Antigen Cross-presentation Research Articles

PH-gated nanoparticles selectively regulate lysosomal function of tumour-associated macrophages for cancer immunotherapy

Tumour-associated macrophages (TAMs), as one of the most abundant tumour-infiltrating immune cells, play a pivotal role in tumour antigen clearance and immune suppression. M2-like TAMs present a heightened lysosomal acidity and protease activity, limiting an effective antigen cross-presentation. How to selectively reprogram M2-like TAMs to reinvigorate anti-tumour immune responses is challenging. Here, we report a pH-gated nanoadjuvant (PGN) that selectively targets the lysosomes of M2-like TAMs in tumours rather than the corresponding organelles from macrophages in healthy tissues. Enabled by the PGN nanotechnology, M2-like TAMs are specifically switched to a M1-like phenotype with attenuated lysosomal acidity and cathepsin activity for improved antigen cross-presentation, thus eliciting adaptive immune response and sustained tumour regression in tumour-bearing female mice. Our findings provide insights into how to specifically regulate lysosomal function of TAMs for efficient cancer immunotherapy.

Surface immunogenic protein from Streptococcus agalactiae and Fissurella latimarginata hemocyanin are TLR4 ligands and activate MyD88- and TRIF dependent signaling pathways.

The development of vaccine adjuvants is of interest for the management of chronic diseases, cancer, and future pandemics. Therefore, the role of Toll-like receptors (TLRs) in the effects of vaccine adjuvants has been investigated. TLR4 ligand-based adjuvants are the most frequently used adjuvants for human vaccines. Among TLR family members, TLR4 has unique dual signaling capabilities due to the recruitment of two adapter proteins, myeloid differentiation marker 88 (MyD88) and interferon-β adapter inducer containing the toll-interleukin-1 receptor (TIR) domain (TRIF). MyD88-mediated signaling triggers a proinflammatory innate immune response, while TRIF-mediated signaling leads to an adaptive immune response. Most studies have used lipopolysaccharide-based ligands as TLR4 ligand-based adjuvants; however, although protein-based ligands have been proven advantageous as adjuvants, their mechanisms of action, including their ability to undergo structural modifications to achieve optimal immunogenicity, have been explored less thoroughly. In this work, we characterized the effects of two protein-based adjuvants (PBAs) on TLR4 signaling via the recruitment of MyD88 and TRIF. As models of TLR4-PBAs, we used hemocyanin from Fissurella latimarginata (FLH) and a recombinant surface immunogenic protein (rSIP) from Streptococcus agalactiae. We determined that rSIP and FLH are partial TLR4 agonists, and depending on the protein agonist used, TLR4 has a unique bias toward the TRIF or MyD88 pathway. Furthermore, when characterizing gene products with MyD88 and TRIF pathway-dependent expression, differences in TLR4-associated signaling were observed. rSIP and FLH require MyD88 and TRIF to activate nuclear factor kappa beta (NF-κB) and interferon regulatory factor (IRF). However, rSIP and FLH have a specific pattern of interleukin 6 (IL-6) and interferon gamma-induced protein 10 (IP-10) secretion associated with MyD88 and TRIF recruitment. Functionally, rSIP and FLH promote antigen cross-presentation in a manner dependent on TLR4, MyD88 and TRIF signaling. However, FLH activates a specific TRIF-dependent signaling pathway associated with cytokine expression and a pathway dependent on MyD88 and TRIF recruitment for antigen cross-presentation. Finally, this work supports the use of these TLR4-PBAs as clinically useful vaccine adjuvants that selectively activate TRIF- and MyD88-dependent signaling to drive safe innate immune responses and vigorous Th1 adaptive immune responses.

A Universal Cyclodextrin-Based Nanovaccine Platform Delivers Epitope Peptides for Enhanced Antitumor Immunity.

Currently, there is still an intense demand for a simple and scalable delivery platform for peptide-based cancer vaccines. Herein, a cyclodextrin-based polymer nanovaccine platform (CDNP) is designed for the codelivery of peptides with two immune adjuvants [the Toll-like receptor (TLR)7/8 agonist R848 and the TLR9 agonist CpG] that is broadly applicable to epitope peptides with diverse sequences. Specifically, the cyclodextrin-based polymers are covalently linked to epitope peptides via a bioreactive bond-containing cross-linker (PNC-DTDE-PNC) and then physically load with R848 and CpG to obtain CDNP. The CDNP efficiently accumulats in the lymph nodes (LNs), greatly facilitating antigen capture and cross-presentation by antigen-presenting cells. The immunogenicity of the epitope peptides is significantly enhanced by the codelivery and synergy of the adjuvants, and the CDNP shows the ability to inhibit tumor progression in diverse tumor-bearing mouse models. It is concluded that CDNP holds promise as an optimized peptide-based cancer vaccine platform.

