Metabolic Regulation of Tumor Microenvironment with Biohybrid Bacterial Bioreactor for Enhanced Cancer Chemo-Immunotherapy

Immunogenic cell death (ICD) induced by specific chemotherapeutic agents is often hampered by the immunosuppressive tumor microenvironment (TME). Here, a bacterial bioreactor E@Fe-DOX, is developed, to enhance ICD-mediated antitumor immunity by in situ manipulation of tumor metabolism-immune interactions. The E@Fe-DOX bioreactor is constructed by depositing doxorubicin-loaded iron-polyphenol nanoparticles on Eubacterium hallii, which can specifically target hypoxic tumor regions and release doxorubicin and Fe³⁺ to induce ICD. In addition, Eubacterium hallii can continuously convert intratumoral lactate to butyrate, which inhibits the polarization of pro-tumoral M2-like macrophages and improves the function of tumor-infiltrating cytotoxic T cells. Furthermore, E@Fe-DOX promotes the formation of immune cell-aggregated tertiary lymph structures (TLS) to augment ICD-induced antitumor immunity. In murine tumor models, E@Fe-DOX significantly inhibits tumor growth and enhances immune checkpoint blockade (ICB) therapy. Overall, the developed living biomaterial offers a promising strategy to potentiate cancer chemo-immunotherapy by continuously regulating the intratumoral immuno-metabolic microenvironment.     

Dynamically Reconstructed Collagen Fibers for Transmitting Mechanical Signals to Assist Macrophages Tracing Breast Cancer Cells

Constructing proper in vitro tumor immune microenvironment (TIME) is important for cancer immune-therapy studies, while the selection of biomaterials is critical. As innate immune cells, macrophages can target and kill cancer cells in vivo at the early stage of tumor development. However, this targeting phenomenon has not been observed in vitro. Herein, a quasi-3D in vitro cell culture model is constructed to mimic TIME by integrating hydrogel collagen as extracellular matrix for cells. In the collagen-based quasi-3D in vitro system, for the first time, it is found that macrophages can be attracted toward cancer cells along the dynamically reconstructed collagen fibers. By combining traction force microscopy and customized micro-manipulator system, it is revealed that the collagen matrix-transmitted tensile force signaling precisely guides the migration of macrophages toward cancer cells. The mechano-responsiveness mechanism is related to the activation of mechanosensitive ion channels, and the induced local increase of calcium signal, which is proved to enhance the F-actin assembly and to guide the cell migration. This novel mechanism advances the understanding of the role of collagen fibers in mechanotaxis of macrophages. Taken together, it has great potential for assisting biomaterial designs in developing new drug-screening models and clinical strategies for cancer immune-therapy.     

Designing Bioinspired 2D MoSe2 Nanosheet for Efficient Photothermal‐Triggered Cancer Immunotherapy with Reprogramming Tumor‐Associated Macrophages

Nonspecific absorption and clearance of nanomaterials during circulation is the major cause for treatment failure in nanomedicine‐based cancer therapy. Therefore, herein bioinspired red blood cell (RBC) membrane is employed to camouflage 2D MoSe₂ nanosheets with high photothermal conversion efficiency to achieve enhanced hemocompatibility and circulation time by preventing macrophage phagocytosis. RBC–MoSe₂‐potentiated photothermal therapy (PTT) demonstrates potent in vivo antitumor efficacy, which triggers the release of tumor‐associated antigens to activate cytotoxic T lymphocytes and inactivate the PD‐1/PD‐L1 pathway to avoid immunologic escape. Furthermore, in the ablated tumor microenvironment, the tumor‐associated macrophages are effectively reprogrammed to tumoricidal M1 phenotype to potentiate the antitumor action. Taken together, this biomimetic functionalization thus provides a substantial advance in personalized PTT‐triggered immunotherapy for clinical translation.     

