Site‐Specific Construction of Long‐Term Drug Depot for Suppression of Tumor Recurrence

Local tumor recurrence after surgical resection is a critical concern in cancer therapy, and the current treatments, such as postsurgical chemotherapy, still show undesired side effects. Here a nonimplant strategy (transformation induced localization, TIL) is presented to in situ construct long‐term retentive drug depots, wherein the sustained drug release from fibrous drug depots results in highly efficient suppression of postsurgical local tumor relapse. The peptide‐based prodrug nanoparticles show favorable tumor targeting and instantly reorganize into fibrous nanostructures under overexpressed enzyme, realizing the construction of long‐term drug depot in the tumor site. After the resection surgery, the remnant cancer cells are still inhibited by the sustained drug release from the fibrous prodrug depot, effectively preventing postsurgical local recurrences. This TIL strategy shows great potential in cancer recurrence therapy and offers a novel perspective for constructing functional biomaterials in vivo.     

In Vivo Bio‐Safety Evaluations and Diagnostic/Therapeutic Applications of Chemically Designed Mesoporous Silica Nanoparticles

The remarkable progress of nanotechnology and its application in biomedicine have greatly expanded the ranges and types of biomaterials from traditional organic material‐based nanoparticles (NPs) to inorganic biomaterials or organic/inorganic hybrid nanocomposites due to the unprecedented advantages of the engineered inorganic material‐based NPs. Colloidal mesoporous silica NPs (MSNs), one of the most representative and well‐established inorganic materials, have been promoted into biology and medicine, and shifted from extensive in vitro research towards preliminary in vivo assays in small‐animal disease models. In this comprehensive review, the recent progresses in chemical design and engineering of MSNs‐based biomaterials for in vivo biomedical applications has been detailed and overviewed. Due to the intrinsic structural characteristics of elaborately designed MSNs such as large surface area, high pore volume and easy chemical functionalization, they have been extensively investigated for therapeutic, diagnostic and theranostic (concurrent diagnosis and therapy) purposes, especially in oncology. Systematic in vivo bio‐safety evaluations of MSNs have revealed the evidences that the in vivo bio‐behaviors of MSNs are strongly related to their preparation prodecures, particle sizes, geometries, surface chemistries, dosing parameters and even administration routes. In vivo pharmacokinetics and pharmacodynamics further demonstrated the effectiveness of MSNs as the passively and/or actively targeted drug delivery systems (DDSs) for cancer chemotherapy. Especially, the advance of nano‐synthetic chemistry enables the production of composite MSNs for advanced in vivo therapeutic purposes such as gene delivery, stimuli‐responsive drug release, photothermal therapy, photodynamic therapy, ultrasound therapy, or anti‐bacteria in tissue engineering, or as the contrast agents for biological and diagnostic imaging. Additionally, the critical issues and potential challenges related to the chemical design/synthesis of MSNs‐based “magic bullet” by advanced nano‐synthetic chemistry and in vivo evaluation have been discussed to highlight the issues scientists face in promoting the translation of MSNs‐based DDSs into clinical trials.     

Implantable Synthetic Immune Niche for Spatiotemporal Modulation of Tumor‐Derived Immunosuppression and Systemic Antitumor Immunity: Postoperative Immunotherapy

The development of biomaterial‐based immune niches that can modulate immunosuppressive factors in tumor microenvironment (TME) will be a key technology for improving current cancer immunotherapy. Here, implantable, engineered 3D porous scaffolds are designed to generate synergistic action between myeloid‐derived suppressor cell (MDSC)‐depleting agents, which can accommodate the establishment of a permissive immunogenic microenvironment to counteract tumor‐induced immunosuppression, and cancer vaccines consisting of whole tumor lysates and nanogel‐based adjuvants, which can generate tumor antigen‐specific T cell responses. The local peritumoral implantation of the synthetic immune niche (termed immuneCare‐DISC, iCD) as a postsurgical treatment in an advanced‐stage primary 4T1 breast tumor model generates systemic antitumor immunity and prevents tumor recurrence at the surgical site as well as the migration of residual tumor cells into the lungs, resulting in 100% survival. These therapeutic outcomes are achieved through the inhibition of immunosuppressive MDSCs in tumors and spleens by releasing gemcitabine and recruitment/activation of dendritic cells, enhanced population of CD4⁺ and CD8⁺ T cells, and increased IFN‐γ production by cancer vaccines from the iCD. This combined spatiotemporal modulation of tumor‐derived immunosuppression and vaccine‐induced immune stimulation through the iCD is expected to provide an immune niche for prevention of postoperative tumor recurrence and metastasis.     