Dendritic cell-based vaccine prepared with recombinant Lactococcus lactis enhances antigen cross-presentation and antitumor efficacy through ROS production.

Lactococcus lactis (L.L) is safe and can be used as vehicle. In this study, the immunoregulatory effect of L.L on dendritic cell (DC) activation and mechanism were investigated. The immune responses and antigen cross-presentation mechanism of DC-based vaccine prepared with OVA recombinant L.L were explored. Confocal microscopy and flow cytometry were used to analyze the mechanism of L.L promoting DC maturation, phagosome membrane rupture and antigen presentation. The antitumor effect of DC vaccine prepared with L.L-OVA was assessed in the B16-OVA tumor mouse model. L.L significantly promoted DC maturation, which was partially dependent on TLR2 and downstream MAPK and NF-κB signaling pathways. L.L was internalized into DCs by endocytosis and did not co-localized with lysosome. OVA recombinant L.L enhanced antigen cross-presentation of DCs through the phagosome-to-cytosol pathway in a reactive oxygen species (ROS)- and proteasome-dependent manner. In mouse experiments, L.L increased the migration of DCs to draining lymph node and DC vaccine prepared with OVA recombinant L.L induced strong antigen-specific Th1 and cytotoxic T lymphocyte responses, which significantly inhibited B16-OVA tumor growth. This study demonstrated that recombinant L.L as an antigen delivery system prepared DC vaccine can enhance the antigen cross-presentation and antitumor efficacy.

Sec22b and Stx4 Depletion Has No Major Effect on Cross-Presentation of PLGA Microsphere-Encapsulated Antigen and a Synthetic Long Peptide InVitro.

The induction of CTL responses by vaccines is important to combat infectious diseases and cancer. Biodegradable poly(lactic-co-glycolic acid) (PLGA) microspheres and synthetic long peptides are efficiently internalized by professional APCs and prime CTL responses after cross-presentation of Ags on MHC class I molecules. Specifically, they mainly use the cytosolic pathway of cross-presentation that requires endosomal escape, proteasomal processing, and subsequent MHC class I loading of Ags in the endoplasmic reticulum (ER) and/or the endosome. The vesicle SNARE protein Sec22b has been described as important for this pathway by mediating vesical trafficking for the delivery of ER-derived proteins to the endosome. As this function has also been challenged, we investigated the role of Sec22b in cross-presentation of the PLGA microsphere-encapsulated model Ag OVA and a related synthetic long peptide. Using CRISPR/Cas9-mediated genome editing, we generated Sec22b knockouts in two murine C57BL/6-derived APC lines and found no evidence for an essential role of Sec22b. Although pending experimental evidence, the target SNARE protein syntaxin 4 (Stx4) has been suggested to promote cross-presentation by interacting with Sec22b for the fusion of ER-derived vesicles with the endosome. In the current study, we show that, similar to Sec22b, Stx4 knockout in murine APCs had very limited effects on cross-presentation under the conditions tested. This study contributes to characterizing cross-presentation of two promising Ag delivery systems and adds to the discussion about the role of Sec22b/Stx4 in related pathways. Our data point toward SNARE protein redundancy in the cytosolic pathway of cross-presentation.

Laponite Lights Calcium Flickers by Reprogramming Lysosomes to Steer DC Migration for An Effective Antiviral CD8+ T-Cell Response.

Immunotherapy using dendritic cell (DC)-based vaccination is an established approach for treating cancer and infectious diseases; however, its efficacy is limited. Therefore, targeting the restricted migratory capacity of the DCs may enhance their therapeutic efficacy. In this study, the effect of laponite (Lap) on DCs, which can be internalized into lysosomes and induce cytoskeletal reorganization via the lysosomal reprogramming-calcium flicker axis, is evaluated, and it is found that Lap dramatically improves the in vivo homing ability of these DCs to lymphoid tissues. In addition, Lap improves antigen cross-presentation by DCs and increases DC-T-cell synapse formation, resulting in enhanced antigen-specific CD8+ T-cell activation. Furthermore, a Lap-modified cocktail (Lap@cytokine cocktail [C-C]) is constructed based on the gold standard, C-C, as an adjuvant for DC vaccines. Lap@C-C-adjuvanted DCs initiated a robust cytotoxic T-cell immune response against hepatitis B infection, resulting in > 99.6% clearance of viral DNA and successful hepatitis B surface antigen seroconversion. These findings highlight the potential value of Lap as a DC vaccine adjuvant that can regulate DC homing, and provide a basis for the development of effective DC vaccines.