An Integrated Nanoaircraft Carrier Modulating Antitumor Immunity to Enhance Immune Checkpoint Blockade Therapy

Immune checkpoint blockade (ICB) therapy revolutionizes cancer therapeutics. However, the effectiveness of ICB therapy is restricted. Focusing on the tumor itself and the immune system, an integrated nanoaircraft carrier that coloaded three therapeutic agents (NNG/OTC) to eradicate tumor cells, enhance T-cells intratumoral infiltration, and relieve the inhibition of tumor immunosuppressive microenvironment (TIM) is designed. First, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is used to combine with oxaliplatin for reducing tumor burden. Second, oxaliplatin is used to elicit immunogenic cell death and combine with cytosine-phosphate-guanine (CpG) to promote dendritic cells maturation, ultimately increasing T-cells intratumoral infiltration. Third, CpG is further used to repolarize M2 type of tumor-associated macrophages, thus reversing immunosuppression of TIM. The nanoaircraft carrier can effectively arrive at the tumor site and detach small-sized nanoparticles under a high concentration of matrix metalloproteinase-2, which promotes deep tumor penetration. Under the mediation of targeting ligands, three therapeutic agents loaded in small-sized nanoparticles could be launched to their target cells. NNG/OTC modulates the antitumor immunity and exhibits excellent tumor inhibition when in combination with ICB therapy, indicating the increased response of ICB therapy. Collectively, NNG/OTC can co-deliver various drugs with different physicochemical properties and provide a promising strategy for enhancing ICB therapy.     

Antibody Engineered Platelets Attracted by Bacteria-Induced Tumor-Specific Blood Coagulation for Checkpoint Inhibitor Immunotherapy

Bacteria can act as a promising anti-tumor platform due to their specific targeting capacity to the tumor microenvironment. In this study, it is discovered that intravenous administration of Escherichia coli TOP10 induces rapid and intense blood coagulation in tumor tissues instead of normal tissues. It is demonstrated that E. coli TOP10 can act as an activator of a coagulation cascade to trigger abnormal hemorrhage, blood coagulation, and inflammation with abundant macrophages recruitment in tumors. In addition, the recruited macrophages are principally polarized by lipopolysaccharide in the bacterial wall to the anti-tumor M1-like phenotype. Based on the above finding, coagulation-tropism blood platelets decorated with CD47 antibodies (Anti-CD47), which possess tropism for bacteria-treated tumors are further prepared. As a result, Anti-CD47 blocks the “don't eat me” signal from tumor cells, consequently promoting the phagocytosis of polarized M1-like phenotype macrophages for tumor cells. This manipulation of local blood coagulation in tumors may find great potential for accurately delivering immune checkpoint inhibitors and facilitating tumor immunotherapy.     

Copper Sulfide Nanoparticle-Redirected Macrophages for Adoptive Transfer Therapy of Melanoma

Adoptive cell therapy (ACT) has achieved landmark advances in treating cancer in clinic. Recent advances in ACT of macrophages engineered to express chimeric antigen receptors (CARs) have shown effectiveness in treating solid tumors. However, the CAR-macrophage therapy is dependent on tumor antigen recognition and gene editing methods. Herein, an adoptive macrophage therapy is presented through copper sulfide nanoparticle-regulation that exhibits substantial antitumor effect in melanoma-bearing mice, without the need for tumor antigen repertoire. Bone marrow derived macrophages (BMDMs) incubated with the nanoparticles promote the cellular production of reactive oxygen species (ROS) through dynamin-related protein 1 (Drp1)-mediated mitochodrial fission. The high intracellular ROS level directs BMDMs polarization toward M1 phenotype by classical IKK-dependent NF-κB activation. Moreover, the copper sulfide nanoparticle-stimulated BMDMs (CuS-MΦ) reduce the expression of programmed death-1 (PD-1) and exhibit enhanced phagocytic and digestive ability. Intratumoral transfer of CuS-MΦ significantly prolongs the median survival time of the tumor-bearing mice, remodels the tumor microenvironment, and elicits systemic antitumor immunity. These results suggest a cancer therapeutic approach of adoptively transferred macrophages through the induction of intracellular ROS with nanomaterials.     

