The role of nanomechanical cues in regulating exosome biogenesis and function is poorly understood. Herein, we engineer silica nanoparticles (SNs) with tunable elasticity (Young’s modulus from 103.2 to 1,064.7 MPa) to probe this mechanism. We demonstrate that softer SNs (20% SNs, 103.2 MPa) significantly boost exosome secretion from bone-marrow-derived macrophages (BMDMs). This process is mediated by the activation of the mechanosensitive ion channel Piezo1, subsequent calcium influx, and the Calcium/Calmodulin-dependent Kinase II Alpha (CAMK2A)/guanosine triphosphate (GTP)-Rab8 signaling axis. Proteomic analysis reveals that these “nanomechanically engineered exosomes” (Exo20% SNs) are enriched with proteins that coordinately amplify T cell receptor signaling. Consequently, Exo20% SNs exhibit superior pro-inflammatory capacity and, in a mouse tumor model, effectively suppress tumor growth and remodel the immunosuppressive tumor microenvironment, outperforming exosomes from lipopolysaccharide (LPS)-activated macrophages. This work establishes a paradigm of nanomechanically engineered exosomes, providing a novel strategy for precision immunotherapy.

Adipocytes constitute a major component of the breast tumor microenvironment and actively fuel tumor growth. In situ browning of adipocytes may restrict tumor nutrient availability, but whether browning-derived thermogenesis can be harnessed to reshape antitumor immunity remains unclear. Here, through screening, we identified Lactobacillus acidophilus (LA) as an effective inducer of adipocyte browning, generating localized and sustained thermogenesis within 24 h, which substantially longer than conventional thermal therapy. Critically, this sustained heat from brown adipocytes drives macrophage polarization toward an M1-like phenotype in a duration-dependent manner, which not observed in white adipocytes. Transcriptomic analyses further implicate transient receptor potential vanilloid 2 (TRPV2) -associated thermosensitive signaling in mediating this response. To further exploit macrophage-mediated antitumor activity, LA was integrated with a phenylboronic acid-modified polyethyleneimine (PEI-PBA) nanocarrier delivering CRISPR/Cas9 plasmids targeting CD47, yielding an engineered construct (PPC@LA). In an orthotopic breast cancer model, PPC@LA induced sustained intratumoral thermogenesis and markedly increased infiltration of M1-like macrophages and remodeled the tumor immune microenvironment. Additionally, brown adipocytes restricted tumor cell uptake of glucose and fatty acids. Consequently, PPC@LA achieved potent tumor suppression, with an inhibition rate of 79.6%. Collectively, this work establishes a bacteria-enabled therapeutic platform that creates a localized thermogenic adipocyte niche to amplify macrophage-centered breast cancer immunotherapy.

Ferroptosis-based cancer immunotherapy is often limited by insufficient intracellular iron and inherent antioxidant defense. Inspired by heme oxygenase 1 (HMOX1), which catalyzes heme to release endogenous Fe2+, and informed by bioinformatics hints indicating a potential correlation between hypoxia-inducible factor-1α (HIF-1α) and HMOX1, as well as the critical role of glutaminase activity in redox metabolism. We rationally designed a hypoxia nanoalleviator (MPCC) co-loaded CaO2 and the glutaminase inhibitor C968 onto mesoporous polydopamine nanocarriers. Under acidic condition, CaO2 can generate O2 and H2O2. The alleviation of hypoxia by the generated O₂ upregulates HMOX1 expression, which subsequently catalyzes heme degradation into Fe2+ while simultaneously downregulating the iron exporter SLC40A1. This dual action disrupts iron homeostasis and promotes intracellular Fe2+ accumulation. The accumulated Fe2+ reacts with H2O2 via a Fenton-like reaction, producing ROS to induce ferroptosis. Concurrently, hypoxia alleviation reduces HIF-1α expression, and thereby inhibiting glutamate transporter SLC1A1 expression, combining with glutaminase inhibitor C968, dual suppressing glutathione production to disrupt redox metabolism, causing ROS storms, thereby robustly enhancing ferroptosis. Enhanced ferroptosis effectively triggers immunogenic cell death, thereby activating T-cell immune responses and potently suppressing tumor growth and metastasis.

