Immunogenic Tumor Cell Death Research Articles

Nanoparticles Encapsulated in Red Blood Cell Membranes for Near-Infrared Second Window Imaging-Guided Photothermal-Enhanced Immunotherapy on Tumors.

Photothermal therapy (PTT), which uses the high thermal conversion ability of photothermal agents to ablate tumor cells at high temperatures, has gained significant attention because it has the advantages of high selectivity and specificity, precise targeting of tumor sites, and low invasiveness and trauma. However, PTT guided by the NIR-I has limitations in tissue penetration depth, resulting in limited imaging monitoring and therapeutic effects on deep-seated tumor tissues. Moreover, nanoparticles are easily cleared by the immune system and difficult to passively target tumor sites during the process of treatment. To address these issues, we prepared nanoparticles using NIR-II dyes IR1048 and DSPE-PEG-OH and further encapsulated them in red blood cell membranes derived from mice. These biomimetic nanoparticles, called RDIR1048, showed reduced clearance by the immune system and had long circulation characteristics. They effectively accumulated at tumor sites, and strong fluorescence could still be observed at the tumor site 96 h after administration. Furthermore, through mouse thermal imaging experiments, we found that RDIR1048 exhibited good PTT ability. When used in combination with an immune checkpoint inhibitor, anti-PD-L1 antibodies, it enhanced the immunogenic cell death of tumor cells caused by PTT and improved the therapeutic effect of immunotherapy, which demonstrated good therapeutic efficacy in the treatment of tumor-bearing mice. This study provides a feasible basis for the future development of NIR-II nanoparticles with long circulation properties.

Tumor Growth Inhibition and Induced the Immunogenic Death of Tumor Cells in Prostate Tumor Bone Metastases by Photothermal Therapy Mediated with Au Nanoparticles Modified with PDA

AbstractUpon progression to the metastatic stage, prostate tumors commonly exhibit multi‐drug resistance. Combining multiple treatment protocols can be beneficial in overcoming this resistance, which is often attributed to tumor heterogeneity. Recently, nano‐photosensitizer‐mediated photothermal therapy is shown to inhibit tumor growth through multiple pathways, including thermal ablation and activation of the antitumor immune response. In this study, gold nanoparticles (Au) are selected as the core photosensitizer. Then, the photothermal conversion of Au is augmented through dopamine coating, and the chemotherapy drug doxorubicin (DOX) is grafted to the dopamine coating. The release of DOX from DOX‐loaded dopamine‐modified gold nanoparticles (Au@PDA@DOX) occurred in response to an acidic environment. The combination of chemotherapy and thermal ablation better inhibits the growth, migration, and invasion of tumor cells and induced tumor cell apoptosis and necrosis in vitro. More importantly, thermal ablation induces the immunogenic death of prostate tumor cells (RM‐1) cells. The transition of prostate tumors from a “cold” to a “hot” tumor with immunogenicity is observed. The combination effectively activates the antitumor immune response, inhibits tumor growth, and alleviated bone damage by tumors in vivo. It is indicated that Au@PDA@DOX nanoparticles will offer a novel treatment protocol for prostate tumor bone metastases.

Self-Illuminating Nanoagonist Simultaneously Induces Dual Cell Death Pathways via Death Receptor Clustering for Cancer Therapy.

Inducing death receptor 5 (DR5) clustering holds particular promise in tumor-specific therapeutics because it could trigger an apoptotic cascade in cancerous cells. Herein, we present a tumor microenvironment H2O2-responsive self-illuminating nanoagonist, which could induce dual tumor cell death pathways through enhancing DR5 clustering. By conjugating DR5 ligand peptides onto the surfaces of self-illuminating nanoparticles with cross-linking capacity, this strategy not only provides scaffolds for ligands to bind receptors but also cross-links them through photo-cross-linking. This strategy allows for efficient activation of DR5 downstream signaling, initiating the extrinsic apoptosis pathway and immunogenic cell death of tumor cells, and contributes to improved tumor-specific immune responses, resulting in enhanced antitumor efficacy and minimized systemic adverse effects.