Engineered Extracellular Vesicles to Enhance Antigen Presentation for Boosting Light-Driven Tumor Immunotherapy.

Extracellular vesicles (EVs) have emerged as potential tools for tumor-target therapy accompanied with activating anticancer immune responses by serving as an integrated platform, but usually suffered from the limited cross presentation of tumor-associated antigen by dendritic cells (DCs). Here, a straightforward engineering strategy to construct heat shock proteins 70 (HSP70) highly expressed EVs incapsulated with Te nanoparticles (Te@EVsHSP70 ) for tumor photothermal therapy triggering improved immunotherapy is proposed. Tumor cells are firstly used as bioreactors for intracellular synthesis of Te nanoparticles, and NIR irradiation is subsequently introduced to upregulate the expression of HSP70 to give engineered Te@EVsHSP70 through exocytosis. Te@EVsHSP70 exhibits excellent photothermal performance and enhanced tumor antigen capture capability, which induces significant immunogenic death of tumor cells and improves DCs maturation both in vitro and in vivo. Thus, the engineered EVs demonstrate superior antitumor efficacy through photothermal effect and following provoked antitumor immune responses. This work provides a facile method to fabricate multifunctional EVs-based drug delivery system for improving photothermal-triggered tumor immunotherapy.

LncRNA-edited biomimetic nanovaccines combined with anti-TIM-3 for augmented immune checkpoint blockade immunotherapy

T-cell immunoglobulin mucin (TIM)-3 blockade ameliorates T cell exhaustion and triggers dendritic cell (DC) inflammasome activation, showing great potential in immune checkpoint blockade (ICB) immunotherapy. However, pharmacokinetic profile and T cell/DC infiltration in tumor microenvironment is still undesired. Here, we develop a long noncoding RNA (lncRNA)-edited biomimetic nanovaccine combined with anti-TIM-3 to mediate dual-effect antigen cross-presentation and dampen T cell immunosuppression for reinforced ICB immunotherapy. LncRNA inducing major histocompatibility complex I and immunogenicity of tumor (LIMIT)-edited tumor cell membrane is used to encapsulate anti-TIM-3, formulating LCCT. Afterward, LCCT nanoparticles are embedded into an alginate-based hydrogel for suppressing post-surgical tumor relapse. LCCT retains TIM-3 blockade efficacy of anti-TIM-3 in both DCs and CD8+ T cells (beyond 75%). Moreover, the integrated anti-TIM-3 augments endocytosis of LCCT in DCs (1.5-fold), amplifying inflammasome activation and antigen cross-presentation. Furthermore, such DC activation synergistic with LCCT-induced CD8+ T-cell dampened immunosuppression and direct cross-presentation stimulates effector and memory-precursor CD8+ T cells against tumors. This lncRNA-edited biomimetic nanovaccine strategy brings a new sight to improve current ICB immunotherapy.

Group 2 innate lymphoid cells boost CD8+ T-cell activation in anti-tumor immune responses

ABSTRACT Group 2 innate lymphoid cells (ILC2s) are essential for orchestrating type 2 immune responses during allergic airway inflammation and infection. ILC2s have been reported to play a regulatory role in tumors; however, this conclusion is controversial. In this study, we showed that IL-33-activated ILC2s could boost CD8+ T-cell function through direct antigen cross-presentation. After activation by IL-33, ILC2s showed an enhanced potential to process antigens and prime CD8+ T cell activation. Activated ILC2s could phagocytose exogenous antigens in vivo and in vitro, promoting antigen-specific CD8+ T cell function to enhance antitumor immune responses. Administration of OVA-loaded ILC2s induces robust antitumor effects on the OVA-expressing tumor model. These findings suggested that the administration of tumor antigen-loaded ILC2s might serve as a potential strategy for cancer treatment.