Synthesis strategies for disulfide bond-containing polymer-based drug delivery system for reduction-responsive controlled release

Tumor micro-environment responsive drug delivery systems (DDSs) have been developed as a potential approach to reduce the side effects of cancer chemotherapy. Glutathione (GSH) has been supposed to the most significant signal of the difference between the normal tissue and the tumor cells, besides the media pH and temperature. In recent years, the reduction-responsive DDSs have attracted more and more attention for delivery of anti-cancer drugs, based on such physiological signal. Among them, disulfide bond-containing polymers have been designed as the main tool for the purpose. The recent progress in the synthesis strategies for the disulfide bond-containing polymer-based DDS is focused in the present review.     

Controlled Release of Antiproliferative Drugs From Polymeric Systems for Stent Applications and Local Cancer Treatment

Restenosis (re‐narrowing of the blood vessel wall) and cancer are two different pathologies that have drawn extensive research attention over the years. Antiproliferative drugs such as paclitaxel inhibit cell proliferation and are therefore effective in the treatment of cancer as well as neointimal hyperplasia, which is known to be the main cause of restenosis. Drug‐eluting stents (DES) significantly reduce the incidence of in‐stent restenosis (ISR), which was once considered a major adverse outcome of percutaneous coronary stent implantations. Localized release of antiproliferative drugs interferes with the pathological proliferation of vascular smooth muscle cells (VSMC), which is the main cause of ISR. Conventional approaches to treating cancer are mainly surgical excision, irradiation, and chemotherapy. In cancer therapy, surgical treatment is usually performed on patients with a resectable carcinoma. An integrated therapeutic approach, such as the addition of a delivery system loaded with an antiproliferative drug at the tumor resection site, is desirable. This will provide a high local concentration of a drug, that is, detrimental to malignant cells which may have survived surgery, thus preventing re‐growth and metastasis of the tumor. The present review describes recent advances in systems for controlled release of antiproliferative agents. It describes basic concepts in drug delivery systems and antiproliferative drugs and then focuses on both types of systems: stents with controlled release of antiproliferative agents, and drug‐eluting particles and implants for local cancer treatment. The last part of this article is dedicated to our novel drug‐eluting composite fiber structures, which can be used as basic stent elements as well as for local cancer treatment.     

Magnetoresponsive Virus‐Mimetic Nanocapsules with Dual Heat‐Triggered Sequential‐Infected Multiple Drug‐Delivery Approach for Combinatorial Tumor Therapy

Stimuli‐responsive drug‐delivery systems constitute an appealing approach to direct and restrict drug release spatiotemporally at the specific site of interest. However, it is difficult for most systems to affect every cancer cell in a tumor tissue due to the presence of the natural tumor barrier, leading to potential tumor recurrence. Here, core–shell magnetoresponsive virus‐mimetic nanocapsules (VNs), which can infect cancer cells sequentially and double as a magnetothermal agent fabricated through anchoring iron oxide nanoparticles in a single‐component protein (lactoferrin) shell, are reported. With large payload of hydrophilic/hydrophobic anticancer cargos, doxorubicin and palictaxel, VNs can simultaneously give a rapid drug release and intense heat while applying an external high‐frequency magnetic field (HFMF). Furthermore, after being liberated from dead cells by HFMF manipulation, the constructive VNs can sequentially infect neighboring cancer cells and deliver sufficient therapeutic agents to next targeted sites. With high efficiency for sequential cell infections, VNs have successfully eliminated subcutaneous tumor after a combinatorial treatment. These results demonstrate that the VNs could be used for locally targeted, on‐demand, magnetoresponsive chemotherapy/hyperthermia, combined with repeated cell infections for tumor therapy and other therapeutic applications.     