PH/glutathione-responsive theranostic nanoprobes for chemoimmunotherapy and magnetic resonance imaging of ovarian cancer cells

The integration of immunotherapy and standard chemotherapy holds great promise for enhanced anticancer effects. In this study, we prepared a pH- and glutathione (GSH)-sensitive manganese-doped mesoporous silicon (MMSNs) based drug delivery system by integrating paclitaxel (PTX) and anti-programmed cell death-ligand 1 antibody (aPD-L1), and encapsulating with polydopamine (PDA) for chemoimmunosynergic treatment of ovarian cancer cells. The nanosystem was degraded in response to the tumor weakly acidic and reductive microenvironment. The Mn2+ produced by degradation can be used as a contrast agent for magnetic resonance (MR) imaging to provide visual exposure to tumor tissue. The released PTX can not only kill tumor cells directly, but also induce immunogenic death (ICD) of tumor cells, which can play a synergistic therapeutic effect with aPD-L1. Therefore, our study is expected to provide a promising strategy for improving the efficacy of cancer immunotherapy and the detection rate of cancer.

In-situ-formed immunotherapeutic and hemostatic dual drug-loaded nanohydrogel for preventing postoperative recurrence of hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is a prevalent malignancy characterized by an exceedingly high recurrence rate post-surgery, significantly impairing the prognosis of HCC patients. However, a standard in-care strategy for postoperative therapy is still lacking. Although encouraging results have been obtained in a newly published clinical trial for postoperative therapy by targeting the vascular endothelial growth factor (VEGF) and programmed death ligand 1 (anti-PD-L1), its efficacy remains constrained. Combining a hemostatic hydrogel with a nanoparticle-based drug delivery system presents an opportunity to optimize the antitumor effect. Herein, we developed a nanoplatform, termed HMSN@Sor/aP@Gel, comprising a hemostatic fibrin hydrogel and functionalized hollow mesoporous silica nanoparticles (HMSNs) loaded with sorafenib and anti-PD-L1 for locally administered targeted-immunotherapy to prevent the postoperative recurrence and metastasis of HCC. The antitumor mechanism is grounded in dual inhibition of Ras/Raf/MEK/ERK (MAPK) and phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT) pathways, synergistically complemented by PD-L1 blockade. HMSN@Sor/aP@Gel facilitates dendritic cell maturation, enhances cytotoxic T-lymphocyte infiltration, promotes the polarization of tumor-associated macrophages to M1 phenotype, induces tumor immunogenic cell death, reverses immunosuppression, and establishes immune memory to counter postoperative recurrence. Animal studies corroborate that HMSN@Sor/aP@Gel-mediated targeted immunotherapy significantly impedes primary and metastatic tumor growth and establishes immune memory to prevent recurrence post-surgery. This investigation presents a promising strategy for postoperative therapy with considerable potential for clinical translation.

Engineered low-pathogenic Helicobacter pylori as orally tumor immunomodulators for the stimulation of systemic immune response

Gastric cancer constitutes a malignant neoplasm characterized by heightened invasiveness, posing significant global health threat. Inspired by the analysis that gastric cancer patients with Helicobacter pylori (H. pylori) infection have higher overall survival, whether H. pylori can be used as therapeutics agent and oral drug delivery system for gastric cancer. Hence, we constructed engineered H. pylori for gastric cancer treatment. A type Ⅱ H. pylori with low pathogenicity, were conjugated with photosensitizer to develop the engineered living bacteria NIR-triggered system (Hp-Ce6). Hp-Ce6 could maintain activity in stomach acid, quickly infiltrate through mucus layer and finally migrate to tumor region owing to the cell morphology and urease of H. pylori. H. pylori, accumulated in the tumor site, severed as vaccine to activate cGAS-STING pathway, and synergistically remodel the macrophages phenotype. Upon irradiation within stomach, Hp-Ce6 directly destroyed tumor cells via photodynamic effect inherited by Ce6, companied by inducing immunogenic tumor cell death. Additionally, Hp-Ce6 exhibited excellent biosafety with fecal elimination and minimal blood absorption. This work explores the feasibility and availability of H. pylori-based oral delivery platforms for gastric tumor and further provides enlightening strategy to utilize H. pylori invariably presented in the stomach as in-situ immunomodulator to enhance antitumor efficacy.