Reshaping Antitumor Immunity with Chemo-Photothermal Integrated Nanoplatform to Augment Checkpoint Blockade-Based Cancer Therapy

Immune checkpoint therapy promotes cytotoxic T lymphocytes (CTLs) activity to eliminate tumors. Nevertheless, their effectiveness in solid tumors is limited by inadequate infiltration of CTLs and suppressive tumor microenvironment (TME). Herein, an anti-PD-1 antibody coupled chemo-photothermal integrated nanoplatform (A/Au@MSMs-P) is proposed to reshape antitumor immunity against cancer. The matrix metalloproteinase-2 (MMP-2) responsive A/Au@MSMs-P promotes the separation of abemaciclib-loaded gold-silica nanoparticles (A/Au@MSMs) and anti-PD-1 antibody, achieving a triple-coordinated strategy to enhance checkpoint blockade therapy. First, chemo-photothermal therapy of A/Au@MSMs induces cell cycle arrest in G1 phase and promotes tumor cells apoptosis to achieve local ablation. Second, immunogenic death of tumor cells promotes the maturation of dendritic cells and recruits antigen-specific CTLs into tumor tissue to promote immune activation. Third, abemaciclib markedly suppresses the proliferation of regulatory T cells (Tregs) to alleviate the immunosuppression of the TME and potentiates the effectiveness of CTLs. This triple-coordinated strategy not only reshapes the antitumor immunity to enhance checkpoint blockade, but also cooperates with chemo-photothermal therapy, leading to improved antitumor efficiency and prolonged survival rate. Taken together, this study presents a promising strategy for improving checkpoint therapy response and has great potential in future cancer therapy.     

Myeloid‐Derived Suppressor Cell Membrane‐Coated Magnetic Nanoparticles for Cancer Theranostics by Inducing Macrophage Polarization and Synergizing Immunogenic Cell Death

A major challenge for traditional cancer therapy, including surgical resection, chemoradiotherapy, and immunotherapy, is how to induce tumor cell death and leverage the host immune system at the same time. Here, a myeloid‐derived suppressor cell (MDSC) membrane‐coated iron oxide magnetic nanoparticle (MNP@MDSC) to overcome this conundrum for cancer therapy is developed. In this study, MNP@MDSC demonstrates its superior performance in immune evasion, active tumor‐targeting, magnetic resonance imaging, and photothermal therapy (PTT)‐induced tumor killing. Compared with red blood cell membrane‐coated nanoparticles (MNPs@RBC) or naked MNPs, MNP@MDSCs are much more effective in active tumor‐targeting, a beneficial property afforded by coating MNP with membranes from naturally occurring MDSC, thus converting the MNP into “smart” agents that like to accumulate in tumors as the source MDSCs. Once targeted to the tumor microenvironment, MNPs@MDSC can act as a PTT agents for enhanced antitumor response by inducing immunogenic cell death, reprogramming the tumor infiltrating macrophages, and reducing the tumor's metabolic activity. These benefits, in combination with the excellent biocompatibility and pharmacological kinetics characteristics, make MNP@MDSC a promising, multimodal agent for cancer theranostics.     

Injectable Scaffolds for In Vivo Programmed Macrophages Manufacture and Postoperative Cancer Immunotherapy

