Tea polyphenol-derived nanomedicine for targeted photothermal thrombolysis and inflammation suppression.

Thrombotic diseases impose a significant global health burden, and conventional drug-based thrombolytic therapies are encumbered by the risk of bleeding complications. In this study, we introduce a novel drug-free nanomedicine founded on tea polyphenols nanoparticles (TPNs), which exhibits multifaceted capabilities for localized photothermal thrombolysis. TPNs were synthesized through a one-pot process under mild conditions, deriving from the monomeric epigallocatechin-3-gallate (EGCG). Within this process, indocyanine green (ICG) was effectively encapsulated, exploiting multiple intermolecular interactions between EGCG and ICG. While both TPNs and ICG inherently possessed photothermal potential, their synergy significantly enhanced photothermal conversion and stability. Furthermore, the nanomedicine was functionalized with cRGD for targeted delivery to activated platelets within thrombus sites, eliciting robust thrombolysis upon laser irradiation across diverse thrombus types. Importantly, the nanomedicine's potent free radical scavenging abilities concurrently mitigated vascular inflammation, thus diminishing the risk of disease recurrence. In summary, this highly biocompatible multifunctional nanomaterial holds promise as a comprehensive approach that combines thrombolysis with anti-inflammatory actions, offering precision in thrombosis treatment.

Mn-phenolic networks as synergistic carrier for STING agonists in tumor immunotherapy.

The cGAS-STING pathway holds tremendous potential as a regulator of immune responses, offering a means to reshape the tumor microenvironment and enhance tumor immunotherapy. Despite the emergence of STING agonists, their clinical viability is hampered by stability and delivery challenges, as well as variations in STING expression within tumors. In this study, we present Mn-phenolic networks as a novel carrier for ADU-S100, a hydrophilic STING agonist, aimed at bolstering immunotherapy. These nanoparticles, termed TMA NMs, are synthesized through the coordination of tannic acid and manganese ions, with surface modification involving bovine serum albumin to enhance their colloidal stability. TMA NMs exhibit pH/GSH-responsive disintegration properties, enabling precise drug release. This effectively addresses drug stability issues and facilitates efficient intracellular drug delivery. Importantly, TMA NMs synergistically enhance the effects of ADU-S100 through the concurrent release of Mn2+, which serves as a sensitizer of the STING pathway, resulting in significant STING pathway activation. Upon systemic administration, these nanoparticles efficiently accumulate within tumors. The activation of STING pathways not only induces immunogenic cell death (ICD) in tumor cells but also orchestrates systemic remodeling of the immunosuppressive microenvironment. This includes the promotion of cytokine release, dendritic cell maturation, and T cell infiltration, leading to pronounced suppression of tumor growth. Combining with the excellent biocompatibility and biodegradability, this Mn-based nanocarrier represents a promising strategy for enhancing tumor immunotherapy through the cGAS-STING pathway.

Activable Photodynamic DNA Probe with an "AND" Logic Gate for Precision Skin Cancer Therapy.

Photodynamic therapy (PDT) has emerged as a promising approach for squamous cell carcinoma treatment but hindered by tumor hypoxia, acquired resistance, phototoxicity, and so on. To address these issues, we developed a smart strategy utilizing activable photosensitizers delivered by an aptamer-functionalized DNA probe (ADP). The ADP incorporated an AS1411 aptamer for tumor targeting and a linear antisense oligonucleotide (ASO) for recognition of Survivin mRNA. In the absence of the target, PDT remained quenched, thereby avoiding phototoxicity during circulation and nonselective distribution. With the aid of the aptamer, ADP achieved selective targeting of tumors. Upon internalization, ADP targeted recognized Survivin mRNA, triggering PDT activation, and releasing ASO to down-regulate Survivin expression and reverse tumor resistance. Consequently, the activable photosensitizers exhibited an "AND" logic gate, combining tumor-targeting delivery and tumor-related gene activation, thus enhancing its specificity. Additionally, the incorporation of hemin into the ADP provided catalase activity, converting tumor-abundant H2O2 into O2, thereby ameliorating tumor hypoxia. The resulting functionalized G-quadruplex/hemin-DNA probe complex demonstrated targeted delivery and activation, minimized side effects, and enhanced PDT efficacy in both xenograft tumor-bearing mice and patient-derived xenograft models. This study offers a unique and promising platform for efficient and safe PDT, thus holding great potential for future clinical translation and improved cancer therapy.