Nanoparticle-mediated celastrol ER targeting delivery amplify immunogenic cell death in melanoma

IntroductionChemoimmunotherapy, which benefits from the combination of chemotherapy and immunotherapy, has emerged as a promising strategy in cancer treatment. However, effectively inducing a robust immune response remains challenging due to the limited responsiveness across patients. Endoplasmic reticulum (ER) stress is essential for activating intracellular signaling pathways associated with immunogenic cell death (ICD), targeting drugs to ER might enhance ER stress and improve ICD-related immunotherapy. ObjectivesTo improve the immune response of Chemoimmunotherapy. MethodsER targeting nanoparticles TSE-CEL/NP were constructed to enhance immunogenic cancer cell death. Flow cytometry, confocal microscope, TEM and immunofluorescence were used to evaluate the ER targeting effect and immunogenic tumor cell death in vitro on B16F10 tumor cells. Unilateral and bilateral tumor models were constructed to investigate the efficacy of anti-tumor and immunotherapy in vivo. Lung metastasis B16F10 melanoma tumor-bearing mice were used to assess the anti-metastasis efficacy. ResultsTSE-CEL/NP could specially accumulate in ER, thereby induce ER stress. High ER stress trigger the exposure of CRT, the extracellular release of HMGB1 and ATP. These danger signals subsequently promote the recruitment and maturation of dendritic cells (DCs), which in turn increase the proliferation of cytotoxic T lymphocytes (CD8+ T cells), ultimately resulted in an improved immunotherapy efficacy against melanoma. Invivo experiments showed that TSE-CEL/NP exhibits excellent antitumor efficacy and triggers a strong immune response. ConclusionOur findings demonstrated that celastrol ER targeting delivery could amplify immunogenic cell death in melanoma, which provide experimental basis for melanoma immunotherapy.

A single-arm phase II study of platinum doublet induction chemotherapy combined with toripalimab for driver gene-negative advanced NSCLC.

e20565 Background: PD-1/PD-L1 inhibitors combined with platinum doublet chemotherapy have become the standard first-line treatment for driver gene-negative advanced non-small cell lung cancer (NSCLC). However, not all patients can benefit from this treatment. Previous studies have shown that induction chemotherapy can reduce tumor burden, induce tumor immunogenic cell death, and improve the tumor immune microenvironment. Therefore, effective induction chemotherapy may enhance the efficacy of PD-1/PD-L1 immunotherapy. This single-arm, phase II clinical trial aims to evaluate the efficacy and safety of induction chemotherapy followed by immunotherapy (Toripalimab: PD-1 inhibitor) in treatment of driver gene-negative advanced NSCLC. Methods: Eligible patients received platinum doublet chemotherapy for 2-4 cycles (pemetrexed + platinum for adenocarcinoma; paclitaxel or gemcitabine + platinum for squamous cell carcinoma). patients who achieved tumor response (CR/PR/SD) received Toripalimab (240mg Q3W) for 2 years or until disease progression or intolerable toxicity. The primary endpoint was progression-free survival (PFS), which was defined as the duration from the initiation of induced chemotherapy to either tumor progression or death from any cause,and the secondary endpoints were toxicity, overall survival (OS), and clinical tumor response including objective response (defined as complete [CR] or partial response [PR]) and disease control (defined as CR, PR, or stable disease [SD]) during the course of combination treatment with Toripalimab following induction chemotherapy. Results: During the period from February 2020 through October 2023, a total of 19 qualified patients were enrolled in the study. As of December 31. 2023,the median follow-up was 22,9 months (range,15.9 to 30 months).11 patients (57.9%) experienced PFS events and 7 (36.8%) died, mOS were not reached. mPFS was 7.9 mo (95% CI,4.8-15.0months).12-month and 18-month PFS rate were 43% and 35%, respectively. One patient has not received tumor response assessment. Among the remaining 18 pts, 10 patients had a PR,5 patients had SD, and 3 patients had PD. The ORR and DCR were 55.6% and 83.3% respectively.42.1% (8/19) pts experienced immune-related adverse events(irAEs), included immune-related pneumonia (21.1%), rash (10.5%), hypothyroidism (10.5%). 2 pts experienced ≥3 grade irAEs, including grade 3 rash and grade 4 immune-related thrombocytopenia. Conclusions: Induction chemotherapy combined with Toripalimab achieved impressive 12-month and 18-month PFS rates in pts with driver gene-negative advanced NSCLC, along with manageable toxicities. These findings demonstrate the potential of induction chemotherapy could enhance the efficacy of immunotherapy. Clinical trial information: NCT04613804 .

