Two-dimensional coordination risedronate-manganese nanobelts as adjuvant for cancer radiotherapy and immunotherapy.

The irradiated tumor itself represents an opportunity to establish endogenous in situ vaccines. However, such in situ cancer vaccination (ISCV) triggered by radiation therapy (RT) alone is very weak and hardly elicits systemic anticancer immunity. In this study, we develop two-dimensional risedronate-manganese nanobelts (RMn-NBs) as an adjuvant for RT to address this issue. RMn-NBs exhibit good T2 magnetic resonance imaging performance and enhanced Fenton-like catalytic activity, which induces immunogenic cell death. RMn-NBs can inhibit the HIF-1α/VEGF axis to empower RT and synchronously activate the cGAS/STING pathway for promoting the secretion of type I interferon, thereby boosting RT-triggered ISCV and immune checkpoint blockade therapy against primary and metastatic tumors. RMn-NBs as a nano-adjuvant for RT show good biocompatibility and therapeutic efficacy, presenting a promising prospect for cancer radiotherapy and immunotherapy.

A Robust ROS Generation and Ferroptotic Lipid Modulation Nanosystem for Mutual Reinforcement of Ferroptosis and Cancer Immunotherapy.

Ferroptosis initiation is often utilized for synergistic immunotherapy. While, current immunotherapy is limited by an immunosuppressive tumor microenvironment (TME), and ferroptosis is limited by insufficient reactive oxygen species (ROS) and ferroptotic lipids in tumor cells. Here, an arachidonic acid (AA) loaded nanosystem (CTFAP) is developed to mutually reinforce ferroptosis and cancer immunotherapy by augmenting ROS generation and modulating ferroptotic lipids. CTFAP is composed of acid-responsive core calcium peroxide (CaO2) nanoparticles, ferroptotic lipids sponsor AA, tetracarboxylic porphyrin (TCPP) and Fe3+ based metal-organic framework structure, and biocompatible mPEG-DSPE for improved stability. Once endocytosed by tumor cells, CTFAP can release oxygen (O2) and hydrogen peroxide (H2O2) in the acidic TME, facilitating TCPP-based sonodynamic therapy and Fe3+-mediated Fenton-like reactions to generate substantial ROS for cell ferroptosis initiation. The immunogenic cell death (ICD) after ferroptosis promotes interferon γ (IFN-γ) secretion to up-regulate the expression of long-chain family member 4 (ACSL4), cooperating with the released AA from CTFAP to accelerate the accumulation of lipid peroxidation (LPO) and thereby promoting ferroptosis in cancer cells.CTFAP with ultrasound treatment efficiently suppresses tumor growth, has great potential to challenges in cancer immunotherapy.

Multifunctional Copper-Phenolic Nanopills Achieve Comprehensive Polyamines Depletion to Provoke Enhanced Pyroptosis and Cuproptosis for Cancer Immunotherapy.

The overexpression of polyamines in tumor cells contributes to the establishment of immunosuppressive microenvironment and facilitates tumor growth. Here, it have ingeniously designed multifunctional copper-piceatannol/HA nanopills (Cu-Pic/HA NPs) that effectively cause total intracellular polyamines depletion by inhibiting polyamines synthesis, depleting intracellular polyamines, and impairing polyamines uptake, resulting in enhanced pyroptosis and cuproptosis, thus activating a powerful immune response to achieve anti-tumor therapy. Mitochondrial dysfunction resulting from overall intracellular polyamines depletion not only leads to the surge of copper ions in mitochondria, thereby causing the aggregation of toxic proteins to induce cuproptosis, but also triggers the accumulation of reactive oxygen species (ROS) within mitochondria, which further upregulates the expression of zDHHC5 and zDHHC9 to promote the palmitoylation of gasdermin D (GSDMD) and GSDMD-N, ultimately inducing enhanced pyroptosis. Then the occurrence of enhanced pyroptosis and cuproptosis is conductive to remodel the immunosuppressive tumor microenvironment, thus activating anti-tumor immune responses and ultimately effectively inhibiting tumor growth and metastasis. This therapeutic strategy of enhanced pyroptosis and cuproptosis through comprehensive polyamines depletion provides a novel template for cancer immunotherapy.

Metal-Phenolic Nanomaterial with Organelle-Level Precision Primes Antitumor Immunity via mtDNA-dependent cGAS-STING Activation.

