-15-crown-5-ether (PFCE), a type of perfluorocarbon with high oxygen solubility, thereby working as both oxygen nanoshuttles and proton sponges to reverse tumor hypoxia and acidity-induced resistance to radiotherapy. The as-prepared PFCE@fCaCO3-PEG could not only function as long-circulating oxygen nanoshuttles to attenuate tumor hypoxia but also neutralize the acidic tumor microenvironment by restricting the production of lactic acid and reacting with extracellular protons. As a result, treatment with PFCE@fCaCO3-PEG could improve the therapeutic outcome of radiotherapy toward two murine tumors with distinct immunogenicity. The PFCE@fCaCO3-PEG-assisted radiotherapy could also collectively inhibit the growth of unirradiated tumors and reject rechallenged tumors by synergistically eliciting protective antitumor immunity. Therefore, our work presents the preparation of fluorinated CaCO3 nanoregulators to reverse tumor immunosuppression and potentiate radiotherapy through chemically modulating tumor hypoxic and acidic microenvironments tightly associated with tumor glucose metabolism.

Liposomal oxaliplatin prodrugs loaded with metformin potentiate immunotherapy for colorectal cancer.

Tumor hypoxia is confirmed to be associated with the formation of tumor immunosuppression, a general feature of solid tumors, and thus attenuates the effectiveness of various cancer therapies in clinic. We herein develop a tumor microenvironment (TME) modulating liposomal nanomedicine by encapsulating metformin with amphiphilic oxaliplatin prodrug constructed liposomes to potentiate cancer immunotherapy. While metformin could regulate metabolisms of tumor cells to reduce their oxygen consumption and relieve tumor hypoxia, oxaliplatin is a chemotherapy drug that induces immunogenic cell death (ICD). The obtained met-oxa(IV)-liposome upon intravenous injection effectively attenuates tumor hypoxia and induce ICD of cancer cells, thereby collectively suppresses the growth of murine colorectal tumors by eliciting potent antitumor immunity and reversing the immunosuppressive TME. As the result, the treatment with met-oxa(IV)-liposome effectively potentiates the immune checkpoint blockade (ICB) therapy against murine colorectal tumors. This liposomal nanomedicine is highlighted to be a TME modulating liposomal nanomedicine with high potency in suppressing tumor growth, particularly promising in synergizing with ICB therapy by boosting antitumor immune responses.

Metallo-alginate hydrogel can potentiate microwave tumor ablation for synergistic cancer treatment.

Microwave ablation (MWA) as a local tumor ablation strategy suffers from posttreatment tumor recurrence. Development of adjuvant biomaterials to potentiate MWA is therefore of practical significance. Here, the high concentration of Ca2+ fixed by alginate as Ca2+-surplus alginate hydrogel shows enhanced heating efficiency and restricted heating zone under microwave exposure. The high concentration of extracellular Ca2+ synergizes with mild hyperthermia to induce immunogenic cell death by disrupting intracellular Ca2+ homeostasis. Resultantly, Ca2+-surplus alginate hydrogel plus MWA can ablate different tumors on both mice and rabbits at reduced operation powers. This treatment can also elicit antitumor immunity, especially if synergized with Mn2+, an activator of the stimulation of interferon genes pathway, to suppress the growth of both untreated distant tumors and rechallenged tumors. This work highlights that in situ-formed metallo-alginate hydrogel could act as microwave-susceptible and immunostimulatory biomaterial to reinforce the MWA therapy, promising for clinical translation.

Ferrous ions doped calcium carbonate nanoparticles potentiate chemotherapy by inducing ferroptosis.

Ferroptosis is a recently identified regulated cell death pathway featured in iron prompted lipid peroxidation inside cells and found to be an effective approach to suppress tumor growth. Motived by the high efficacy of ferrous ions (Fe2+) in initiating intracellular lipid peroxidation via the Fenton reaction, this study herein prepares a pH-responsive Fe2+ delivery nanocarrier by coating calcium carbonate (CaCO3) nanoparticles with a metal-polyphenol coordination polymer composed of gallic acid (GA) and Fe2+. Together with simultaneous encapsulation of succinic acid conjugated cisplatin prodrugs (Pt(IV)-SA) and Fe2+, the yielded nanoparticles, coined as PGFCaCO3, are synthesized and exhibit uniform hollow structure. After PEGylation, the resulted PGFCaCO3-PEG shows increased physiological stability and pH-dependent decomposition, drug release and catalytic capability in initiating lipid peroxidation. After being endocytosed, PGFCaCO3-PEG effectively promoted intracellular generation of cytotoxic reactive oxygen species including lipid peroxide, thereby exhibited superior inhibition effect towards both murine 4T1 and CT26 cancer cells over Pt(IV)-SA and GFCaCO3-PEG. As a result, treatment with systemic administration of PGFCaCO3-PEG effectively suppressed 4T1 tumor growth via combined Fe2+ initiated ferroptosis and Pt(IV)-SA mediated chemotherapy. This work highlights that intracellular delivery of Fe2+ is a robust approach to enhance tumor chemotherapy by inducing ferroptosis.