Fusogenic vesicular stomatitis virus combined with natural killer T cell immunotherapy controls metastatic breast cancer

BackgroundMetastatic breast cancer is a leading cause of cancer death in woman. Current treatment options are often associated with adverse side effects and poor outcomes, demonstrating the need for effective new treatments. Immunotherapies can provide durable outcomes in many cancers; however, limited success has been achieved in metastatic triple negative breast cancer. We tested whether combining different immunotherapies can target metastatic triple negative breast cancer in pre-clinical models.MethodsUsing primary and metastatic 4T1 triple negative mammary carcinoma models, we examined the therapeutic effects of oncolytic vesicular stomatitis virus (VSVΔM51) engineered to express reovirus-derived fusion associated small transmembrane proteins p14 (VSV-p14) or p15 (VSV-p15). These viruses were delivered alone or in combination with natural killer T (NKT) cell activation therapy mediated by adoptive transfer of α-galactosylceramide-loaded dendritic cells.ResultsTreatment of primary 4T1 tumors with VSV-p14 or VSV-p15 alone increased immunogenic tumor cell death, attenuated tumor growth, and enhanced immune cell infiltration and activation compared to control oncolytic virus (VSV-GFP) treatments and untreated mice. When combined with NKT cell activation therapy, oncolytic VSV-p14 and VSV-p15 reduced metastatic lung burden to undetectable levels in all mice and generated immune memory as evidenced by enhanced in vitro recall responses (tumor killing and cytokine production) and impaired tumor growth upon rechallenge.ConclusionCombining NKT cell immunotherapy with enhanced oncolytic virotherapy increased anti-tumor immune targeting of lung metastasis and presents a promising treatment strategy for metastatic breast cancer.

Biomimetic Dual-Target Theranostic Nanovaccine Enables Magnetic Resonance Imaging and Chemo/Chemodynamic/Immune Therapy of Glioma.