Mesoporous Silica Nanoparticles: Synthesis,Biocompatibility and Drug Delivery

In the past decade, mesoporous silica nanoparticles (MSNs) have attracted more and more attention for their potential biomedical applications. With their tailored mesoporous structure and high surface area, MSNs as drug delivery systems (DDSs) show significant advantages over traditional drug nanocarriers. In this review, we overview the recent progress in the synthesis of MSNs for drug delivery applications. First, we provide an overview of synthesis strategies for fabricating ordered MSNs and hollow/rattle‐type MSNs. Then, the in vitro and in vivo biocompatibility and biotranslocation of MSNs are discussed in relation to their chemophysical properties including particle size, surface properties, shape, and structure. The review also highlights the significant achievements in drug delivery using mesoporous silica nanoparticles and their multifunctional counterparts as drug carriers. In particular, the biological barriers for nano‐based targeted cancer therapy and MSN‐based targeting strategies are discussed. We conclude with our personal perspectives on the directions in which future work in this field might be focused.     

Fast‐Clearable Nanocarriers Conducting Chemo/Photothermal Combination Therapy to Inhibit Recurrence of Malignant Tumors

Inhomogeneous heating by photothermal therapy (PTT) during cancer treatment often results in the recurrence of tumors. Thus, integrating PTT with chemotherapy (CHT) may provide a complementary treatment for enhanced therapeutic efficiency. Herein, this study develops a hollow structured polymer–silica nanohybrid (HPSN) as a nanocarrier to simultaneously deliver the anticancer drug paclitaxel and photothermal agent palladium phthalocyanine to tumors through enhanced permeation and the retention effect. A combinational CHT/PTT therapy on mice bearing aggressive tumor grafts is conducted. The highly malignant tumor model, which recurs after sole treatment of PTT, can be eradicated by the combined CHT/PTT treatment. In addition, most of the off‐targeted HPSN nanocarriers can be excreted through a hepatobiliary pathway in about 10 d. Serology results show that the fast‐clearable HPSN can significantly reduce the side effect of the loaded paclitaxel drug. The present work provides an alternative approach for combinational cancer treatment with high therapeutic efficiency.     

Cell-Based Drug Delivery Systems Participate in the Cancer Immunity Cycle for Improved Cancer Immunotherapy

Immunotherapy aims to activate the cancer patient's immune system for cancer therapy. The whole process of the immune system against cancer referred to as the “cancer immunity cycle”, gives insight into how drugs can be designed to affect every step of the anticancer immune response. Cancer immunotherapy such as immune checkpoint inhibitor (ICI) therapy, cancer vaccines, as well as small molecule modulators has been applied to fight various cancers. However, the effect of immunotherapy in clinical applications is still unsatisfactory due to the limited response rate and immune-related adverse events. Mounting evidence suggests that cell-based drug delivery systems (DDSs) with low immunogenicity, superior targeting, and prolonged circulation have great potential to improve the efficacy of cancer immunotherapy. Therefore, with the rapid development of cell-based DDSs, understanding their important roles in various stages of the cancer immunity cycle guides the better design of cell-based cancer immunotherapy. Herein, an overview of how cell-based DDSs participate in cancer immunotherapy at various stages is presented and an outlook on possible challenges of clinical translation and application in future development.     

MSN Anti‐Cancer Nanomedicines: Chemotherapy Enhancement,Overcoming of Drug Resistance,and Metastasis Inhibition

In the anti‐cancer war, there are three main obstacles resulting in high mortality and recurrence rate of cancers: the severe toxic side effect of anti‐cancer drugs to normal tissues due to the lack of tumor‐selectivity, the multi‐drug resistance (MDR) to free chemotherapeutic drugs and the deadly metastases of cancer cells. The development of state‐of‐art nanomedicines based on mesoporous silica nanoparticles (MSNs) is expected to overcome the above three main obstacles. In the view of the fast development of anti‐cancer strategy, this review highlights the most recent advances of MSN anti‐cancer nanomedicines in enhancing chemotherapeutic efficacy, overcoming the MDR and inhibiting metastasis. Furthermore, we give an outlook of the future development of MSNs‐based anti‐cancer nanomedicines, and propose several innovative and forward‐looking anti‐cancer strategies, including tumor tissue?cell?nuclear successionally targeted drug delivery strategy, tumor cell‐selective nuclear‐targeted drug delivery strategy, multi‐targeting and multi‐drug strategy, chemo‐/radio‐/photodynamic‐/ultrasound‐/thermo‐combined multi‐modal therapy by virtue of functionalized hollow/rattle‐structured MSNs.     