Precise regulation of macrophage fate is crucial for effective management of inflammation. However, conventional biochemical strategies often suffer from limitations in safety and efficiency, necessitating the development of more effective and controllable alternatives. In this study, we develop an ultrasound-engineered cell culture device capable of delivering finely tuned ultrasonic mechanical stimulation and demonstrate for the first time that ultrasound can remotely and dynamically modulate macrophage phenotypic fate. Our results demonstrate that ultrasound stimulation not only induces flexible transitions between macrophage subtypes but also exhibits superior immunomodulatory performance in induction efficiency, dynamic responsiveness, and spatio-temporal controllability compared to classical biochemical methods. Transcriptome sequencing reveals that ultrasound directionally polarizes M2a macrophages via activation of the integrin alpha X beta 2/TGF-beta/c-Fos/IL-10 pathway. Based on the programmable dynamic control of macrophage phenotype, we propose "sequential ultrasound therapy" and combine it with metformin hydrogel with controlled-release function to construct a physicochemically coordinated "inflammatory switch and angiogenesis promotion" therapeutic platform, exhibiting superior inflammatory repair effects than single treatment for in vivo diabetic wounds and myocardial infarction models. Overall, this study not only advances the mechanistic understanding of ultrasound in tissue repair but also proposes a remote, non-invasive ultrasound immunotherapy paradigm with clinical translation potential.

The inevitable splenic sequestration of nanomedicine represents a major delivery challenge that compromises tumor accumulation and may contribute to off-target burden. Rather than attempting to eliminate this fate, we propose to functionally repurpose it into an immunologically productive process. Distinct from conventional spleen-targeted strategies, we aimed to modulate the biological fate of tumor-targeted nanomedicines by engineering their surface with screening-selected hybrid cell membranes. A tumor cell membrane-to-erythrocyte membrane ratio of 10:1(TRM) was identified as a representative balance point that preserves optimal tumor-associated accumulation while biasing a fraction of off-target nanoparticles (NPs) toward the spleen. Zinc imidazolate framework-8 (ZIF-8) NPs were employed as a model therapeutic core. The resulting hybrid cell membrane–camouflaged nanoplatform (TRM@ZIF-8) exhibited immune-associated effects, where the tumor-associated fraction was linked to inflammasome-related signaling and inflammatory cell death–associated responses, while the spleen-biased fraction was associated with activation of splenic antigen-presenting cells. This behavior is consistent with the collective influence of membrane-associated protein features, including functions related to cluster of differentiation 47(CD47) and Band 3, together with the intrinsic immunostimulatory properties of the ZIF-8 core. Importantly, splenectomy markedly attenuated the therapeutic effect, providing organ-level evidence that spleen involvement is functionally associated with the observed antitumor immune response and tumor growth suppression. This work provides a proof-of-concept framework for guiding off-targeted nanomedicine repurposing in spleen for cancer immunotherapy, rather than regarding it solely as a delivery limitation.