Development of theranostic nanomedicines to tackle glioma remains to be challenging. Here, we present an advanced blood-brain barrier (BBB)-crossing nanovaccine based on cancer cell membrane-camouflaged poly(N-vinylcaprolactam) (PVCL) nanogels (NGs) incorporated with MnO2 and doxorubicin (DOX). We show that the disulfide bond-cross-linked redox-responsive PVCL NGs can be functionalized with dermorphin and imiquimod R837 through cell membrane functionalization. The formed functionalized PVCL NGs having a size of 220 nm are stable, can deplete glutathione, and responsively release both Mn2+ and DOX under the simulated tumor microenvironment to exert the chemo/chemodynamic therapy mediated by DOX and Mn2+, respectively. The combined therapy induces tumor immunogenic cell death to maturate dendritic cells (DCs) and activate tumor-killing T cells. Further, the nanovaccine composed of cancer cell membranes as tumor antigens, R837 as an adjuvant with abilities of DC maturation and macrophages M1 repolarization, and MnO2 with Mn2+-mediated stimulator of interferon gene activation of tumor cells can effectively act on both targets of tumor cells and immune cells. With the dermorphin-mediated BBB crossing, cell membrane-mediated homologous tumor targeting, and Mn2+-facilitated magnetic resonance (MR) imaging property, the designed NG-based theranostic nanovaccine enables MR imaging and combination chemo-, chemodynamic-, and imnune therapy of orthotopic glioma with a significantly decreased recurrence rate.

As1411-modified liposomes to enhance drug utilization and augment the anti-tumor efficacy

BackgroundThe utilization of liposomes in drug delivery has garnered significant attention due to their efficient drug loading capacity and excellent biocompatibility, rendering them a promising platform for tumor therapy. However, the average size of liposomes ~ 100 nm leads to liposomes being susceptible to hepatic and renal metabolism to excretion outside the body leading to poor drug delivery efficiency with a total utilization rate of less than 0.7%, resulting in unfavorable treatment outcomes.ResultsWe have developed a novel liposome platform equipped with tumor surface nucleolin-targeting capacity to enhance drug accumulation at the tumor in vivo. The encapsulation of doxorubicin through thin film hydration has resulted in the formation of D@L-AS1411. Through in vivo experiments, we have demonstrated the effective accumulation of D@L-AS1411 at the tumor site and its ability to improve doxorubicin utilization rates by 40%. Additionally, D@L-AS1411 induces immunogenic death of tumor cells, release of tumor-associated antigens, upregulation of calreticulin expression, and recruitment of active T cell infiltration, and ultimately improves the therapeutic efficacy against tumors (70%).ConclusionsBased on the nucleic acid aptamer AS1411, D@L-1411 is developed to specifically enhance the accumulation of Dox at tumor sites, thereby inhibiting and enhancing the anti-tumor effect. In summary, this study not only provides an efficient tumor-targeting delivery platform but also contributes to the improvement of chemotherapy–immunotherapy combination for tumor treatment strategy in the clinic.

A Synergistic Chemoimmunotherapy System Leveraging PD-L1 Blocking and Bioorthogonal Prodrug Activation.

Novel strategies to facilitate tumor-specific drug delivery and restore immune attacks remain challenging in overcoming the current limitations of chemoimmunotherapy. An antitumor chemoimmunotherapy system comprising bioorthogonal reaction-ready group tetrazine (TZ) modified with an anti-PD-L1 antibody (αPD-L1TZ) and TZ-activatable prodrug vinyl ether-doxorubicin (DOX-VE) for self-reinforced anti-tumor chemoimmunotherapy is proposed. The αPD-L1TZ effectively disrupts the PD-L1/PD-1 interaction and activates the DOX prodrug in situ through the bioorthogonal click reaction of TZ and VE. Conversely, the activated DOX upregulates PD-L1 on the surface of tumor cells, facilitating tumor accumulation of αPD-L1TZ and enhancing DOX-VE activation. Furthermore, the activated DOX-induced immunogenic cell death of tumor cells, substantially improving the response efficiency of αPD-L1 in an immune-suppressive tumor microenvironment. Thus, PD-L1 blocking and bioorthogonal in situ prodrug activation synergistically enhance the antitumor efficacy of the chemoimmunotherapy system. Therefore, the system significantly enhances αPD-L1 tumor accumulation and prodrug activation and induces a robust immunological memory effect to prevent tumor recurrence and metastasis. Thus, a feasible chemoimmunotherapy combination regimen is presented.

Photosynthetic Bacteria-Hitchhiking 2D iMXene-mRNA Vaccine to Enable Photo-Immunogene Cancer Therapy.