G-Quadruplex/Hemin DNAzyme-Functionalized Silver Nanoclusters with Synergistic Antibacterial and Wound Healing Capabilities for Infected Wound Management.

Systematic management of infected wounds requires simultaneous antiinfection and wound healing, which has become the current treatment dilemma. Recently, a multifunctional silver nanoclusters (AgNCs)-based hydrogel dressing to meet these demands is developed. Here a diblock DNA with a cytosine-rich fragment (as AgNCs template) and a guanine-rich fragment (to form G-quadruplex/hemin DNAzyme, termed G4/hemin) is designed, for G4/hemin functionalization of AgNCs. Inside bacteria, G4/hemin can not only accelerate the oxidative release of Ag+ from AgNCs but also generate reactive oxygen species (ROS) via catalase- and peroxidase-mimic activities, which enhance the antibacterial effect. On the other hand, the AgNCs exhibit robust anti-inflammatory and antioxidative activities to switch M1 macrophages into M2 phenotype, which promotes wound healing. Moreover, the hemin is released to upregulate the heme oxygenase-1, an intracellular enzyme that can relieve oxidative stress, which significantly alleviates the cytotoxicity of silver. As a result, such silver-based dressing achieves potent therapeutic efficacy on infected wounds with excellent biosafety.

Converting bacteria into autologous tumor vaccine via surface biomineralization of calcium carbonate for enhanced immunotherapy.

Autologous cancer vaccine that stimulates tumor-specific immune responses for personalized immunotherapy holds great potential for tumor therapy. However, its efficacy is still suboptimal due to the immunosuppressive tumor microenvironment (ITM). Here, we report a new type of bacteria-based autologous cancer vaccine by employing calcium carbonate (CaCO3) biomineralized Salmonella (Sal) as an in-situ cancer vaccine producer and systematical ITM regulator. CaCO3 can be facilely coated on the Sal surface with calcium ionophore A23187 co-loading, and such biomineralization did not affect the bioactivities of the bacteria. Upon intratumoral accumulation, the CaCO3 shell was decomposed at an acidic microenvironment to attenuate tumor acidity, accompanied by the release of Sal and Ca2+/A23187. Specifically, Sal served as a cancer vaccine producer by inducing cancer cells' immunogenic cell death (ICD) and promoting the gap junction formation between tumor cells and dendritic cells (DCs) to promote antigen presentation. Ca2+, on the other hand, was internalized into various types of immune cells with the aid of A23187 and synergized with Sal to systematically regulate the immune system, including DCs maturation, macrophages polarization, and T cells activation. As a result, such bio-vaccine achieved remarkable efficacy against both primary and metastatic tumors by eliciting potent anti-tumor immunity with full biocompatibility. This work demonstrated the potential of bioengineered bacteria as bio-active vaccines for enhanced tumor immunotherapy.

The obesogenic side of Genistein.

Genistein (GN) has been highly recommended for its medicinal properties like anticancer, antidiabetic, antihyperlipidemic, antiviral, and antioxidant activities among others. Recently, scientists realized that Genistein is an endocrine disruptor. It is an obesogen that interferes with the endocrine system causing obesity through many mechanisms like inducing adipocyte differentiation, lipid accumulation, and transformation of some stem cells into adipocytes (bone marrow mesenchymal stem cells for example) in vitro. Animal studies show that GN upregulates genes associated with adipogenesis like CCAAT/enhancer binding protein alpha (Cebpα), CCAAT/enhancer binding protein beta (Cebpß), and PPARγ. In silico studies reveal a strong binding affinity for estrogen receptors. All these findings were contingent on concentration and tissues. It is beyond dispute that obesity is one of the most frustrating medical conditions under the sun. The pathophysiology of this disease was first attributed to a high-calorie diet and lack of physical activity. However, studies proved that these two factors are not enough to account for obesity in both children and adults. This mini review highlights how Genistein interaction with the peroxisome proliferator-activated receptor gamma protein can cause obesity.

CpG-Conjugated Silver Nanoparticles as a Multifunctional Nanomedicine to Promote Macrophage Efferocytosis and Repolarization for Atherosclerosis Therapy.