The efficacy of immunotherapy in treating triple-negative breast cancer remains limited, primarily due to the low immunogenicity of tumor cells. Herein, bioinformatics analyses indicate a significant interplay between cuproptosis and ferroptosis in breast cancer. Given that both processes are closely associated with mitochondrial damage and cell death, we aimed to investigate the crosstalk between cuproptosis and ferroptosis as a potential therapeutic strategy for breast cancer. To this end, we developed a copper-deposited metal-phenolic network (TAF-CuET), which serves as an efficient carrier for both copper and iron ions. Mechanistically, TAF-CuET catalyzes Fenton reactions to generate reactive oxygen species (ROS) and depletes endogenous glutathione (GSH), thereby enhancing both cuproptosis and ferroptosis. This synergistic effect amplifies mitochondrial damage, which disrupts ATP production and subsequently suppresses the expression of copper exporters ATP7A and ATP7B, leading to intracellular copper overload and further promoting cuproptosis. Simultaneously, copper imbalance promotes glutathione peroxidase 4 (GPX4) degradation and suppresses cystine/glutamate transporter SLC7A11 expression, thereby augmenting ferroptosis. The TAF-CuET-enabled crosstalk between cuproptosis and ferroptosis creates a mutually reinforcing therapeutic effect, triggering robust antitumor T cell immunity through immunogenic cell death and reversing the tumor immunosuppressive microenvironment. This study offers novel insights into the synergistic application of cuproptosis and ferroptosis in nanomedicine-based breast cancer immunotherapy.

Tumor-associated macrophages (TAMs) play a crucial role in tumor progression and therapy resistance. The mechanochemical synergy has emerged as a key mechanism regulating the polarization of TAMs toward the tumor-promoting M2 phenotype. However, whether this synergy can be exploited to reprogram TAMs to a tumor-suppressive M1 phenotype remains an unexplored therapeutic strategy. Here, we report a mechanochemically synergistic nanoplatform, RMSN@EXO, designed to reprogram TAMs efficiently and enhance the anti-tumor immune microenvironment. This nanoplatform is composed of mesoporous silica nanoparticles (MSNs) with tailored elasticity and is loaded with the immunomodulator resiquimod (R848). Both MSNs and R848 were identified through screening based on the M1-specific metabolic marker, lactate. And RMSN is subsequently encapsulated within exosomes derived from M1 macrophage. Surprisingly, this nanoplatform efficiently reprograms TAMs into a pro-inflammatory M1-phenotype more effectively than either R848 or MSNs alone. Benefiting from the superior penetration of mechanically tailored MSNs in the TME and the exosome-mediated tumor targeting, RMSN@EXO exhibits enhanced accumulation in hypoxic regions of solid tumors. In vivo experiments further show that repolarized TAMs in hypoxic areas have a significant inhibitory effect on tumor growth. In conclusion, this study establishes a "nano-mechanochemical synergy" strategy to efficiently reprogram TAMs to enhance robust anti-tumor immunity. It provides a fundamental framework for designing nanomedicines based on mechanical properties to improve cancer immunotherapy.

Targeted drug delivery remains pivotal for enhancing therapeutic efficacy in cancer treatment. While nanomedicines harness the enhanced permeability and retention (EPR) effect for passive tumor accumulation, their efficacy is often hindered by physiological barriers that limit optimal delivery. Active delivery strategies by immune cell (neutrophils etc.) hitchhiking offer a promising approach to surmount these obstacles; however, attenuated tumor-associated inflammation restricts their tumor-directed migration. Here, we present a biomimetic nanoplatform based on polydopamine nanoparticles coated with bacterial outer membrane vesicles (OMV@PDA). Upon single injection, these nanoparticles not only passively accumulate in tumors via the EPR effect and generate localized hyperthermia under near-infrared irradiation to ablate tumor cells and trigger inflammation, but also leverage their pathogen-mimicking coating to promote efficient uptake by circulating neutrophils (83.2% phagocytosis rate). The photothermally amplified inflammation broadcasts "find-me" signals to recruit nanoparticle-laden neutrophils to tumor sites. Consequently, a single injection orchestrates EPR effect and neutrophil hitchhiking for spatiotemporal accumulation, achieving high-intensity and sustained tumor accumulation. Notably, this strategy yielded an remarkable tumor inhibition rate of 95%, underscoring superior therapeutic efficacy. Our findings establish a self-reinforcing paradigm for advancing targeted drug delivery in oncology.