New generation of nanomaterials with organelle-level precision provide significant promise for targeted attacks on mitochondria, exhibiting remarkable therapeutic potency. Here, we report a novel amphiphilic phenolic polymer (PF) for the mitochondria-targeted photodynamic therapy (PDT), which can trigger excessive mitochondrial DNA (mtDNA) damage by the synergistic action of oxidative stress and furan-mediated DNA cross-linking. Moreover, the phenolic units on PF enable further self-assembly with Mn2+ via metal-phenolic coordination to form metal-phenolic nanomaterial (PFM). We focus on the synergistic activation of the cGAS-STING pathway by Mn2+ and tumor-derived mtDNA in tumor-associated macrophages (TAMs), and subsequently repolarizing M2-like TAMs to M1 phenotype. We highlight that PFM facilitates the cGAS-STING-dependent immunity at the organelle level for potent antitumor efficacy.

High-Lactate-Metabolizing Photosynthetic Bacteria Reprogram Tumor Immune Microenvironment.

The elevated levels of lactate in tumor tissue play a pivotal role in fostering an immunosuppressive microenvironment. Therefore, efficiently reducing lactate levels to reprogram tumor immune microenvironment (TIM) is considered a crucial step for boosted immunotherapy. Here, a high-lactate-metabolizing photosynthetic bacteria (LAB-1) is selectively screened for TIM reprogramming, which then improves the efficacy of tumor immunotherapy. The culture medium for LAB-1 screening is initially developed through an orthogonal experiment, simulating the tumor microenvironment (TME) and utilizing lactate as the sole organic carbon source. As demonstrated in a murine 4T1 model, LAB-1 colonizes the TME selectively, resulting in a significant reduction in lactate levels and a subsequent increase in pH values within the tumor tissue. Furthermore, single-cell RNA sequencing analysis reveals that LAB-1 effectively reprograms the TIM, thereby enhancing the effectiveness of antitumor immune therapy. This approach of utilizing lactate-consuming bacteria represents a potent tool for augmenting tumor immunotherapy efficiency.

Cuproptotic nanoinducer-driven proteotoxic stress potentiates cancer immunotherapy by activating the mtDNA-cGAS-STING signaling.

Proteotoxic stress, caused by the accumulation of abnormal unfolded or misfolded cellular proteins, can efficiently activate inflammatory innate immune response. Initiating the mitochondrial proteotoxic stress might go forward to enable the cytosolic release of intramitochondrial DNA (mtDNA) for the immune-related mtDNA-cGAS-STING activation, which however is easily eliminated by a cell self-protection, i.e., mitophagy. In light of this, a nanoinducer (PCM) is reported to trigger mitophagy-inhibited cuproptotic proteotoxicity. Through a simple metal-phenolic coordination, PCMs reduce the original Cu2+ with the phenolic group of PEG-polyphenol-chlorin e6 (Ce6) into Cu+. Cu+ thereby performs its high binding affinity to dihydrolipoamide S-acetyltransferase (DLAT) and aggregates DLAT for cuproptotic proteotoxic stress and mitochondrial respiratory inhibition. Meanwhile, intracellular oxygen saved from the respiratory failure can be utilized by PCM-conjugated Ce6 to boost the proteotoxic stress. Next, PCM-loaded mitophagy inhibitor (Mdivi-1) protects proteotoxic products from being mitophagy-eliminated, which allows more mtDNA to be released in the cytosol and successfully stimulate the cGAS-STING signaling. In vitro and in vivo studies reveal that PCMs can upregulate the tumor-infiltrated NK cells by 24% and enhance the cytotoxic killing of effector T cells. This study proposes an anti-tumor immunotherapy through mitochondrial proteotoxicity.

Dual-Epigenetically Relieving the MYC-Correlated Immunosuppression via an Advanced Nano-Radiosensitizer Potentiates Cancer Immuno-Radiotherapy.