Atherosclerosis (AS) is a major contributor to cardiovascular diseases, necessitating the development of novel therapeutic strategies to alleviate plaque burden. Macrophage efferocytosis, the process by which macrophages clear apoptotic and foam cells, plays a crucial role in plaque regression. However, this process is impaired in AS lesions due to the overexpression of CD47, which produces a "do not eat me" signal. In this study, we investigated the potential of CpG, a toll-like receptor 9 agonist, to enhance macrophage efferocytosis for AS therapy. We demonstrated that CpG treatment promoted the engulfment of CD47-positive apoptotic cells and foam cells by macrophages. Mechanistically, CpG induced a metabolic shift in macrophages characterized by enhanced fatty acid oxidation and de novo lipid biosynthesis, contributing to its pro-efferocytic effect. To enable in vivo application, we conjugated CpG on silver nanoparticles (AgNPs) to form CpG-AgNPs, which could protect CpG from biological degradation, promote its cellular uptake, and release CpG in response to intracellular glutathione. Combining the intrinsic antioxidative and anti-inflammatory abilities of AgNPs, such nanomedicine displayed multifunctionalities to simultaneously promote macrophage efferocytosis and repolarization. In an ApoE-/- mouse model, intravenous administration of CpG-AgNPs effectively targeted atherosclerotic plaques and exhibited potent therapeutic efficacy with excellent biocompatibility. Our study provides valuable insights into CpG-induced macrophage efferocytosis and highlights the potential of CpG-AgNPs as a promising therapeutic strategy for AS.

Cryopreservation of bioflavonoid-rich plant sources and bioflavonoid-microcapsules: emerging technologies for preserving bioactivity and enhancing nutraceutical applications.

Bioflavonoids are natural polyphenolic secondary metabolites that are medicinal. These compounds possess antitumor, cardioprotective, anti-inflammatory, antimicrobial, antiviral, and anti-psoriasis properties to mention a few. Plant species that contain bioflavonoids should be preserved as such. Also, the bioactivity of the bioflavonoids as neutraceutical compounds is compromised following extraction due to their sensitivity to environmental factors like light, pH, and temperature. In other words, the bioflavonoids' shelf-life is affected. Scientists noticed that bioflavonoids have low solubility properties, poor absorption, and low bioavailability following consumption. Researchers came up with methods to encapsulate bioflavonoids in order to circumvent the challenges above and also to mask the unpleasant order these chemicals may have. Besides, scientists cryopreserve plant species that contain bioflavonoids. In this review, we discuss cryopreservation and bioflavonoid microencapsulation focusing mainly on vitrification, slow freezing, and freeze-drying microencapsulation techniques. In addition, we highlight bioflavonoid extraction techniques, medicinal properties, challenges, and future perspectives of cryopreservation and microencapsulation of bioflavonoids. Regardless of the uniqueness of cryopreservation and microencapsulation as methods to preserve bioflavonoid sources and bioflavonoids' bioactivity, there are challenges reported. Freeze-drying technology is costly. Cryoprotectants damage the integrity of plant cells, to say the least. Researchers are working very hard to overcome these challenges. Encapsulating bioflavonoids via coaxial electrospray and then cryopreserving the micro/nanocapsules produced can be very interesting.

Starting Editorial of "Cellular Damage: Protection and Induction" Addressing Hot Topics in Cellular Damage, Protection of Cells and Therapy Targeting Bad Cells.

The cell, the fundamental unit of life, is constantly subjected to a myriad of molecular biophysical disturbances [...].

Bacterial Drug Delivery Systems for Cancer Therapy: "Why" and "How".

Cancer is one of the major diseases that endanger human health. However, the use of anticancer drugs is accompanied by a series of side effects. Suitable drug delivery systems can reduce the toxic side effects of drugs and enhance the bioavailability of drugs, among which targeted drug delivery systems are the main development direction of anticancer drug delivery systems. Bacteria is a novel drug delivery system that has shown great potential in cancer therapy because of its tumor-targeting, oncolytic, and immunomodulatory properties. In this review, we systematically describe the reasons why bacteria are suitable carriers of anticancer drugs and the mechanisms by which these advantages arise. Secondly, we outline strategies on how to load drugs onto bacterial carriers. These drug-loading strategies include surface modification and internal modification of bacteria. We focus on the drug-loading strategy because appropriate strategies play a key role in ensuring the stability of the delivery system and improving drug efficacy. Lastly, we also describe the current state of bacterial clinical trials and discuss current challenges. This review summarizes the advantages and various drug-loading strategies of bacteria for cancer therapy and will contribute to the development of bacterial drug delivery systems.