Fever, a conserved physiological response, orchestrates robust immunomodulation with significant therapeutic potential. Engineered fever therapy (EFT) leverages this mechanism to activate systemic immune response, emerging as a transformative adjuvant strategy for disease management, particularly in oncology. However, achieving precise and safe EFT remains challenging, largely due to unpredictable temperature fluctuations and inconsistent immune responses. To address these limitations, thermal immunotherapy integrates precision thermal modulation with nanotechnology, enabling targeted induction of fever-range temperatures (38.5-40 °C) within tumor sites. Building upon physiological fever mechanisms and precision bioengineering, controllable EFT establishes a new paradigm with three core principles: i) precise fever induction with input and process control, ii) quantitative reprogramming of immune pathways, and iii) enhanced safety through optimized fever dynamics. This review comprehensively summarizes the molecular and physiological underpinnings of fever, evaluates its therapeutic potential in disease management, and presents recent progress in thermal immunotherapy and the EFT. Furthermore, future perspectives for controllable EFT are discussed and critically assessed, along with its opportunities and main challenges for clinical translation in precision oncology.

Chemotherapy, the primary treatment for triple-negative breast cancer (TNBC), is frequently compromised by reduced sensitivity associated with amino acid metabolic reprogramming. Here, it is found that chemotherapy significantly upregulates the expression of arginine transporter SLC7A2, supporting tumor cell survival in TNBC mice and patients. The Slc7a2 gene is thus purposefully knocked down via the CRISPR/Cas9 system to enhance chemotherapy efficacy by regulating arginine metabolism. A self-guiding living bacteria system is engineered for precise CRISPR/Cas9 transport, capable of tumor intracellular colonization and achieving endo-/lysosomal escape. The engineered bacteria (PDC@V) selectively targeted hypoxic tumor regions in vivo, and exhibited an intracellular invasion efficiency 23.7-fold higher than that of nonintracellular bacteria. Their inherent ability to escape the endo-/lysosome ensured the CRISPR/Cas9 plasmids are efficiently released in response to cytoplasmic esterase activity, leading to a five fold increase in gene editing efficiency. This self-guiding living system restricted tumor arginine uptake, alleviating resistance to the chemotherapeutic agent DOX and achieving a tumor inhibition rate 3.2 times greater than the DOX alone group. Furthermore, this strategy activated both the innate and adaptive immune systems. Together, the study presents a novel approach for delivering gene-editing tools and highlights the potential of targeting arginine metabolic reprogramming to sensitize tumor chemotherapy.

This study presents a novel injectable sodium alginate hydrogel designed to enhanc stem cell therapy for endometrial regeneration. Using calcium gluconate as a crosslinking agent, we achieved improved homogeneity and injectability compared to traditional calcium chloride crosslinking. RGD modification further enhanced cell adhesion, proliferation, and differentiation in vitro, creating a bioactive scaffold for umbilical cord mesenchymal stem cells (UCMSCs) delivery. In a mouse model of endometrial injury, intrauterine transplantation of RGD-modified hydrogel encapsulating UCMSCs significantly improved endometrial thickness, reduced fibrosis, enhanced angiogenesis, and increased pregnancy rates compared to both untreated controls and UCMSCs alone. These results suggest that this injectable hydrogel system combined with stem cells holds significant promise for future applications in treating endometrial damage and improving reproductive outcomes in women.