Therapeutic mRNA vaccines have become powerful therapeutic tools for severe diseases, including infectious diseases and malignant neoplasms. mRNA vaccines encoding tumor-associated antigens provide unprecedented hope for many immunotherapies that have hit the bottleneck. However, the application of mRNA vaccines is limited because of biological instability, innate immunogenicity, and ineffective delivery in vivo. This study aims to construct a novel mRNA vaccine delivery nanosystem to successfully co-deliver a tumor-associated antigen (TAA) encoded by the Wilms' tumor 1 (WT1) mRNA. In this system, named PSB@Nb1.33C/mRNA, photosynthetic bacteria (PSB) efficiently delivers the iMXene-WT1 mRNA to the core tumor region using photo-driven and hypoxia-driven properties. The excellent photothermal therapeutic (PTT) properties of PSB and 2D iMxene (Nb1.33C) trigger tumor immunogenic cell death, which boosts the release of the WT1 mRNA. The released WT1 mRNA is translated, presenting the TAA and amplifying immune effect in vivo. The designed therapeutic strategy demonstrates an excellent ability to inhibit distant tumors and counteract postsurgical lung metastasis. Thus, this study provides an innovative and effective paradigm for tumor immunotherapy, i.e., photo-immunogene cancer therapy, and establishes an efficient delivery platform for mRNA vaccines, thereby opening a new path for the wide application of mRNA vaccines.

A new MVA ancestor-derived oncolytic vaccinia virus induces immunogenic tumor cell death and robust antitumor immune responses

Vaccinia viruses (VACV) are versatile therapeutic agents and different features of various VACV strains allow for a broad range of therapeutic applications. Modified Vaccinia virus Ankara (MVA) is a particularly altered VACV strain that is highly immunogenic, incapable of replicating in mammalian hosts, and broadly used as a safe vector for vaccination. Alternatively, Western Reserve (WR) or Copenhagen (Cop) are VACV strains that efficiently replicate in cancer cells and therefore are used to develop oncolytic viruses. However, the immune evasion capacity of WR or Cop hinders their ability to elicit antitumor immune responses, which is crucial for efficacy in the clinic. Here, we describe a new VACV strain named Immune-Oncolytic Vaccinia virus Ankara (IOVA), which combines efficient replication in cancer cells with induction of immunogenic tumor cell death (ICD). IOVA was engineered from an MVA ancestor and shows superior cytotoxicity in tumor cells. In addition, the IOVA genome incorporates mutations that lead to massive fusogenesis of tumor cells, which contributes to improved antitumor effects. In syngeneic mouse tumor models, induction of ICD results in robust antitumor immunity directed against tumor neo-epitopes and eradication of large established tumors. These data present IOVA as an improved immunotherapeutic oncolytic vector.

Biomimetic piezoelectric nanomaterial-modified oral microrobots for targeted catalytic and immunotherapy of colorectal cancer.

Lactic acid (LA) accumulation in the tumor microenvironment poses notable challenges to effective tumor immunotherapy. Here, an intelligent tumor treatment microrobot based on the unique physiological structure and metabolic characteristics of Veillonella atypica (VA) is proposed by loading Staphylococcus aureus cell membrane-coating BaTiO3 nanocubes (SAM@BTO) on the surface of VA cells (VA-SAM@BTO) via click chemical reaction. Following oral administration, VA-SAM@BTO accurately targeted orthotopic colorectal cancer through inflammatory targeting of SAM and hypoxic targeting of VA. Under in vitro ultrasonic stimulation, BTO catalyzed two reduction reactions (O2 → •O2- and CO2 → CO) and three oxidation reactions (H2O → •OH, GSH → GSSG, and LA → PA) simultaneously, effectively inducing immunogenic death of tumor cells. BTO catalyzed the oxidative coupling of VA cells metabolized LA, effectively disrupting the immunosuppressive microenvironment, improving dendritic cell maturation and macrophage M1 polarization, and increasing effector T cell proportions while decreasing regulatory T cell numbers, which facilitates synergetic catalysis and immunotherapy.