Strengthened EPR effect of AIEgen-Poly(I:C) composite nanoparticles to facilitate antigen cross-presentation and improve melanoma prognosis by evoking immunity

Nanoparticles offer a promising platform for drug delivery due to their long circulation time, enhanced solubility, low toxicity and excellent targeting of lesions. Herein, we report an AIEgen-Poly (I:C) composite nanoparticle (P@AP) for dual-modality tumor photodynamic-immunotherapy. Its specific size and capacity for partial degradation under acidic conditions determine its enhanced EPR effect. By complexing with the immunoadjuvant Poly(I:C), the immune silencing mechanism induced by apoptosis can be overcome and ICD is evoked efficiently at the cellular level. In the process of antigen presentation, P@AP, as an exogenous antigen, on the one hand, strengthens the expression of antigen presentation signal molecule MHC II and activates CD4+ T cells, on the other hand, enhancing pAPC infiltration by the increase of endogenous antigens represented by damage-associated molecular patterns while expressing MHC I via antigenic cross-presentation remarkably induces activation of CD8+ T cells, directly enhancing the killing of target cells. Massive immune arousal results in sustained tissue-resident memory T-cell residency in melanoma and reduces expression of CD4+ subsets of Treg cells, thereby prolonging the survival of subcutaneous melanoma mice and ridding of the poor prognosis of malignant melanoma stemming from its auto-immunosuppressive properties.

Virus-Like Nanotherapeutic for Spatiotemporally Enhancing Antigen Presentation and Cross-Presentation toward Potential Personalized Immunotherapy.

One of the major causes of immunotherapy resistance is the loss of major histocompatibility complex class I (MHC-I) molecules in tumor cells or the downregulation of the class I antigen presentation pathway. In this study, a novel virus-like nanotherapeutic (siRNA@HCM) is developed via encapsulating nanosized siRNA nanoparticles in a hybrid membrane comprising a personalized tumor cell membrane and a universal 293T membrane expressing the mutant vesicular stomatitis virus glycoprotein (mVSV-G). Upon intravenous administration, siRNA@HCM accumulates at the tumor site and provides two potentdrivingforces for antitumor immunity. First, mVSV-G induces the fusion of siRNA@HCM with tumor cell membranes and directly injects siRNAs into the cytoplasm, significantly improving tumor intrinsic MHC-I antigen presentation. Moreover, mVSV-G can promote the maturation of dendritic cells, thereby achieving highly efficient antigen cross-presentation. The results demonstrate that spatiotemporally enhancing tumor intrinsic antigen presentation and cross-presentation via siRNA@HCM can achieve satisfactory antitumor efficacy and excellent biocompatibility. Immune infiltration analysis shows that siRNA@HCM treatment turns cold tumors into hot tumors. In addition, it significantly promotes the therapeutic effect of programmed death-1 inhibitor. In summary, virus-like nanotherapeutics present a promising approach to enhance the antitumor immune response, with distinct advantages for potential personalized therapy and clinical applications.

Multifunctional Calcium-Manganese Nanomodulator Provides Antitumor Treatment and Improved Immunotherapy via Reprogramming of the Tumor Microenvironment.

Ions play a vital role in regulating various biological processes, including metabolic and immune homeostasis, which involves tumorigenesis and therapy. Thus, the perturbation of ion homeostasis can induce tumor cell death and evoke immune responses, providing specific antitumor effects. However, antitumor strategies that exploit the effects of multiion perturbation are rare. We herein prepared a pH-responsive nanomodulator by coloading curcumin (CU, a Ca2+ enhancer) with CaCO3 and MnO2 into nanoparticles coated with a cancer cell membrane. This nanoplatform was aimed at reprogramming the tumor microenvironment (TME) and providing an antitumor treatment through ion fluctuation. The obtained nanoplatform, called CM NPs, could neutralize protons by decomposing CaCO3 and attenuating cellular acidity, they could generate Ca2+ and release CU, elevating Ca2+ levels and promoting ROS generation in the mitochondria and endoplasmic reticulum, thus, inducing immunogenic cell death. Mn2+ could decompose the endogenous H2O2 into O2 to relieve hypoxia and enhance the sensitivity of cGAS, activating the cGAS-STING signaling pathway. In addition, this strategy allowed the reprogramming of the immune TME, inducing macrophage polarization and dendritic cell maturation via antigen cross-presentation, thereby increasing the immune system's ability to combat the tumor effectively. Moreover, the as-prepared nanoparticles enhanced the antitumor responses of the αPD1 treatment. This study proposes an effective strategy to combat tumors via the reprogramming of the tumor TME and the alteration of essential ions concentrations. Thus, it shows great potential for future clinical applications as a complementary approach along with other multimodal treatment strategies.