Cancer cells can upregulate the MYC expression to repair the radiotherapy-triggered DNA damage, aggravating therapeutic resistance and tumor immunosuppression. Epigenetic treatment targeting the MYC-transcriptional abnormality may intensively solve this clinical problem. Herein, 5-Aza (a DNA methyltransferase inhibitor) and ITF-2357 (a histone deacetylase inhibitor) are engineered into a tungsten-based nano-radiosensitizer (PWAI), to suppress MYC rising and awaken robust radiotherapeutic antitumor immunity. Individual 5-Aza depletes MYC expression but cannot efficiently awaken radiotherapeutic immunity. This drawback can be overcome by the addition of ITF-2357, which triggers cancer cellular type I interferon (IFN-I) signaling. Coupling 5-Aza with ITF-2357 ensures that PWAI does not evoke the treated model with high MYC-related immune resistance while amplifying the radiotherapeutic tumor killing, and more importantly promotes the generation of IFN-I signal-related proteins involving IFN-α and IFN-ß. Unlike the radiation treatment alone, PWAI-triggered immuno-radiotherapy remarkably enhances antitumor immune responses involving the tumor antigen presentation by dendritic cells, and improves intratumoral recruitment of cytotoxic T lymphocytes and their memory-phenotype formation in 4T1 tumor-bearing mice. Downgrading the radiotherapy-induced MYC overexpression via the dual-epigenetic reprogramming strategy may elicit a robust immuno-radiotherapy.

An Ultrasound-Triggered STING Pathway Nanoagonist for Enhanced Chemotherapy-Induced Immunogenic Cell Death.

Although chemotherapy has the potential to induce tumor immunotherapy via immunogenic cell death (ICD) effects, how to control the intensity of the immune responses still deserves further exploration. Herein, a controllable ultrasound (US)-triggered chemo-immunotherapy nanoagonist is successfully synthesized by utilizing the pH and reactive oxygen species (ROS) dual-responsive PEG-polyphenol to assemble sonosensitizer zinc oxide (ZnO) and doxorubicin (DOX). The PZnO@DOX nanoparticles have an intelligent disassembly to release DOX and zinc ions in acidic pH conditions. Notably, US irradiation generates ROS by sonodynamic therapy and accelerates the drug release process. Interestingly, after the PZnO@DOX+US treatment, the injured cells release double-stranded DNA (dsDNA) from the nucleus and mitochondria into the cytosol. Subsequently, both the dsDNA and zinc ions bind with cyclic GMP-AMP synthase and activate the stimulator of interferon genes (STING) pathway, resulting in the dendritic cell maturation, ultimately promoting DOX-induced ICD effects and antigen-specific T cell immunity. Therefore, chemotherapy-induced immune responses can be modulated by non-invasive control of US.

Nanoghosts: Harnessing Mesenchymal Stem Cell Membrane for Construction of Drug Delivery Platforms Via Optimized Biomimetics.

Mesenchymal stem cells (MSCs) are becoming hotspots for application in disease therapies recently, combining with biomaterials and drug delivery system. A major advantage of MSCs applied in drug delivery system is that these cells enable specific targeting and releasing of cargos to the disease sites. However, the potential tumor tropic effects of MSCs raised concerns on biosafety. To solve this problem, there are emerging methods of isolating cell membranes and developing nanoformulations to perform drug delivery, which avoids concerns on biosafety without disturbing the membrane functions of specific polarizing and locating. These cargoes are so called "nanoghosts." This review article summarizes the current applications of nanoghosts, the promising potential of MSCs to be applied in membrane isolation and nanoghost construction, and possible approaches to develop better drug delivery system harnessing from MSC ghost cell membranes.

PhotoPyro-Induced cGAS-STING Pathway Activation Enhanced Anti-Melanoma Immunotherapy via a Manganese-Coordinated Nanomedicine.

Malignant melanoma is an aggressive skin cancer with a high metastatic and mortality rate. Owing to genetic alterations, melanoma cells are resistant to apoptosis induction, which reduces the efficacy of most adjuvant systemic anticancer treatments in clinical. Here, a noninvasive strategy for anti-melanoma immunotherapy based on a manganese-coordinated nanomedicine is provided. Supplemented with photoirradiation, photon-mediated reactive oxygen species generation by photosensitizer chlorin e6 initiates photon-controlled pyroptosis activation (PhotoPyro) and promotes antitumor immunity. Simultaneously, photoirradiation-triggered double-stranded DNA generation in the cytosol would activate the Mn2+ -sensitized cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway, which further augment the PhotoPyro-induced immune response. The syngeneic effect of these immunostimulatory pathways significantly benefits dendritic cell maturation by damage-associated molecular patterns and proinflammatory cytokines secretion, thereby activating T cells and remarkably eliciting a systemic antitumor immune response to inhibiting both primary and distant tumor growth. Collaboratively, the photoirradiation-triggered PhotoPyro and cGAS-STING pathway activation by nanomedicine administration could enhance the antitumor capacity of immunotherapy and serve as a promising strategy for melanoma treatment.