Cancer recurrence and metastasis after surgical resection is a vital reason of treatment failure. The modification of immune cells through implanted biomaterials is a promising postoperative immunotherapy. Herein, an injectable hydrogel scaffold loaded with engineered exosome mimetics that in vivo recruits and programs endogenous macrophages into M1 binding with anti-CD47 antibody (M1-aCD47 macrophages) for postoperative cancer immunotherapy is developed. Briefly, M1 macrophages-derived exosome mimetics co-modified with vesicular stomatitis virus glycoprotein (VSV-G) and aCD47 (V-M1EM-aCD47) are encapsulated in injectable chitosan hydrogel. Such hydrogel recruits inherent macrophages in situ and releases V-M1EM-aCD47 that programs M2 to M1-aCD47 macrophages. M1-aCD47 macrophages own dual-functions of tumor-homing and enhanced phagocytosis. They can actively target to tumor cells for delivery of aCD47 that blocks the “don't eat me” signal, thereby promoting phagocytosis of macrophages to cancer cells. Furthermore, V-M1EM-aCD47 hydrogel implanted into resection site of 4T1 breast tumor inhibits tumor recurrence and metastasis by phagocytosis of M1-aCD47 macrophages and T cell-mediated immune responses. The findings demonstrate that biomaterials can be designed in vivo to program inherent macrophages, thereby activating the innate and adaptive immune systems for prevention of postoperative tumor recurrence and metastasis.     

Cancer Stem Cell‐Platelet Hybrid Membrane‐Coated Magnetic Nanoparticles for Enhanced Photothermal Therapy of Head and Neck Squamous Cell Carcinoma

Cell membrane–based nanosystems with desirable characteristics have been studied extensively for many therapeutic applications. However, current research has focused on single cell membrane, and multifunctional fused membrane materials from different membrane types are still rare. Herein, a platelet–cancer stem cell (CSC) hybrid membrane‐coated iron oxide magnetic nanoparticle (MN) {[CSC‐P]MN} is presented for the first time for the enhanced photothermal therapy of head and neck squamous cell carcinoma (HNSCC). Inherited from the original source cells, the platelet membrane shows immune evading ability due to the surface marker comprising a number of “don't eat me” signals, and the CSC membrane has homotypic targeting capabilities due to the specific surface adhesion molecules. The [CSC‐P]MNs possess superior characteristics for immune evasion, active cancer targeting, magnetic resonance imaging, and photothermal therapy. Compared with single cell membrane–coated MNs, [CSC‐P]MNs exhibit prolonged circulation times and enhanced targeting abilities. Moreover, the [CSC‐P]MNs exhibit a superior photothermal ability that provides excellent HNSCC tumor growth inhibition, particularly in an immunocompetent Tgfbr1/Pten conditional double knockout HNSCC mouse model that contains a more complex tumor microenvironment that is similar to the human HNSCC microenvironment. Collectively, this biomimetic multimembrane‐coated nanoplatform may provide enhanced antitumor efficacy in the complex tumor microenvironment.     

Engineered Oxygen Factories Synergize with STING Agonist to Remodel Tumor Microenvironment for Cancer Immunotherapy

Immunotherapy is a revolutionary achievement in cancer treatment. However, inadequate immune cells infiltration in tumor microenvironment (TME) always leads to treatment failure. Moreover, hypoxic TME hampers normal functions of immune cells. Here, it is found that hypoxia suppresses the STING signaling and immune cells activation in the work. Remodeling tumor immune microenvironment and relieving hypoxia are thus essential for enhancing immunotherapy efficiency. Herein, a spirulina platensis (SP)-based magnetic biohybrid system is constructed as an oxygen factory and loaded with stimulator of interferon genes (STING) agonist ADU-S100 (ADU@Fe-SP) for tumor immunotherapy. Magnet-guided biohybrid SP can actively target tumor tissues and produce oxygen in situ through photosynthesis, which reverses the hypoxic TME and facilitates the function of immune cells. Besides, the targeted delivery of ADU-S100 can activate the STING/TBK1/IRF3 signaling and boost cytokines production in tumor and innate immune cells. The ADU@Fe-SP system thus induces efficient immune cells infiltration in TME, which efficiently inhibits tumor progression and significantly enhances anti-PD-1 therapy efficiency in SCC VII-bearing tumor xenograft. ADU@Fe-SP exerts antitumor effect in a STING-dependent manner by in vivo STING-knockout mice model. The efficiency of this immunotherapy strategy is also demonstrated in patient-derived xenograft model originating from oral cancer, showing great clinical potential.     