The work investigated the volatile fatty acids (VFAs) production during anaerobic co-fermentation system of food waste (FW) and sewage sludge (SS), facilitated by graphene oxide (GO) as redox mediator (RM). In the presence of GO, there was a 35.4 % increase in VFAs production, with 26.5 % of acetate compared to the Control. Protease activity increased by 20.7 % to promote protein hydrolysis, while acidification was supported by 10.1 % increase in the activities of acetate kinase, phosphate transacetylase and oxaloacetic acid carboxylase, coupled with 3.5- fold enhancement in intracellular electron transfer activity, augment of amino acid redox reactions and a favorable intracellular redox state (IROS). The microbiota conducive to VFAs production (e.g., Bacteroides and Proteobacteria) was also enriched. Metagenomic analysis indicated that the relative abundance of functional genes related to substrate hydrolysis (e.g., BglX and CLPP) and transport (e.g., gtsA, gltK, and gltI) and VFAs production (e.g., kor, pta, ackA and atoD) was upgraded by 3.5-29.2 %, along with a downregulation (4.7-20.8 %) of genes (e.g., GLO1, gloB and pflD) associated with by-products (e.g., lactate and ethanol). Proteomics of proteiniphilum acetatigenes demonstrated acetate accumulation was boosted through GO-mediated protein hydrolysis and inhibition of by-products that consume pyruvate. This study provided a promising strategy for VFAs production by GO as RM, which reinforced the redox reaction of amino acid degradation, modulated metabolic pathways and maintained lower reduced nicotinamide adenine dinucleotide (NADH) favorable for VFAs production during anaerobic co-fermentation of FW and SS.

Therapeutic strategies targeting iron metabolism to disturb the physiological functions of tumor cells have emerged as promising avenues in cancer treatment. Deferoxamine (DFOM) is an effective FDA-approved iron chelator that actively eliminates iron from cells, inducing iron-related dysfunction. However, its use is considerably limited by off-target toxicities and the innate metabolic compensatory capacity of tumor cells. To address these challenges, herein, we developed a facile manganese-doped calcium phosphate mineralized nanoparticle loaded with DFOM (termed BSA@MnCaP@DFOM). These nanoparticles polarized tumor-associated macrophages to M1 phenotype via activating Toll-like receptor 4 (TLR4) pathway, thereby cutting off their iron supply to tumor cells. This promoted the iron depletion effect of DFOM, reduced ferritin heavy chain 1 (FTH1) expression, disrupted iron metabolism, and efficiently induced mitochondrial dysfunction in the highly iron-dependent 4 T1 breast cancer cells. Consequently, the treatment triggered immunogenic cell death in tumor cells, eliciting a robust antitumor T cells immune response. Combined with mitigation of the immunosuppressive microenvironment, tumor suppression was achieved (72.5 % inhibition rate). In summary, our nanoparticles offer a promising strategy for iron metabolism disruption-mediated breast cancer immunotherapy.

Pyroptosis is a critical pathological mechanism implicated in myocardial damage following myocardial infarction (MI), and the crosstalk between macrophages and pyroptotic cardiomyocytes presents a formidable challenge for anti-pyroptosis therapies of MI. However, as single-target pyroptosis inhibitors frequently fail to address this crosstalk, the efficacy of anti-pyroptosis treatment post-MI remains inadequate. Therefore, the exploration of more potent anti-pyroptosis approaches is imperative for improving outcomes in MI treatment, particularly in addressing the crosstalk between macrophages and pyroptotic cardiomyocytes. Here, in response to this crosstalk, we engineered an anti-pyroptosis biomimetic nanoplatform (NM@PDA@PU), employing polydopamine (PDA) nanoparticles enveloped with neutrophil membrane (NM) for targeted delivery of puerarin (PU). Notably, network pharmacology is deployed to discern the most efficacious anti-pyroptosis drug (puerarin) among the 7 primary active monomers of TCM formulations widely applied in clinical practice and reveal the effect of puerarin on the crosstalk. Additionally, targeted delivery of puerarin could disrupt the malignant crosstalk between macrophages and pyroptotic cardiomyocytes, and enhance the effect of anti-pyroptosis by not only directly inhibiting cardiomyocytes pyroptosis through NLRP3-CASP1-IL-1β/IL-18 signal pathway, but reshaping the inflammatory microenvironment by reprogramming macrophages to anti-inflammatory M2 subtype. Overall, NM@PDA@PU could enhance anti-pyroptosis effect by disrupting the crosstalk between M1 macrophages and pyroptotic cardiomyocytes to protect cardiomyocytes, ameliorate cardiac function and improve ventricular remodeling, which providing new insights for the efficient treatment of MI.