Lipid-coated CaCO3-PDA nanoparticles as a versatile nanocarrier to enable pH-responsive dual modal imaging-guided combination cancer therapy.

Development of an intelligent and versatile delivery system to achieve tumor-targeted delivery and controlled release of diverse functional moieties is of great significance to realize precise cancer theranostics. In this study, we use pH-dissociable calcium carbonate-polydopamine (pCaCO3) nanocomposites as a template to guide the formation of a lipid bilayer on their surface, yielding lipid-coated pCaCO3 nanoparticles with high loading efficacies towards gadolinium ions (Gd3+), doxorubicin (DOX) and 1,1'-dioctadecyl-3,3,3',3'-tetramethylindotricarbocyanine iodide (DiR). The obtained liposomal nanotheranostics show excellent physiological stability and pH-dependent release of DOX and Gd3+; the latter could lead to pH-dependent T1 signal enhancement under magnetic resonance (MR) imaging, as well as efficient photothermal conversion efficacy. Then, we found that tumors in mice with intravenous injection of DiR-DOX-Gd@pCaCO3-PEG could be clearly visualized in a real-time manner by recording their near-infrared (NIR) fluorescence and T1 MR signal. Furthermore, treatment with such liposomal nanotheranostics injection and NIR laser irradiation could enable collective suppression of the growth of 4T1 tumors in Balb/c mice via combined chemo- and photothermal therapies. Therefore, this work highlights the concise preparation of lipid-coated pCaCO3 nanocomposites, which could be utilized for the construction of diverse cancer nanotheranostics by exploiting their versatile loading capacities.

Lipid-Coated CaCO3 Nanoparticles as a Versatile pH-Responsive Drug Delivery Platform to Enable Combined Chemotherapy of Breast Cancer.

The development of smart drug delivery nanocarriers for tumor-targeted delivery and controllable release of therapeutic agents is appealing to achieve effective cancer chemotherapy. We herein use CaCO3 nanoparticles as the core to load doxorubicin (DOX) and direct the assembly of amphiphilic oxaliplatin prodrugs (Pt(IV)) in the presence of other commercial lipids. The obtained DOX-Pt(IV)-CaCO3-PEG with excellent physiological stability exhibits instant pH-responsive degradation, thus enabling efficient pH-dependent release of DOX. Via detailed pharmacokinetic study, it is shown that DOX-Pt(IV)-CaCO3-PEG shows significantly improved pharmacokinetic behaviors compared to these free drugs, featured in prolonged blood circulation time and superior tumor homing efficacy. Resultantly, treatment with systemic administration of DOX-Pt(IV)-CaCO3-PEG was the most effective in suppressing the growth of tumors in Balb/c mice. This study highlights that our liposomal CaCO3 is a robust and biocompatible platform for preparing pH-responsive drug delivery systems, due to its multifaceted drug loading capacity, and thus is promising for potential clinical translation.

Immunogenic nanomedicine based on GSH-responsive nanoscale covalent organic polymers for chemo-sonodynamic therapy.

Sonodynamic therapy (SDT) is emerging as a non-invasive strategy to eradicate tumors, but its therapeutic efficacy is still not ideal. To achieve more effective SDT, water insoluble sonosensitizer meso-5, 10, 15, 20-tetra(4-hydroxylphenyl)porphyrin (THPP) is here esterified with succinic acid conjugated oxaliplatin prodrug (Oxa(IV)SA2) and carboxyl group terminated PEG (PEG5k-COOH). The obtained covalent organic polymer (COP) of THPP-Oxa(IV)-PEG with good physiological stability, sonosensitization efficacy and glutathione (GSH) responsive oxalipatin responsive behaviors can induce effective immunogenic cancer cell death upon the ultrasound exposure. In addition, THPP-Oxa(IV)-PEG is shown to be a versatile carrier for both hydrophobic near infrared dye and radioisotope 99mTc, thereby enabling real-time tracking of its pharmacokinetics behavior under corresponding imaging facilities. Furthermore, treatment with THPP-Oxa(IV)-PEG injection and ultrasound exposure is shown to be most effectively in suppressing tumor growth, with 3 of 6 CT26 tumor bearing mice fully cured, ascribing to its high potency in eliciting profound antitumor immune responses. This work highlights a promising strategy in constructing multifunctional nanosonosensitizer as a potent immunogenic nanomedicine to enhance the treatment outcome of SDT.