Living Cell-Derived Intelligent Nanobots for Precision Oncotherapy

The progress of precision oncology medicine is always limited by the tumor off-targeting, the drug side effects, and the treatment inefficiency due to the complex and ever-changing tumor microenvironment. Living cells, such as blood cells and immune cells, exhibit natural tumor tropism, controllable physicochemical modification, and excellent biocompatibility, which provide an advantageous pathway for innovative and efficient tumor suppression. Armed with nanoengineering techniques, artificial living cells harness their inherent biological properties to precisely identify and eradicate tumors, demonstrating broad biological application prospects and great transformational potential in personalized cancer therapy. Here, the recent advances of living cell-based bionanobots including platelets, red blood cells, neutrophil, macrophage, and CAR-T cells for cancer precision therapy and immune regulation are summarized, and the efficient anti-tumor strategies for engineering living cell nanorobots to overcome complex biological barriers and immune suppression are also outlined (e.g., immunotherapy, sonodynamic therapy, chemo/radiotherapy, and phototherapy). In addition, the study discusses the advantages, limitations, and current challenges of artificial living cell-based drug delivery systems, and provide perspectives on the future development of living cell-mediated precision tumor nanomedicine.     

Precise RNA Editing: Cascade Self-Uncloaking Dual-Prodrug Nanoassemblies Based on CRISPR/Cas13a for Pleiotropic Immunotherapy of PD-L1-Resistant Colorectal Cancer

CRISPR/Cas13a is a powerful genome editing system for RNA knockdown that holds enormous potential for cancer treatment by targeting currently undruggable oncogenes or immune checkpoints. However, the precise intratumoral activation of CRISPR/Cas13a to maximize the therapeutic efficiency while guaranteeing biosafety remains a daunting challenge. Here, a cascade self-uncloaking nanoassembly (SRC) based on a dual-prodrug comprising SN38 and Cas13a/RNP is developed, and the external encapsulation is performed by coating with a ROS-responsive probe, which is stimulated by the tumor microenvironment to achieve the efficient NIR-II imaging by CH10055 due to disaggregation into single molecules, while the second release of prodrug in the hypoxic environment enables targeted controlled release. SN38 not only induces immunogenic cell death (ICD), but significantly combats the immunosuppressive microenvironment of colorectal cancer in combination with the RNA editing targeting the novel immune checkpoint TIM3 to regulate the cGAS-STING pathways, resulting in synergistic activation of both innate and adaptive immunity. The treatment of SRC exhibits a tenfold increase in tumor regression of α-PD-L1 in PD-L1-resistant orthotopic and xenograft models by inducing effective tumor immune infiltration. These results demonstrate the feasibility of using CRISPR/Cas13a in cancer treatment, and SRC holds immense promise as a neoadjuvant strategy for enhancing CRC immunotherapy.     

Synergy of Immunostimulatory Genetherapy with Immune Checkpoint Blockade Motivates Immune Response to Eliminate Cancer

Normalizing the tumor-induced immune deficiency in the immunosuppressive tumor microenvironment (TME) through increasing the efficient infiltration and activation of antitumoral immunity in TME is the core of promising immunotherapy. Herein, a Cyclo(Arg-Gly-Asp-d -Phe-Lys) (RGD) peptides-modified combinatorial immunotherapy system based on the self-assembly of the nanoparticles named RGD-DMA composed of RGD-PEG-PLA, methoxy poly(ethylene glycol)-poly(lactide) (MPEG-PLA) and 1,2-Dioleoyl-3-trimethylammonium-propane (DOTAP) is used to codeliver the immunostimulatory chemokine CCL19-encoding plasmid DNA (CCL19 pDNA) and immune checkpoint ligand PD-L1 inhibitor (BMS-1). The RGD-DMA/pCCL19-BMS-1 system not only exhibited significant inhibition of tumor progression but also induced locally high concentrations of immunostimulatory cytokines at tumor sites without causing an obviously systemic inflammatory response. The immunosuppressive TME is efficaciously reshaped by the coadministration of RGD-DMA/pCCL19 and BMS-1, as indicated by the activated T lymphocytes, increased intratumoral-infiltration of mature dendritic cells (DCs), and the repolarization of macrophages from pro-tumoral M2-phenotype toward tumoricidal M1-phenotype. The upregulated PD-L1 expression at tumor sites caused by the increased IFN-γ levels after immunostimulatory gene therapy further demonstrated the synergistic effects of BMS-1 in counteracting the inhibitory role of PD-L1 expression in antitumor immunity. Therefore, the combination of immunostimulating therapy and immune checkpoint inhibitor that synergistically target multiple immune regulatory pathways demonstrates significant potential as a novel immunotherapy approach.     