The dense physical barrier of tumors and abnormal metabolism hinders the infiltration of T cells into the tumor microenvironment (TME) and weakens the efficacy of T-cell-mediated immunotherapy, such as immune checkpoint blockade (ICB) therapy. Herein, we specifically designed a pH-responsive peroxynitrite (ONOO-) nanogenerator (aPP-ArgNPFe, 127 +/- 5 nm) based on an ArgNP and iron-phenolic-antibody (aPDL1) network to remodel the physical barriers and abnormal metabolism within the TME to enhance ICB immunotherapy. The aPP-ArgNPFe with PDL1 blocking ability to restore the effector function of T cells in TME. Upon cellular entry, the aPP-ArgNPFe structure disassembles completely (12 +/- 5 nm) and leverages an iron-phenolic network and Arg to achieve sustained ONOO-generation via center dot OH/NO cascade reactions. Notably, aPP-ArgNPFe degrades collagen in the tumor extracellular matrix, thereby increasing T cell infiltration in the TME. Besides, aPP-ArgNPFe effectively inhibits lactic acid production at the tumor site, benefiting from restoring abnormal metabolism. Significantly, aPP-ArgNPFe-mediated immunotherapy effectively reverses the immunosuppressive TME, evoking potent antitumor immune responses, including the restoration of CD8+IFN-gamma+ T cell and M1-like macrophages infiltration, as well as the reduction of T regulatory cells and myeloid-derived suppressor cells. This study provides a novel strategy for enhancing the sensitivity of immunotherapy.

Chronic inflammation significantly impedes diabetic wound healing by disrupting keratinocyte repair mechanisms and macrophage polarization. In this study, we identify ALDH3A1 as a therapeutic protein and develop a metal-polyphenol network-synthesized nanosystem "AL@FG" to enhance wound healing in diabetic mice. ALDH3A1 promotes keratinocyte proliferation and migration while reducing inflammation through its interaction with HSPA1A and activation of the estrogen signaling pathway. The AL@FG nanosystem, engineered to overcome lysosomal degradation, enhances intracellular delivery efficiency of ALDH3A1 by 9.4-fold. Local application of AL@FG alleviates hyperinflammation, promotes macrophage M1-to-M2 polarization, and enhances angiogenesis, resulting in a nearly 50 % faster wound healing rate compared to untreated controls. This surpasses the efficacy of ALDH3A1 protein therapy alone and standard treatment with recombinant human basic fibroblast growth factor (rb-bFGF). The work proposes a simple strategy to effectively improve keratinocyte inflammation, restore macrophage polarization function, and accelerate the wound healing process in diabetes. It also provides a strategy for designing protein delivery systems for anti-inflammatory treatment.

Cuproptosis and ferroptosis exhibit superior synergistic advantages in antitumor therapy. While glutathione (GSH) has been identified as a key molecule in enhancing the synergistic effects of these two processes, inherent cellular redox homeostasis mechanisms limit its therapeutic efficacy. This inspired us to explore other new regulators to potentiate the synergistic effect. Through bioinformatics analysis and preliminary experimental validation, we discovered that lactate metabolism is closely associated with both ferroptosis and cuproptosis. Therefore, this work strategically targets lactate metabolism to synergistically activate cuproptosis and ferroptosis, and elucidate its immunotherapeutic mechanisms. For this purpose, we constructed a Syr-loaded nanodelivery system (Syr@mPDA@CP) using biocompatible mesoporous polydopamine (mPDA) as the carrier. Upon targeting tumor tissues, the released Syr significantly inhibits lactate efflux, leading to intracellular lactate accumulation. This lactate buildup further induces intracellular acidification, exerting dual effects: (1) promoting ferritin (FTH1) dissociation to release endogenous iron stores, thereby elevating intracellular iron levels; and (2) suppressing glycolysis and reducing ATP levels, which inactivates the copper export protein ATP7B. Combined with copper peroxide (CP)-derived Cu2+, these effects synergistically amplify intracellular copper accumulation. The elevated intracellular Cu and Fe concentrations subsequently induce dual cell death pathways of cuproptosis and ferroptosis, effectively enhancing cancer immunotherapy. This study pioneers a lactate metabolism-regulating strategy to synergistically amplify both ferroptosis and cuproptosis, offering novel perspectives for antitumor therapy.