Biomimetic Extracellular Environment Based on Natural Origin Polyelectrolyte Multilayers

Surface modification of biomaterials is a well‐known approach to enable an adequate biointerface between the implant and the surrounding tissue, dictating the initial acceptance or rejection of the implantable device. Since its discovery in early 1990s layer‐by‐layer (LbL) approaches have become a popular and attractive technique to functionalize the biomaterials surface and also engineering various types of objects such as capsules, hollow tubes, and freestanding membranes in a controllable and versatile manner. Such versatility enables the incorporation of different nanostructured building blocks, including natural biopolymers, which appear as promising biomimetic multilayered systems due to their similarity to human tissues. In this review, the potential of natural origin polymer‐based multilayers is highlighted in hopes of a better understanding of the mechanisms behind its use as building blocks of LbL assembly. A deep overview on the recent progresses achieved in the design, fabrication, and applications of natural origin multilayered films is provided. Such films may lead to novel biomimetic approaches for various biomedical applications, such as tissue engineering, regenerative medicine, implantable devices, cell‐based biosensors, diagnostic systems, and basic cell biology.     

Subcellular‐Scale Drug Transport via Ultrasound‐Degradable Mesoporous Nanosilicon to Bypass Cancer Drug Resistance

Delivering and releasing anticancer agents directly to their subcellular targets of action in a controlled manner are almost the ultimate goal of pharmacology, but it is challenging. In recent decades, plenty of efforts have been made to send drugs to tumor tissue or even specifically to cancer cells; however, at the subcellular scale, cancer cells have multiple cunning ways to hinder drugs from reaching their final action targets. Here, we demonstrate a strategy to bypass the last defense of cancer drug resistance by contolling the drug transportation and release at subcellular scale. We developed a platform based on ultrasound‐degradable mesoporous nanosilicon, which allows drug delivery towards, ultrasound controlled drug release into the cell nucleus. This strategy altered the drug distribution within cells and remarkably enhanced the drug accumulation ratio at the action target, i.e. nucleus. In vitro and in vivo studies proved that this strategy reduced the drug dosage by an order of magnitude, prolonged drug retention and amplified therapeutic efficacy in tumor‐bearing mice. These results offer new insights into bypassing cancer drug resistance through transport and release drugs directly to their action targets in a controlled manner.     

Immune Cell‐Mediated Biodegradable Theranostic Nanoparticles for Melanoma Targeting and Drug Delivery

Although tremendous efforts have been made on targeted drug delivery systems, current therapy outcomes still suffer from low circulating time and limited targeting efficiency. The integration of cell‐mediated drug delivery and theranostic nanomedicine can potentially improve cancer management in both therapeutic and diagnostic applications. By taking advantage of innate immune cell's ability to target tumor cells, the authors develop a novel drug delivery system by using macrophages as both nanoparticle (NP) carriers and navigators to achieve cancer‐specific drug delivery. Theranostic NPs are fabricated from a unique polymer, biodegradable photoluminescent poly (lactic acid) (BPLP‐PLA), which possesses strong fluorescence, biodegradability, and cytocompatibility. In order to minimize the toxicity of cancer drugs to immune cells and other healthy cells, an anti‐BRAF V600E mutant melanoma specific drug (PLX4032) is loaded into BPLP‐PLA nanoparticles. Muramyl tripeptide is also conjugated onto the nanoparticles to improve the nanoparticle loading efficiency. The resulting nanoparticles are internalized within macrophages, which are tracked via the intrinsic fluorescence of BPLP‐PLA. Macrophages carrying nanoparticles deliver drugs to melanoma cells via cell–cell binding. Pharmacological studies also indicate that the PLX4032 loaded nanoparticles effectively kill melanoma cells. The “self‐powered” immune cell‐mediated drug delivery system demonstrates a potentially significant advancement in targeted theranostic cancer nanotechnologies.     