Gelatin-Hyaluronan Click-Crosslinked Cryogels Elucidate Human Macrophage Invasion Behavior

Hydrogel models of metastasis traditionally focus on the invasion of cancer cells; however, other cells in the tumor microenvironment that are associated with metastasis also have the ability to migrate. Macrophage phenotype plays a key role in the tumor microenvironment, yet understanding their migration within tunable 3D in vitro models has been limited. To gain a greater understanding of macrophage invasive behavior, stable and transparent oxime-crosslinked cryogels comprised of click-crosslinked gelatin-oxyamine and hyaluronan-aldehyde (GELox-HAa) are synthesized. Fibronectin-derived, oxyamine-modified PHSRN-RGDSP peptides are incorporated to further mimic the tumor extracellular matrix without impacting cryogel mechanics. It is found that primary human macrophages migrate to a greater depth in cryogels with greater porosity and pore size. To better understand the mechanism of migration, cells are treated with either inhibitors of matrix metalloproteinases (MMPs) or rho-associated protein kinase (ROCK) and a predominantly MMP-mediated mechanism of invasion is found. Macrophage polarization studies reveal that anti-inflammatory, interleukin-4/13 (IL4/IL13)-treated macrophages migrate through cryogels to a greater extent than pro-inflammatory, interferon-gamma/lipopolysaccharide (IFNγ/LPS)-treated cells. Interestingly, polarized macrophages move through cryogels using a combination of amoeboid and mesenchymal migration. These findings of macrophage invasion in this cryogel platform set the stage for their further study in a biomimetic tumor microenvironment.     

Immune Cycle-Based Strategies for Cancer Immunotherapy

The immune system is composed of immune organs, immune cells, and immunoactive substances, which plays a vital role in antitumor immunity in cancer immunotherapy. During the process of the antitumor immune response, many factors are involved in the cancer immune cycle. Therefore, developing intelligent strategies based on the steps of the cancer immune cycle to elicit the immune responses for enhanced cancer immunotherapy is of great significance. In this review, the key factors in each step of the cancer immune cycle are discussed, and then, the intelligent therapeutic strategies for modulating the immune surveillance against cancer are highlighted. Considering the demand for cancer immunotherapy in clinic, some suggestions for constructing new intelligent strategies are also put forward, which will make antitumor immunity more effective and advance the development of cancer immunotherapy.     

A Near-Infrared Light-Responsive ROS Cascade Nanoplatform for Synergistic Therapy Potentiating Antitumor Immune Responses