Mechanosensitive signaling pathways in immune cells drive exhaustion and ultimately facilitate tumor immune escape. In situ mechanical modulation strategies, leveraging the tumor's mechanical features, may provide a distinctive perspective for immunotherapy. We repurpose conventional silica nanocarriers from mere "drug delivery vehicles" into "Piezo1 mechanotransduction modulators" by precisely tuning their mechanical properties to directly intervene in tumor-associated macrophages (TAMs) mechanosignaling. Our study revealed that Piezo1 acts as a mechano-immunological switch in tumors: its downregulation in large tumors promotes M2-like TAMs polarization, whereas its upregulation in small tumors drives M1-mediated antitumor immunity. This directly couples mechanical cues to immune reprogramming during cancer progression. To target this pathway, we engineered mesoporous silica nanoparticles (mSNs) with tunable stiffness (253-1084.5 MPa), which were loaded with the Piezo1 agonist Yoda1 and TAMs-targeting peptide CRV (YmSNs@CRV) to precisely modulate TAMs mechanosignaling. Results demonstrated that softer 20% mSN achieved dual regulation of both macrophage phenotypic reprogramming and exosome-mediated communication via Piezo1 activation. Specifically, softer 20% mSNs enhanced pro-inflammatory markers (CD80), increased cytokine secretion, and promoted exosome production 5-fold more effectively than stiffer 80% mSNs. Proteomic analysis revealed that exosomes from 20% mSN-treated macrophages activated the TCR signaling, amplifying immune responses. In vivo, 20% YmSNs@CRV improved tumor penetration, repolarized TAMs toward an antitumor phenotype, and boosted cytotoxic T cell infiltration, significantly inhibiting tumor growth. This study integrates the mechanical characteristics of tumor tissues and proposes an "in situ mechanical dual-regulation" strategy, which combines mechano-regulated TAMs reprogramming with exosome-triggered immune responses, introducing a distinctive mechano-immunotherapeutic paradigm.

Cell metabolite adenosine can induce extensive and persistent immunosuppression by binding to adenosine receptors on immune cells. Seriously, the hypoxia‐driven adenosinergic axis aggravates adenosine accumulation via dephosphorizing immune‐activating adenosine triphosphate (ATP) released during immunogenic cell death (ICD). Different from direct adenosine clearance or adenosine receptor blockade or directly using ecto‐enzyme (CD39/CD73) antagonist, it is hoped to use an innovative small science engineering to regulate the upstream hypoxia/HIF‐1α signal of the hypoxia‐adenosinergic axis, thereby reducing the immunosuppressive extracellular adenosine and enhancing ICD‐triggered antitumor immunity. PM@Mn is constructed by gradually integrating metformin and MnO 2 on polydopamine (PDA) nanoparticles. PM@Mn can effectively suppress hypoxia‐adenosinergic axis via combining catalytic oxygen production with reduced endogenous oxygen consumption. Such motif of hypoxia relief suppresses the metabolism of ATP to adenosine via down‐regulating the expression of HIF‐1α, CD39, and CD73. Meanwhile, PDA in PM@Mn can induce local tumor ablation and trigger the “vaccine effect” of ICD under near‐infrared radiation. In a mouse breast cancer model with low immunogenicity, our strategy can effectively reduce adenosine accumulation, PM@Mn group exhibits 4.51‐fold cytotoxic T lymphocyte infiltration and tumor inhibition rate of 75.4%. This study provides a new strategy to advance ICD‐triggered antitumor immunity through supressing hypoxia‐adenosinergic axis.