Programmable Codelivery of Doxorubicin and Apatinib Using an Implantable Hierarchical‐Structured Fiber Device for Overcoming Cancer Multidrug Resistance

Multiple drug resistance (MDR) of cancer cells is a major cause of chemotherapy failure. It is currently a great challenge to develop a direct and effective strategy for continuously inhibiting the P‐glycoprotein (P‐gp) drug pump of MDR tumor cells, thus enhancing the intracellular concentration of the therapeutic agent for effectively killing MDR tumor cells. Here, a new implantable hierarchical‐structured ultrafine fiber device is developed via a microfluidic‐electrospinning technology for localized codelivery of doxorubicin (DOX) and apatinib (AP). An extremely high encapsulation efficiency of ≈99% for the dual drugs is achieved through this strategy. The release of the loaded dual drugs can be controlled in a programmable release model with a rapid release of the micelles, while AP is slowly released. The sustained release of AP can continuously inhibit the P‐gp drug pump of MDR tumor cells, increasing the intracellular DOX accumulation. The in vivo DOX biodistribution displays that the DOX accumulation in the tumor tissues achieves 17.82% after implanting the fiber device for 72 h, which is 6.36‐fold higher than that of the intravenously injected DOX. Importantly, the fiber device shows an excellent antitumor effect on MDR tumor‐bearing mice with low systemic toxicity.     

Highly Augmented Drug Loading and Stability of Micellar Nanocomplexes Composed of Doxorubicin and Poly(ethylene glycol)–Green Tea Catechin Conjugate for Cancer Therapy

Low drug loading and instability in blood circulation are two key challenges that impede the successful clinical translation of nanomedicine, as they result in only marginal therapeutic efficacy and toxic side effects associated with premature drug leakage, respectively. Herein, highly stable and ultrahigh drug loading micellar nanocomplexes (MNCs) based on the self‐assembly of the anticancer drug doxorubicin (DOX) and a poly(ethylene glycol)–epigallocatechin‐3‐O‐gallate (EGCG) conjugate are developed. The formation of these MNCs is facilitated by strong favorable intermolecular interactions between the structurally similar aromatic EGCG and DOX molecules, which impart exceptionally high drug‐loading capability of up to 88% and excellent thermodynamic and kinetic stability. Unlike two clinical formulations of DOX—free DOX and liposomal DOX, which are not effective below their lethal dosages, these DOX‐loaded MNCs demonstrate significant tumor growth inhibition in vivo on a human liver cancer xenograft mouse model with minimal unwanted toxicity. Overall, these MNCs can represent a safe and effective strategy to deliver DOX for cancer therapy.     

Neoadjuvant Chemotherapy Based on Abraxane/Human Neutrophils Cytopharmaceuticals with Radiotherapy for Gastric Cancer

Gastric cancer remains one of the most lethal cancers with high incidence and mortality worldwide. The majority of gastric cancer patients are those who have first been diagnosed in advanced stage, in which the standard chemo‐radiotherapy produces limited benefit along with severe general toxicity, thus the demand for improved therapeutic efficacy and decreased side effects drives the development of novel therapeutic strategies. Here, a neoadjuvant chemotherapy based on Abraxane/human neutrophils (NEs) cytopharmaceuticals with radiotherapy is presented for effective cancer treatment. Human NEs, the most abundant white blood cells in peripheral blood, are developed to carry Abraxane, the commercial albumin‐bound paclitaxel nanoparticle, to form cytopharmaceuticals (Abraxane/NEs) which have been confirmed to maintain the intrinsic functions of human NEs. The modest radiation is applied not only to exert tumor disruption, but also to increase the release of inflammatory factors which guide the NEs homing to the tumoral sites. These amplified inflammatory factors at tumor sites excessively activate Abraxane/NEs to form neutrophil extracellular traps, along with a burst release of Abraxane to induce superior tumor suppression. This adjuvant chemo‐radiotherapy based on cytopharmaceuticals may provide new opportunities for advanced cancer treatment, which reveals the huge clinical potential of human neutrophils as drug delivery vectors.     

Implantable,Degradable, Therapeutic Terahertz Metamaterial Devices

Metamaterial (MM) sensors and devices, usually consisting of artificially structured composite materials with engineered responses that are mainly determined by the unit structure rather than the bulk properties or composition, offer new functionalities not readily available in nature. A set of implantable and resorbable therapeutic MM devices at terahertz (THz) frequencies are designed and fabricated by patterning magnesium split ring resonators on drug‐loaded silk protein substrates with controllable device degradation and drug release rates. To demonstrate proof‐of‐concept, a set of silk‐based, antibiotics‐loaded MM devices, which can serve as degradable antibacterial skin patches with capabilities to monitor drug‐release in real time are fabricated. The extent of drug release, which correlates with the degradation of the MM skin patch, can be monitored by analyzing the resonant responses in reflection during degradation using a portable THz camera. Animal experiments are performed to demonstrate the in vivo degradation process and the efficacy of the devices for antibacterial treatment. Thus, the implantable and resorbable therapeutic MM devices do not need to be retrieved once implanted, providing an appealing alternative for in‐vivo sensing and in situ treatment applications.     