A cooperation tale of biomolecules and nanomaterials in nanoscale chiral sensing and separation.

The cooperative relationship between biomolecules and nanomaterials makes up a beautiful tale about nanoscale chiral sensing and separation. Biomolecules are considered a fabulous chirality 'donor' to develop chiral sensors and separation systems. Nature has endowed biomolecules with mysterious chirality. Various nanomaterials with specific physicochemical attributes can realize the transmission and amplification of this chirality. We focus on highlighting the advantages of combining biomolecules and nanomaterials in nanoscale chirality. To enhance the sensors' detection sensitivity, novel cooperation approaches between nanomaterials and biomolecules have attracted tremendous attention. Moreover, innovative biomolecule-based nanocomposites possess great importance in developing chiral separation systems with improved assay performance. This review describes the formation of a network based on nanomaterials and biomolecules mainly including DNA, proteins, peptides, amino acids, and polysaccharides. We hope this tale will record the perpetual relation between biomolecules and nanomaterials in nanoscale chirality.

Biophysics in Membrane of Cells.

The membrane of a cell, often compared to a dynamic city border, carries out an intricate dance of controlling entry and exit, guarding the valuable life processes occurring inside [...].

Enhancing bioavailability of natural extracts for nutritional applications through dry powder inhalers (DPI) spray drying: technological advancements and future directions.

Natural ingredients have many applications in modern medicine and pharmaceutical projects. However, they often have low solubility, poor chemical stability, and low bioavailability in vivo. Spray drying technology can overcome these challenges by enhancing the properties of natural ingredients. Moreover, drug delivery systems can be flexibly designed to optimize the performance of natural ingredients. Among the various drug delivery systems, dry powder inhalation (DPI) has attracted much attention in pharmaceutical research. Therefore, this review will focus on the spray drying of natural ingredients for DPI and discuss their synthesis and application.

A General and Efficient Strategy for Gene Delivery Based on Tea Polyphenols Intercalation and Self-Polymerization.

Gene therapy that employs therapeutic nucleic acids to modulate gene expression has shown great promise for diseases therapy, and its clinical application relies on the development of effective gene vector. Herein a novel gene delivery strategy by just using natural polyphenol (-)-epigallocatechin-3-O-gallate (EGCG) as raw material is reported. EGCG first intercalates into nucleic acids to yield a complex, which then oxidizes and self-polymerizes to form tea polyphenols nanoparticles (TPNs) for effective nucleic acids encapsulation. This is a general method to load any types of nucleic acids with single or double strands and short or long sequences. Such TPNs-based vector achieves comparable gene loading capacity to commonly used cationic materials, but showing lower cytotoxicity. TPNs can effectively penetrate inside cells, escape from endo/lysosomes, and release nucleic acids in response to intracellular glutathione to exert biological functions. To demonstrate the in vivo application, an anti-caspase-3 small interfering ribonucleic acid is loaded into TPNs to treat concanavalin A-induced acute hepatitis, and excellent therapeutic efficacy is obtained in combination with the intrinsic activities of TPNs vector. This work provides a simple, versatile, and cost-effective gene delivery strategy. Given the biocompatibility and intrinsic biofunctions, this TPNs-based gene vector holds great potential to treat various diseases.

Topical Delivery of Ketorolac Tromethamine via Cataplasm for Inflammatory Pain Therapy.

Nonsteroidal anti-inflammatory drugs (NSAIDs) have been widely used in the treatment of inflammatory pain, such as in osteoarthritis. Ketorolac tromethamine is considered to be an NSAID with strong anti-inflammatory and analgesic potency, however, traditional applications, such as oral administration and injections, often induce high systemic exposure, leading to adverse events such as gastric ulceration and bleeding. To address this key limitation, herein we designed and fabricated a topical delivery system for ketorolac tromethamine via cataplasm, which is based on a three-dimensional mesh structure formed by the cross-linking of dihydroxyaluminum aminoacetate (DAAA) and sodium polyacrylate. The viscoelasticity of the cataplasm was characterized by rheological methods and exhibited a "gel-like" elastic property. The release behavior showed a Higuchi model characteristic with a dose dependence. To enhance the skin permeation, permeation enhancers were added and screened utilizing ex vivo pig skin, in which 1,2-propanediol was found to have the optimal permeation-promoting effect. The cataplasm was further applied to a rat carrageenan-induced inflammatory pain model, which showed comparable anti-inflammatory and analgesic effects with oral administration. Finally, the biosafety of the cataplasm was tested in healthy human volunteers, and reduced side effects were achieved as compared to the tablet formulation, which can be ascribed to less systemic drug exposure and lower blood drug concentrations. Therefore, the constructed cataplasm can reduce the risk of adverse events while maintaining efficacy, thus serving as a better alternative for the treatment of inflammatory pain, including osteoarthritis.