Tumor occurrence is closely related to the unlimited proliferation and the evasion of the immune surveillance. However, it remains a challenge to kill tumor cells and simultaneously activate antitumor immunity upon spatially localized external stimuli. Herein, a robust tumor synergistic therapeutic nanoplatform is designed in combination with dual photosensitizers-loaded upconversion nanoparticles (UCNPs) and ferric-tannic acid (FeTA) nanocomplex. Dual photosensitizers-loaded UCNPs can induce photodynamic therapy (PDT) effect by generation of cytotoxic reactive oxygen species (ROS) on demand under near-infrared (NIR) light irradiation. FeTA can robustly respond to acidic tumor microenvironment to produce Fe²⁺ and subsequently induce chemodynamic therapy (CDT) by reacting with H₂O₂ in the tumor microenvironment. More importantly, the CDT/PDT synergy can not only exhibit significant antitumor ability but also induce ROS cascade to evoke immunogenic cell death. It increases tumor immunogenicity and promotes immune cell infiltration at tumor sites allowing further introduction of systemic immunotherapy responsiveness to inhibit the primary and distant tumor growth. This study provides a potential tumor microenvironment-responsive nanoplatform for imaging-guided diagnosis and combined CDT/PDT with improved immunotherapy responses and an external NIR-light control of photoactivation.     

A Self-Enhancing Nanoreactor Reinforces Radioimmunotherapy by Reprogramming Nutrients and Redox Metabolisms

Altered metabolism of cancer cells reshapes the unique tumor microenvironment (TME) with glucose addiction and high antioxidant levels, resulting in a strong alliance to promote tumor progression and treatment failure. Herein, a Pd/Pt/Au tri-metallic mesoporous nanoparticle coated with pH-responsive tannic acid-iron ion (Fe^IIITA) network (PdPtAu@TF) is fabricated, aiming at reinforcing radioimmunotherapy by reprogramming nutrients and redox metabolisms. PdPtAu@TF has a fine hierarchical structure and demonstrates high glucose oxidase, peroxidase-, catalase- and glutathione peroxidase-mimic activities, acting as a self-enhancing nanoreactor to consume endogenous glucose and break redox homeostasis in the harsh TME. As a result, cancer cells accelerate the uptake of lipids, especially polyunsaturated fatty acids when glucose is deficient, and then fall into lipid peroxidation-induced ferroptosis trap to sensitize radiotherapy (RT), inhibiting tumor progression. More significantly, combined treatment with PdPtAu@TF can promote the polarization of pro-inflammatory M1-type macrophages as well as inhibit the proliferation of cancer-associated fibroblasts to overcome RT-induced immunosuppression and eliminate excessive tissue fibrosis, thereby eliciting antitumor immunity and suppressing tumor metastasis. Consequently, this study describes a promising strategy to enhance the efficacy of radioimmunotherapy by reprogramming tumor nutrients and redox metabolisms, which has great potential to benefit cancer treatments.     

Enhancing Triple Negative Breast Cancer Immunotherapy by ICG‐Templated Self‐Assembly of Paclitaxel Nanoparticles

Combination cancer immunotherapy has shown promising potential for simultaneously eliciting antitumor immunity and modulating the immunosuppressive tumor microenvironment (ITM). However, combination immunotherapy with multiple regimens suffers from the varied chemo‐physical properties and inconsistent pharmacokinetic profiles of the different therapeutics. To achieve tumor‐specific codelivery of the immune modulators, an indocyanine green (ICG)‐templated self‐assembly strategy for preparing dual drug‐loaded two‐in‐one nanomedicine is reported. ICG‐templated self‐assembly of paclitaxel (PTX) nanoparticles (ISPN), and the application of ISPN for combination immunotherapy of the triple negative breast cancer (TNBC) are demonstrated. The ISPN show satisfied colloidal stability and high efficacy for tumor‐specific codelivery of ICG and PTX through the enhanced tumor permeability and retention effect. Upon laser irradiation, the ICG component of ISPN highly efficiently induces immunogenic cell death of the tumor cells via activating antitumor immune response through photodynamic therapy. Meanwhile, PTX delivered by ISPN suppresses the regulatory T lymphocytes (T_regs) to combat ITM. The combination treatment of TNBC with ISPN and αPD‐L1‐medaited immune checkpoint blockade therapy displays a synergistic effect on tumor regression, metastasis inhibition, and recurrence prevention. Overall, the ICG‐templated nanomedicine may represent a robust nanoplatform for combination immunotherapy.