Universal Fe/Mn Nanoadjuvant with T1/T2 MRI Self-Navigation and Gas Generation for Ideal Vaccines with Precise Tracking.

Because of the distinguished properties between nanovaccine and traditional vaccine, the precise guidelines for nanovaccines with an optimal vaccination strategy to induce ideal immunities are greatly desired for combating major diseases, including cancer and infections. Herein, we designed and synthesized a self-navigating nanoadjuvant composed of Fe-doped manganese carbonate and its nanovaccine via a facile method. First, the degradation of the nanoadjuvant under acidic milieu of immune cells in lymph nodes would generate T1 and T2 MR imaging (MRI) signals to reflect the transformation dynamics of the nanovaccine and inform us when the next vaccination needed. Under this guideline, nanovaccines with a precise vaccination strategy triggered robust antigen-specific immune responses and immunological memory to effectively prevent ovalbumin (OVA)-expressing melanoma relapse by activating dendritic cells via a stimulator of interferon genes (STING) signaling pathway and inducing antigen cross-presentation by shaping lysosome integrity with CO2 generation and upregulating transporter associated antigen processing 1 (TAP-1) transporter. This study provides a universal nanoadjuvant with imaging self-guidance, immunopotentiating, and cross-priming activities for developing precise vaccines with an optimal immunization strategy to combat major diseases.

Saponin-based adjuvants enhance antigen cross-presentation in human CD11c+ CD1c+ CD5− CD163+ conventional type 2 dendritic cells

BackgroundAdjuvants are key for effective vaccination against cancer and chronic infectious diseases. Saponin-based adjuvants (SBAs) are unique among adjuvants in their ability to induce robust cell-mediated immune responses in addition...

An antigen self-assembled and dendritic cell-targeted nanovaccine for enhanced immunity against cancer.

The rise of nanotechnology has opened new horizons for cancer immunotherapy. However, most nanovaccines fabricated with nanomaterials suffer from carrier-related concerns, including low drug loading capacity, unpredictable metabolism, and potential systemic toxicity, which bring obstacles for their clinical translation. Herein, we developed an antigen self-assembled nanovaccine, which was resulted from a simple acryloyl modification of the antigen to induce self-assembly. Furthermore, a dendritic cell targeting head mannose monomer and a mevalonate pathway inhibitor zoledronic acid (Zol) were integrated or absorbed onto the nanoparticles (denoted as MEAO-Z) to intensify the immune response. The synthesized nanovaccine with a diameter of around 70nm showed successful lymph node transportation, high dendritic cell internalization, promoted costimulatory molecule expression, and preferable antigen cross-presentation. In virtue of the above superiorities, MEAO-Z induced remarkably higher titers of serum antibody, stronger cytotoxic T lymphocyte immune responses and IFN-γ secretion than free antigen and adjuvants. Invivo, MEAO-Z significantly suppressed EG7-OVA tumor growth and prolonged the survival time of tumor-bearing mice. These results indicated the translation promise of our self-assembled nanovaccine for immune potentiation and cancer immunotherapy.

A distinct stimulatory cDC1 subpopulation amplifies CD8+ Tcell responses in tumors for protective anti-cancer immunity.

Type 1 conventional dendritic cells (cDC1) can support Tcell responses within tumors but whether this determines protective versus ineffective anti-cancer immunity is poorly understood. Here, we use imaging-based deep learning to identify intratumoral cDC1-CD8+ Tcell clustering as a unique feature of protective anti-cancer immunity. These clusters form selectively in stromal tumor regions and constitute niches in which cDC1 activate TCF1+ stem-like CD8+ Tcells. We identify a distinct population of immunostimulatory CCR7neg cDC1 that produce CXCL9 to promote cluster formation and cross-present tumor antigens within these niches, which is required for intratumoral CD8+ Tcell differentiation and expansion and promotes cancer immune control. Similarly, in human cancers, CCR7neg cDC1 interact with CD8+ Tcells in clusters and are associated with patient survival. Our findings reveal an intratumoral phase of the anti-cancer Tcell response orchestrated by tumor-residing cDC1 that determines protective versus ineffective immunity and could be exploited for cancer therapy.

Adding liposomal doxorubicin enhances the abscopal effect induced by radiation/αPD1 therapy depending on tumor cell mitochondrial DNA and cGAS/STING

BackgroundLocalized radiotherapy (RT) can cause a T cell-mediated abscopal effect on non-irradiated tumor lesions, especially in combination with immune checkpoint blockade. However, this effect is still clinically rare and improvements...