ATP Suppression by pH‐Activated Mitochondria‐Targeted Delivery of Nitric Oxide Nanoplatform for Drug Resistance Reversal and Metastasis Inhibition

Mitochondria, which are important mediators for cancer initiation, growth, metastasis, and drug resistance, have been considered as a major target in cancer therapy. Herein, an acid‐activated mitochondria‐targeted drug nanocarrier is constructed for precise delivery of nitric oxide (NO) as an adenosine triphosphate (ATP) suppressor to amplify the therapeutic efficacy in cancer treatments. By combining α‐cyclodextrin (α‐CD) and acid‐cleavable dimethylmaleic anhydride modified PEG conjugated mitochondria‐targeting peptide, the nanocarrier shows prolonged blood circulation time and enhanced cellular uptake together with selectively restoring mitochondria‐targeting capability under tumor extracellular pH (6.5). Such specific mitochondria‐targeted delivery of NO proves crucial in inducing mitochondria dysfunction through facilitating mitochondrial membrane permeabilization and downregulating ATP level, which can inhibit P‐glycoprotein‐related bioactivities and formation of tumor‐derived microvesicles to combat drug resistance and cancer metastasis. Therefore, this pioneering acid‐activated mitochondria‐targeted NO nanocarrier is supposed to be a malignant tumor opponent and may provide insights for diverse NO‐relevant cancer treatments.     

Somatostatin Receptor‐Mediated Tumor‐Targeting Nanocarriers Based on Octreotide‐PEG Conjugated Nanographene Oxide for Combined Chemo and Photothermal Therapy

Nano‐sized in vivo active targeting drug delivery systems have been developed to a high anti‐tumor efficacy strategy against certain cancer‐cells‐specific. Graphene based nanocarriers with unique physical and chemical properties have shown significant potentials in this aspect. Here, octreotide (OCT), an efficient biotarget molecule, is conjugated to PEGylated nanographene oxide (NGO) drug carriers for the first time. The obtained NGO‐PEG‐OCT complex shows low toxicity and excellent stability in vivo and is able to achieve somatostatin receptor‐mediated tumor‐specific targeting delivery. Owing to the high loading efficiency and accurate targeting delivery of anti‐cancer drug doxorubicin (DOX), our DOX loaded NGO‐PEG‐OCT complex offers a remarkably improved cancer‐cell‐specific cellular uptake, chemo‐cytotoxicity, and decreased systemic toxicity compared to free DOX or NGO‐PEG. More importantly, due to its strong near‐infrared absorption, the NGO‐PEG‐OCT complex further enhances efficient photothermal ablation of tumors, delivering combined chemo and photothermal therapeutic effect against cancer cells.     

A Designer Scaffold with Immune Nanoconverters for Reverting Immunosuppression and Enhancing Immune Checkpoint Blockade Therapy

Current cancer immunotherapy based on immune checkpoint blockade (ICB) still suffers from low response rate and systemic toxicity. To overcome the limitation, a novel therapeutic platform that can revert nonimmunogenic tumors into immunogenic phenotype is highly required. Herein, a designer scaffold loaded with both immune nanoconverters encapsulated with resiquimod (iNCVs (R848)) and doxorubicin, which provides the polarization of immunosuppressive tumor‐associated macrophages (TAMs) and myeloid‐derived suppressor cells (MDSCs) into tumoricidal antigen‐presenting cells (APCs), rather than depleting them, as well as in situ vaccination that can be generated in vivo without the need to previously analyze and sequence tumor antigens to favor neoantigen‐specific T cell responses is suggested. Local and sustained release of iNCVs (R848) and doxorubicin from the designer scaffold not only reduces the frequency of immunosuppressive cells in tumors but also increases systemic antitumor immune response, while minimizing systemic toxicity. Reshaping the tumor microenivronment (TME) using the designer‐scaffold‐induced synergistic antitumor immunity with ICB effects and long‐term central and effector memory T cell responses, results in the prevention of postsurgical tumor recurrence and metastasis. The spatiotemporal modulation of TMEs through designer scaffolds is expected to be a strategy to overcome the limitations and improve the therapeutic efficacy of current immunotherapies with minimized systemic toxicity.