Polydopamine nanoparticles cross-linked hyaluronic acid photothermal hydrogel with cascading immunoinducible effects for in situ antitumor vaccination

Tumor vaccine, which can effectively prevent tumor recurrence and metastasis, is a promising tool in tumor immunotherapy. However, heterogeneity of tumors and the inability to achieve a cascade effect limit the therapeutic effects of most developing tumor vaccine. We have developed a cascading immunoinducible in-situ mannose-functionalized polydopamine loaded with imiquimod phenylboronic hyaluronic acid nanocomposite gel vaccine (M/P-PDA@IQ PHA) through a boronic ester-based reaction. This reaction utilizes mannose-functionalized polydopamine loaded with imiquimod (M/P-PDA@IQ NAs) as a cross-linking agent to react with phenylboronic-grafted hyaluronic acid. Under near-infrared light irradiation, the M/P-PDA@IQ PHA caused local hyperthermia to trigger immunogenic cell death of tumor cells and tumor-associated antigens (TAAs) releasing. Subsequently, the M/P-PDA@IQ NAs which were gradually released by the pH/ROS/GSH-triggered degradation of M/P-PDA@IQ PHA, could capture and deliver these TAAs to lymph nodes. Finally, the M/P-PDA@IQ NAs facilitated maturation and cross-presentation of dendritic cells, as well as activation of cytotoxic T lymphocytes. Overall, the M/P-PDA@IQ PHA could serve as a novel in situ vaccine to stimulate several key nodes including TAAs release and capture, targeting lymph nodes and enhanced dendritic cells uptake and maturation as well as T cells activation. This cascading immune activation strategy can effectively elicit antitumor immune response.

Long-term combined blockade of CXCR4 and PD-L1 with in vivo reassembly for intensive tumor interference

Negative immunoregulatory signal (PD-L1, CXCR4, et al.) and weak immunogenicity elicited immune system failing to detect and destroy cancerous cells. CXCR4 blockade promoted T cell tumor infiltration and increased tumor sensitivity to anti-PD-L1 therapy. Here, pH-responsive reassembled nanomaterials were constructed with anti-PD-L1 peptide and CXCR4 antagonists grafting (APAB), synergized with photothermal therapy for melanoma and breast tumor interference. The self-assembled APAB nanoparticles accumulated in the tumor and rapidly transformed into nanofibers in response to the acidic tumor microenvironment, leading to the exposure of grafted therapeutic agents. APAB enabling to reassemble around tumor cells and remained stable for over 96 h due to the aggregation induced retention (AIR) effect, led to long-term efficiently combined PD-L1 and CXCR4 blockade. Photothermal efficiency (ICG) induced immunogenic cell death (ICD) of tumor cells so as to effectively improve the immunogenicity. The combined therapy (ICG@APAB) could effectively inhibit the growth of primary tumor (∼83.52%) and distant tumor (∼76.24%) in melanoma-bearing mice, and significantly (p < 0.05) prolong the survival time over 42 days. The inhibition assay on tumor metastasis in 4 T1 model mice exhibited ICG@APAB almostly suppressed the occurrence of lung metastases and the expression levels of CD31, MMP-9 and VEGF in tumor decreased by 82.26%, 90.45% and 41.54%, respectively. The in vivo reassembly strategy will offer novel perspectives benefical future immunotherapies and push development of combined therapeutics into clinical settings.

Immunogenic cell death-based cancer vaccines: promising prospect in cancer therapy.