Restoring tumor immunogenicity with dendritic cell reprogramming.

Decreased antigen presentation contributes to the ability of cancer cells to evade the immune system. We used the minimal gene regulatory network of type 1 conventional dendritic cells (cDC1) to reprogram cancer cells into professional antigen-presenting cells (tumor-APCs). Enforced expression of the transcription factors PU.1, IRF8, and BATF3 (PIB) was sufficient to induce the cDC1 phenotype in 36 cell lines derived from human and mouse hematological and solid tumors. Within 9 days of reprogramming, tumor-APCs acquired transcriptional and epigenetic programs associated with cDC1 cells. Reprogramming restored the expression of antigen presentation complexes and costimulatory molecules on the surfaces of tumor cells, allowing the presentation of endogenous tumor antigens on MHC-I and facilitating targeted killing by CD8+ T cells. Functionally, tumor-APCs engulfed and processed proteins and dead cells, secreted inflammatory cytokines, and cross-presented antigens to naïve CD8+ T cells. Human primary tumor cells could also be reprogrammed to increase their capability to present antigen and to activate patient-specific tumor-infiltrating lymphocytes. In addition to acquiring improved antigen presentation, tumor-APCs had impaired tumorigenicity in vitro and in vivo. Injection of in vitro generated melanoma-derived tumor-APCs into subcutaneous melanoma tumors delayed tumor growth and increased survival in mice. Antitumor immunity elicited by tumor-APCs was synergistic with immune checkpoint inhibitors. Our approach serves as a platform for the development of immunotherapies that endow cancer cells with the capability to process and present endogenous tumor antigens.

Targeting the Siglec-sialic acid axis promotes antitumor immune responses in preclinical models of glioblastoma.

Glioblastoma (GBM) is the most aggressive form of primary brain tumor, for which effective therapies are urgently needed. Cancer cells are capable of evading clearance by phagocytes such as microglia- and monocyte-derived cells through engaging tolerogenic programs. Here, we found that high expression of sialic acid-binding immunoglobulin-like lectin 9 (Siglec-9) correlates with reduced survival in patients with GBM. Using microglia- and monocyte-derived cell-specific knockouts of Siglec-E, the murine functional homolog of Siglec-9, together with single-cell RNA sequencing, we demonstrated that Siglec-E inhibits phagocytosis by these cells, thereby promoting immune evasion. Loss of Siglec-E on monocyte-derived cells further enhanced antigen cross-presentation and production of pro-inflammatory cytokines, which resulted in more efficient T cell priming. This bridging of innate and adaptive responses delayed tumor growth and resulted in prolonged survival in murine models of GBM. Furthermore, we showed the combinatorial activity of Siglec-E blockade and other immunotherapies demonstrating the potential for targeting Siglec-9 as a treatment for patients with GBM.

Zinc-Organometallic Framework Vaccine Controlled-Release Zn2+ Regulates Tumor Extracellular Matrix Degradation Potentiate Efficacy of Immunotherapy.

Tumor extracellular matrix (ECM) not only forms a physical barrier for T cells infiltration, but also regulates multiple immunosuppressive pathways, which is an important reason for immunotherapy failure. The cyclic guanosine monophosphate-adenosine monophosphate synthase-stimulator of interferon genes (cGAS-STING) pathway plays a key role in activating CD8+ T cells, maintaining CD8+ T cells stemness and enhancing the antitumor effect. Herein, a zinc-organometallic framework vaccine (ZPM@OVA-CpG) prepared by self-assembly, which achieves site-directed release of Zn2+ in dendritic cell (DC) lysosomes and tumor microenvironment under acidic conditions, is reported. The vaccine actively targets DC, significantly enhances cGAS-STING signal, promotes DC maturation and antigen cross-presentation, and induces strong activation of CD8+ T cells. Meanwhile, the vaccine reaches the tumor site, releasing Zn2+ , significantly up-regulates the activity of matrix metalloproteinase-2, degrades various collagen components of tumor ECM, effectively alleviates immune suppression, and significantly enhances the tumor infiltration and killing of CD8+ T cells. ZPM@OVA-CpG vaccine not only solves the problem of low antigen delivery efficiency and weak CD8+ T cells activation ability, but also achieves the degradation of tumor ECM via the vaccine for the first time, providing a promising therapeutic platform for the development of efficient novel tumor vaccines.