Gel/hydrogel-based in situ biomaterial platforms for cancer postoperative treatment and recovery.

Tumor surgical resection is the major strategy for cancer treatment. Meanwhile, perioperative treatment especially the postoperative adjuvant anticancer strategies play essential roles in satisfying therapeutic results and rapid recovery. Postoperative tumor recurrence, metastasis, bleeding, inter-tissue adhesion, infection, and delayed wound healing are vital risks that could lead to poor prognosis or even treatment failure. Therefore, methods targeting these postoperative complications are in desperate need. In situ biomaterial-based drug delivery platforms are promising candidates for postoperative treatment and recovery, resulting from their excellent properties including good biocompatibility, adaptive shape, limited systemic effect, designable function, and easy drug loading. In this review, we focus on introducing the gel/hydrogel-based in situ biomaterial platforms involving their properties, advantages, and synthesis procedures. Based on the loaded contents in the gel/hydrogel such as anticancer drugs, immunologic agents, cell components, and multifunctional nanoparticles, we further discuss the applications of the in situ platforms for postoperative tumor recurrence and metastasis inhibition. Finally, other functions aiming at fast postoperative recovery were introduced, including hemostasis, antibacterial infection, adhesion prevention, tissue repair, and wound healing. In conclusion, gel/hydrogel is a developing and promising platform for postoperative treatment, exhibiting gratifying therapeutic effects and inconspicuous toxicity to normal tissues, which deserves further research and exploration.

Lipid bilayer-based biological nanoplatforms for sonodynamic cancer therapy.

Sonodynamic therapy (SDT) has been developed as a promising alternative therapeutic modality for cancer treatment, involving the synergetic application of sonosensitizers and low-intensity ultrasound. However, the antitumor efficacy of SDT is significantly limited due to the poor performance of conventional sonosensitizers in vivo and the constrained tumor microenvironment (TME). Recent breakthroughs in lipid bilayer-based nanovesicles (LBBNs), including multifunctional liposomes, exosomes, and isolated cellular membranes, have brought new insights into the advancement of SDT. Despite their distinct sources and preparation methods, the lipid bilayer structure in common allows them to be functionalized in many comparable ways to serve as ideal nanocarriers against challenges arising from the tumor-specific sonosensitizer delivery and the complicated TME. In this review, we provide a comprehensive summary of the recent advances in LBBN-based SDT, with particular attention on how LBBNs can be engineered to improve the delivery efficiency of sonosensitizers and overcome physical, biological, and immune barriers within the TME for enhanced sonodynamic cancer therapy. We anticipate that this review will offer valuable guidance in the construction of LBBN-based nanosonosensitizers and contribute to the development of advanced strategies for next-generation sonodynamic cancer therapy.

Advanced Metallized Nanofibers for Biomedical Applications.

Nanofibers are long, wire-like materials with nanoscale diameters and specific length diameter ratios. Nanofibers have porous reticular networks with remarkably high specific surface areas and significant interconnectivity between pores, allowing for the chemical modification and loading of drugs. Metallized nanofibers are novel materials that enhance the performance of attributes of conventional nanofibers by combining metals with nanofibers through electrostatic spinning doping, chemical modification, and loading approaches. Due to their unique physical and chemical properties, metallized nanofibers are diverse, rapidly developed materials in the fields of physical chemistry, materials science, and battery preparation. To date, with improvement in advanced preparation techniques and biocompatibility levels for materials, metallized nanofiber applications are gradually expanding into the biomedical field due to their excellent thermal and electrical conductivities and unique metal properties. In this review, the applications of metallized nanofibers in biomedicine are summarized. It is suggested to prepare metallized multifunctional nanofibers for tissue engineering, drug delivery, tumor treatment, wound healing, and biosensing applications by taking safety and stability as the main material selection guidelines. Finally, the development of nanofibers for biomedical applications is summarized and discussed.

Metal-Phenolic Nanomedicines Regulate T-Cell Antitumor Function for Sono-Metabolic Cancer Therapy.