A comparative study of the neuroprotective effects of dl-3-n-butylphthalide and edaravone dexborneol on cerebral ischemic stroke rats.

INTRODUCTION: DL-3-n-butylphthalide (NBP) and edaravone dexborneol (Eda-Dex) are two promising reagents for stroke treatment. However, the impacts of NBP and Eda-Dex on poststroke mental deficits are still poorly understood. In this study, we aimed to investigate and compare the influences of NBP and Eda-Dex on neurological function and cognitive behavior in rats with ischemic stroke. METHODS: An ischemic stroke model was established by middle cerebral artery occlusion (MCAO). After peritoneal administration of the drugs, the rats were subjected to neurological deficit evaluation, cerebral blood flow (CBF) assays, cerebral infarct area evaluations or behavioral tests. Brain tissues were collected and further analyzed by enzyme-linked immunosorbent assay (ELISA), western blotting or immunohistochemistry. RESULTS: NBP and Eda-Dex significantly decreased the neurological score, reduced the cerebral infarct area and improved CBF. Behavioral changes as assessed in the sucrose preference test, novel object recognition test, and social interaction test were significantly alleviated by NBP and Eda-Dex in rats with ischemic stroke. Moreover, NBP and Eda-Dex significantly suppressed inflammation by targeting the nuclear factor kappa-B/inducible nitric oxide synthase (NF-κB/iNOS) pathway and significantly inhibited oxidative stress by targeting the kelch-1ike ECH-associated protein l/nuclear factor erythroid 2-related factor 2 (Keap1/Nrf2) pathway. In addition, NBP and Eda-Dex distinctly suppressed the activation of microglia and astrocytes and improved neuronal viability in the ischemic brain. CONCLUSIONS: NBP and Eda-Dex improved neurological function and alleviated cognitive disorders in rats with ischemic stroke by synergistically inhibiting inflammation and oxidative stress.

Photodynamic therapy combined with surgery versus Mohs micrographic surgery for the treatment of difficult-to-treat basal cell carcinoma: a retrospective clinical study.

BACKGROUND: Mohs micrographic surgery (MMS) is the preferable surgery for difficult -to-treat basal cell carcinoma (BCC) but is an expensive, labor-intensive, and time-consuming technique. The aim of this study is to compare the efficacy and safety of photodynamic therapy combined with surgery(S-PDT) versus Mohs micrographic surgery (MMS) for the treatment of difficult-to-treat BCC. METHODS: This was a retrospective, comparative study. A total of 32 patients, 16 patients with 48 lesions, were treated with S-PDT, and the other 16 patients with 17 lesions treated by MMS were enrolled in this study. Follow-up was at least 36 months posttreatment. RESULTS: The recurrence rate was no statistical difference between the S-PDT and MMS (p = 1.000, Fishers exact test). The median follow-up was 42.5 months (range 36-63 months). The mean healing time in the S-PDT [17.9 d (SD 9.8)] is longer than in MMS [7.5 d (SD 1.5)] during follow-up (p＜.001, Independent T-test). On the whole, the cosmetic outcome of patients in S-PDT was statistically no significant difference with that in MMS according to a 4-point scale (p = .719, chi-squared test). CONCLUSIONS: S-PDT is a safe, effective, and novel cosmetic treatment, which holds the potential to be an alternative treatment to MMS for some cases.

Targeting lncRNA DDIT4-AS1 Sensitizes Triple Negative Breast Cancer to Chemotherapy via Suppressing of Autophagy.