Tumor immunotherapy is a promising approach for addressing the limitations of conventional tumor treatments, such as chemotherapy and radiotherapy, which often have side effects and fail to prevent recurrence and metastasis. However, the effectiveness and sustainability of immune activation in tumor immunotherapy remain challenging. Tumor immunogenic cell death, characterized by the release of immunogenic substances, damage associated molecular patterns (DAMPs), and tumor associated antigens, from dying tumor cells (DTCs), offers a potential solution. By enhancing the immunogenicity of DTCs through the inclusion of more immunogenic antigens and stimulating factors, immunogenic cell death (ICD) based cancer vaccines can be developed as a powerful tool for immunotherapy. Integrating ICD nanoinducers into conventional treatments like chemotherapy, photodynamic therapy, photothermal therapy, sonodynamic therapy, and radiotherapy presents a novel strategy to enhance treatment efficacy and potentially improve patient outcomes. Preclinical research has identified numerous potential ICD inducers. However, effectively translating these findings into clinically relevant applications remains a critical challenge. This review aims to contribute to this endeavor by providing valuable insights into the in vitro preparation of ICD-based cancer vaccines. We explored established tools for ICD induction, followed by an exploration of personalized ICD induction strategies and vaccine designs. By sharing this knowledge, we hope to stimulate further development and advancement in the field of ICD-based cancer vaccines.

Combined mild magnetic hyperthermia and calcium ion regulation for enhanced immunotherapy of orthotopic liver cancer

Cancer immunotherapy relies on immune cells activation to fight malignancies. Liver serves as the important organs with abundant immune cells. However, in the process of liver tumor development, immune cells lose original function of fighting tumors affected by tumor immunosuppressive microenvironment. Here, a hyaluronic acid-modified calcium phosphate-coated magnetic nanoparticles (named as MSCH) is used to remodel immunosuppressive microenvironment of liver tumors to multiple activate immune cells based on mild magnetic hyperthermia therapy (MHT) and calcium ions regulation strategy. In detail, intra-tumoral acidic microenvironment and mild MHT effectively promote calcium ions release from MSCH to activate casepase-1, resulting in tumor-associated macrophages (TAMs) M1 polarization. Meanwhile, mild MHT significantly upregulate RAE-1ɛ proteins expression in liver cancer cells, ligands for natural killer group 2 member D (NKG2D), resulting in natural killer (NK) cell activation. Moreover, the synergistic effect of mild MHT and calcium overload in cancer cells enables tumor immunogenic cell death (ICD) to activate robust adaptive immune responses. Most importantly, the mild MHT featuring excellent deep tissue penetration ensures the heat accumulation in liver tumors. The multi-activated immune cells therapy strategy based on mild MHT and calcium ions regulation has demonstrated excellent therapeutic effects for orthotopic liver cancer tumor.

Core-shell nanomedicine based on multifunctional tetrahedral DNA nanostructures for synergistic enhancement of tumor chemodynamic/chemo-immunotherapy

Immune checkpoint blockade therapy has made great strides in cancer treatment, but conventional immune checkpoint blockade antibodies often lead to overactivation of the immune system and severe immune-related adverse effects. Herein, we report the design of a nanomedicine (denoted as CPD@M−TDN) based on multifunctional tetrahedral DNA nanostructures (M−TDN). In this system, a bimetallic metal–organic framework (Cu/ZIF-8) is synthesized as the core; doxorubicin-loaded polydopamine acts as a shell to reduce the immunogenicity of the nanomaterials in peripheral blood. Finally, the CpG oligodeoxynucleotides and PD-L1 aptamer-based M−TDN are coupled to the core–shell structure nanomedicine through the biotin-avidin-system. Under the acidic tumor microenvironment, the decomposition of Cu/ZIF-8 and the release of copper ions and doxorubicin can lead to immunogenic death of tumor cells through chemodynamic/chemotherapy. Furthermore, the M−TDN has the dual effects of weakening the immunosuppressive microenvironment with PD-L1 aptamer and promoting dendritic cell activation with the immunostimulant CpG. Overall, the developed CPD@M−TDN can effectively enhance the response rate to immunotherapy and has excellent potential in the field of integrated tumor treatment.