Cancer cells outcompete tumor-infiltrating T lymphocytes (TILs) for glucose uptake, manipulating a glucose-deprived tumor microenvironment (TME) with high accumulation of lactate, which impairs CD8+ TIL effector function, however supports the immune suppression of regulatory T (Treg) cells. Aerobic glycolysis inhibition coupled with mitochondrial dysfunction in cancer cells may reprogram TME to destabilize Treg cells and, more importantly, facilitate CD8+ T cell activation and cytotoxic killing. Here, a sono-metabolic cancer therapy via hyaluronic acid (HA)-modified metal-phenolic nanomedicine (HPP-Ca@GSK) is proposed to accomplish the aforementioned goals. Abrogating lactate dehydrogenase A (LDHA) by delivering GSK2837808A (GSK, LDHA inhibitor) successfully suppresses aerobic glycolysis in cancer cells and creates high-glucose, low-lactate conditions, satisfying the glucose nutrition required by CD8+ TILs but destabilizing Treg cells. Meanwhile, depending on ultrasound-mediated oxidative stress, more than 3-fold of calcium (from HPP-Ca@GSK) is mitochondrion-overloaded, amplifying mitochondrial dysfunction and promoting the cancer cellular release of damage-associated molecular patterns for more CD8+ T cell activation and tumor infiltration. In vitro and in vivo studies demonstrate that HPP-Ca@GSK-based sono-metabolic treatment exhibits impressive anticancer activity. Cooperating with anticytotoxic T lymphocyte-associated protein-4 antibodies for enhanced Treg cell destabilization further improves therapeutic efficacy. These findings provide a metabolic intervention strategy for cancer immunotherapy.

BRCA1 Insufficiency Induces a Hypersialylated Acidic Tumor Microenvironment That Promotes Metastasis and Immunotherapy Resistance.

Cancer metastasis is an extremely complex process affected by many factors. An acidic microenvironment can drive cancer cell migration toward blood vessels while also hampering immune cell activity. Here, we identified a mechanism mediated by sialyltransferases that induces an acidic tumor-permissive microenvironment (ATPME) in BRCA1-mutant and most BRCA1-low breast cancers. Hypersialylation mediated by ST8SIA4 perturbed the mammary epithelial bilayer structure and generated an ATPME and immunosuppressive microenvironment with increased PD-L1 and PD1 expressions. Mechanistically, BRCA1 deficiency increased expression of VEGFA and IL6 to activate TGFß-ST8SIA4 signaling. High levels of ST8SIA4 led to accumulation of polysialic acid (PSA) on mammary epithelial membranes that facilitated escape of cancer cells from immunosurveillance, promoting metastasis and resistance to αPD1 treatment. The sialyltransferase inhibitor 3Fax-Peracetyl Neu5Ac neutralized the ATPME, sensitized cancers to immune checkpoint blockade by activating CD8 T cells, and inhibited tumor growth and metastasis. Together, these findings identify a potential therapeutic option for cancers with a high level of PSA. SIGNIFICANCE: BRCA1 deficiency generates an acidic microenvironment to promote cancer metastasis and immunotherapy resistance that can be reversed using a sialyltransferase inhibitor.

Fueling sentinel node via reshaping cytotoxic T lymphocytes with a flex-patch for post-operative immuno-adjuvant therapy.

Clinical updates suggest conserving metastatic sentinel lymph nodes (SLNs) of breast cancer (BC) patients during surgery; however, the immunoadjuvant potential of this strategy is unknown. Here we leverage an immune-fueling flex-patch to animate metastatic SLNs with personalized antitumor immunity. The flex-patch is implanted on the postoperative wound and spatiotemporally releases immunotherapeutic anti-PD-1 antibodies (aPD-1) and adjuvants (magnesium iron-layered double hydroxide, LDH) into the SLN. Genes associated with citric acid cycle and oxidative phosphorylation are enriched in activated CD8+ T cells (CTLs) from metastatic SLNs. Delivered aPD-1 and LDH confer CTLs with upregulated glycolytic activity, promoting CTL activation and cytotoxic killing via metal cation-mediated shaping. Ultimately, CTLs in patch-driven metastatic SLNs could long-termly maintain tumor antigen-specific memory, protecting against high-incidence BC recurrence in female mice. This study indicates a clinical value of metastatic SLN in immunoadjuvant therapy.

Self-delivery of metal-coordinated NIR-II nanoadjuvants for multimodal imaging-guided photothermal-chemodynamic amplified immunotherapy.