Engineering bioluminescent bacteria to boost photodynamic therapy and systemic anti-tumor immunity for synergistic cancer treatment.

The limited penetration depth of external excitation light would remarkably impair the therapeutic efficacy of photodynamic therapy (PDT) and its clinical utilization. Herein, we engineered bioluminescent bacteria by transforming attenuated Salmonella typhimurium strain ΔppGpp (S.T.ΔppGpp) with firefly-luciferase-expressing plasmid (Luc-S.T.ΔppGpp) as an internal light source to evenly illuminate whole tumors. Upon being fixed inside tumors with in-situ formed hydrogel, the colonized Luc-S.T.ΔppGpp together with D-luciferin could continuously generate light to excite photosensitizer chlorin e6 (Ce6), leading to effective suppression of different types of tumors including opaque melanoma and large rabbit tumors. Such bioluminescence-triggered PDT presented significant advantages over conventional PDT excited with an external 660-nm light, which at a much high light energy could only slightly retard the growth of small subcutaneous tumors. Furthermore, we uncovered that Luc-S.T.ΔppGpp boosted PDT could also elicit potent antitumor immunity post the treatment to inhibit tumor metastasis and prevent tumor challenge. Therefore, this work highlights that such bioluminescent bacteria boosted PDT is a general and highly effective therapeutic approach toward diverse cancers with varying light-absorbing capacities and tumor sizes, promising for potential clinical translation because of their acceptable safety profiles.

Coordination Polymer-Coated CaCO3 Reinforces Radiotherapy by Reprogramming the Immunosuppressive Metabolic Microenvironment.

Radiotherapy is widely exploited for the treatment of a large range of cancers in clinic, but its therapeutic effectiveness is seriously crippled by the tumor immunosuppression, mainly driven by the altered metabolism of cancer cells. Here, a pH-responsive nanomedicine is prepared by coating calcium carbonate (CaCO3 ) nanoparticles with 4-phenylimidazole (4PI), an inhibitor against indoleamine 2,3-dioxygenase 1 (IDO-1), together with zinc ions via the coordination reaction, aiming at reinforcing the treatment outcome of radiotherapy. The obtained pH-responsive nanomedicine, coined as acidity-IDO1-modulation nanoparticles (AIM NPs), is able to instantly neutralize protons, and release 4PI to suppress the IDO1-mediated production of kynurenine (Kyn) upon tumor accumulation. As a result, treatment with AIM NPs can remarkably enhance the therapeutic efficacy of radiotherapy against both murine CT26 and 4T1 tumors by eliciting potent antitumor immunity. Furthermore, it is shown that such combination treatment can effectively suppress the growth of untreated distant tumors via the abscopal effect, and result in immune memory responses to reject rechallenged tumors. This work highlights a novel strategy of simultaneous tumor acidity neutralization and IDO1 inhibition to potentiate radiotherapy, with great promises to suppress tumor metastasis and recurrence by eliciting robust antitumor immunity.

Perfluorocarbon loaded fluorinated covalent organic polymers with effective sonosensitization and tumor hypoxia relief enable synergistic sonodynamic-immunotherapy.

Relieving tumor hypoxia has recently been found to be a promising approach to reverse tumor immunosuppression and thus enhance the treatment outcomes of diverse cancer treatments. Herein, we prepared a type of fluorinated covalent conjugate polymers (COPs) with sonosensitizer meso-5, 10, 15, 20-tetra (4-hydroxylphenyl) porphyrin (THPP) and perfluorosebacic acid (PFSEA) as cross-linkers, yielding THPPpf-COPs with efficient sonodynamic efficacy and loading capacity towards perfluoro-15-crown-5-ether (PFCE), a model perfluorocarbon molecule. Upon intratumoral injection, such PFCE@THPPpf-COPs could not only attenuate tumor hypoxia, but also exhibit the most effective suppression effect on tumor growth in the presence of ultrasound exposure by inducing immunogenic cell death of cancer cells. Furthermore, we found that the sonodynamic therapy of PFCE@THPPpf-COPs together with anti-CD47 immunotherapy would synergistically suppress tumor growth by increasing the tumor-infiltrating frequencies of phagocytic M1 macrophages and cytotoxic CD3+CD8+ T cells, while reducing the frequency of immunosuppressive regulatory T cells. Moreover, such combination treatment could also elicit potent protective memory antitumor immunity to prevent tumor challenge. Therefore, this work presents PFCE@THPPpf-COPs are a type of multifunctional nano-sonosensitizers potent in removing negative impacts of inherent tumor hypoxia and immunosuppression, and suppressing tumor growth and tumor recurrence by priming host's antitumor immunity, particularly in synergizing with anti-CD47 immunotherapy.