In this study, it is found that the lncRNA, DNA damage inducible transcript 4 antisense RNA1 (DDIT4-AS1), is highly expressed in triple-negative breast cancer (TNBC) cell lines and tissues due to H3K27 acetylation in the promoter region, and promotes the proliferation, migration, and invasion of TNBC cells via activating autophagy. Mechanistically, it is shown that DDIT4-AS1 induces autophagy by stabilizing DDIT4 mRNA via recruiting the RNA binding protein AUF1 and promoting the interaction between DDIT4 mRNA and AUF1, thereby inhibiting mTOR signaling pathway. Furthermore, silencing of DDIT4-AS1 enhances the sensitivity of TNBC cells to chemotherapeutic agents such as paclitaxel both in vitro and in vivo. Using a self-activatable siRNA/drug core-shell nanoparticle system, which effectively deliver both DDIT4-AS1 siRNA and paclitaxel to the tumor-bearing mice, a significantly enhanced antitumor activity is achieved. Importantly, the codelivery nanoparticles exert a stronger antitumor effect on breast cancer patient-derived organoids. These findings indicate that lncRNA DDIT4-AS1-mediated activation of autophagy promotes progression and chemoresistance of TNBC, and targeting of DDIT4-AS1 may be exploited as a new therapeutic approach to enhancing the efficacy of chemotherapy against TNBC.

Salmonella-mediated blood‒brain barrier penetration, tumor homing and tumor microenvironment regulation for enhanced chemo/bacterial glioma therapy.

Chemotherapy is an important adjuvant treatment of glioma, while the efficacy is far from satisfactory, due not only to the biological barriers of blood‒brain barrier (BBB) and blood‒tumor barrier (BTB) but also to the intrinsic resistance of glioma cells via multiple survival mechanisms such as up-regulation of P-glycoprotein (P-gp). To address these limitations, we report a bacteria-based drug delivery strategy for BBB/BTB transportation, glioma targeting, and chemo-sensitization. Bacteria selectively colonized into hypoxic tumor region and modulated tumor microenvironment, including macrophages repolarization and neutrophils infiltration. Specifically, tumor migration of neutrophils was employed as hitchhiking delivery of doxorubicin (DOX)-loaded bacterial outer membrane vesicles (OMVs/DOX). By virtue of the surface pathogen-associated molecular patterns derived from native bacteria, OMVs/DOX could be selectively recognized by neutrophils, thus facilitating glioma targeted delivery of drug with significantly enhanced tumor accumulation by 18-fold as compared to the classical passive targeting effect. Moreover, the P-gp expression on tumor cells was silenced by bacteria type III secretion effector to sensitize the efficacy of DOX, resulting in complete tumor eradication with 100% survival of all treated mice. In addition, the colonized bacteria were finally cleared by anti-bacterial activity of DOX to minimize the potential infection risk, and cardiotoxicity of DOX was also avoided, achieving excellent compatibility. This work provides an efficient trans-BBB/BTB drug delivery strategy via cell hitchhiking for enhanced glioma therapy.

Mn-based cGAS-STING activation for tumor therapy.

Immunotherapy has efficiently revolutionized the treatment of human neoplastic diseases. However, the overall responsive rate of current immunotherapy is still unsatisfactory, benefiting only a small proportion of patients. Therefore, significant attention has been paid to the modulation of tumor microenvironment (TME) for the enhancement of immunotherapy. Interestingly, recent studies have shown that cyclic GMP-AMP synthase-stimulator of interferon gene (cGAS-STING) was initially found as an innate immune sensor to recognize cytoplasmic DNA (such as bacterial, viral, micronuclei, and mitochondrial). It is a promising signaling pathway to activate antitumor immune responses via type I interferon production. Notably, Mn2+ was found to be a critical molecule to sensitize the activation of the cGAS-STING pathway for better immunotherapy. This activation led to the development of Mn2+-based strategies for tumor immunotherapy via the activation of the cGAS-STING pathway. In this critical review, we aimed to summarize the recent progress of this field, focusing on the following three aspects. First, we briefly introduced the signaling pathway of cGAS-STING activation, and its regulation effect on the antitumor immunity cycle has been discussed. Along with this, several agonists of the cGAS-STING pathway were introduced with their potential as immunotherapeutic drugs. Then, the basic biological functions of Mn2+ have been illustrated, focusing on its critical roles in the cGAS-STING pathway activation. Next, we systematically reviewed the Mn2+-based strategies for tumor immunotherapy, which can be classified by the methods based on Mn2+ alone or Mn2+ combined with other therapeutic modalities. We finally speculated the future perspectives of the field and provided rational suggestions to develop better Mn2+-based therapeutics.