The effectiveness of phototheranostics induced immunotherapy is still hampered by limited light penetration depth, the complex immunosuppressive tumor microenvironment (TME) and the low efficiency of immunomodulator drug delivery. Herein, self-delivery and TME responsive NIR-II phototheranostic nanoadjuvants (NAs) were fabricated to suppress the growth and metastasis of melanoma through the integration of photothermal-chemodynamic therapy (PTT-CDT) and immune remodeling. The NAs were constructed by the self-assembly of ultrasmall NIR-II semiconducting polymer dots and the toll-like receptor agonist resiquimod (R848) utilizing manganese ions (Mn2+) as coordination nodes. Under acidic TME, the NAs responsively disintegrated and released therapeutic components, which enable NIR-II fluorescence/photoacoustic/magnetic resonance imaging-guided tumor PTT-CDT. Moreover, the synergistic treatment of PTT-CDT could induce significant tumor immunogenic cell death and evoke highly efficacious cancer immunosurveillance. The released R848 stimulated the maturation of dendritic cells, which both amplified the antitumor immune response by modulating and remodeling the TME. The NAs present a promising integration strategy of polymer dot-metal ion coordination and immune adjuvants for precise diagnosis and amplified anti-tumor immunotherapy against deep-seated tumors. STATEMENT OF SIGNIFICANCE: The efficiency of phototheranostics induced immunotherapy is still limited by insufficient light penetration depth, low immune response and the complex immunosuppressive tumor microenvironment (TME). In order to improve the efficacy of immunotherapy, self-delivery NIR-II phototheranostic nanoadjuvants (PMR NAs) were successfully fabricated via the facile coordination self-assembly of ultra-small NIR-II semiconducting polymer dots and toll-like receptor agonist resiquimod (R848) utilizing manganese ions (Mn2+) as coordination nodes. PMR NAs not only enable TME responsive cargo release and NIR-II fluorescence/photoacoustic/magnetic resonance imaging mediated precise localization of tumors, but also achieve synergistic photothermal-chemodynamic therapy, evoking an effective anti-tumor immune response by ICD effect. The responsively released R848 could further amplify the efficiency of immunotherapy by reversing and remodeling the immunosuppressive tumor microenvironment, thereby effectively inhibiting tumor growth and lung metastasis.

Self-Degradable Nanogels Reshape Immunosuppressive Tumor Microenvironment via Drug Repurposing Strategy to Reactivate Cytotoxic CD8+ T Cells.

Intratumoral CD8+ T cells are crucial for effective cancer immunotherapy, but an immunosuppressive tumor microenvironment (TME) contributes to dysfunction and insufficient infiltration. Drug repurposing has successfully led to new discoveries among existing clinical drugs for use as immune modulators to ameliorate immunosuppression in TME and reactivate T-cell-mediated antitumor immunity. However, due to suboptimal tumor bioavailability, the full potential of immunomodulatory effects of these old drugs has not been realized. The self-degradable PMI nanogels carrying two repurposed immune modulators, imiquimod (Imi) and metformin (Met), are reported for TME-responsive drug release. It remodels the TME through the following aspects: 1) promoting dendritic cells maturation, 2) repolarizing M2-like tumor-associated macrophages, and 3) downregulating PD-L1 expression. Ultimately, PMI nanogels reshaped the immunosuppressive TME and efficiently promote CD8+ T cell infiltration and activation. These results support that PMI nanogels can potentially be an effective combination drug for enhancing the antitumor immune response of anti-PD-1 antibodies.

Engineering metal-phenolic networks for enhancing cancer therapy by tumor microenvironment modulation.

The complicated tumor microenvironment (TME) is featured by low pH values, high redox status, and hypoxia, which greatly supports the genesis, development, and metastasis of tumors, leading to drug resistance and clinical failure. Moreover, a lot of immunosuppressive cells infiltrate in such TME, resulting in depressing immunotherapy. Therefore, the development of TME-responsive nanoplatforms has shown great significance in enhancing cancer therapeutics. Metal-phenolic networks (MPNs)-based nanosystems, which self-assemble via coordination of phenolic materials and metal ions, have emerged as excellent TME theranostic nanoplatforms. MPNs have unique properties including fast preparation, tunable morphologies, pH response, and biocompatibility. Besides, functionalization and surface modification can endow MPNs with specific functions for application requirements. Here, the representative engineering strategies of various polyphenols are first introduced, followed by the introduction of the engineering mechanisms of polyphenolic nanosystems, fabrication, and distinct properties of MPNs. Then, their advances in TME modulation are highlighted, such as antiangiogenesis, hypoxia relief, combination therapy sensitization, and immunosuppressive TME reversion. Finally, we will discuss the challenges and future perspectives of MPNs-based nanosystems for enhancing cancer therapy. This article is categorized under: Nanotechnology Approaches to Biology > Nanoscale Systems in Biology Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease.