Sarcomas are highly malignant tumors characterized by their heterogeneity and resistance to conventional therapies, which significantly limit treatment options. EZH2 is highly expressed in sarcomas, but targeting it is difficult. In this study, we uncovered the non-canonical transcriptional mechanisms of EZH2 in sarcoma and highlighted the essential role of EZH2 in regulating YAP1 through non-canonical transcriptional pathways in the progression of sarcoma. Building on this, we developed YM@VBM, a novel and versatile nano-PROTAC (proteolysis-targeting chimera), by integrating a polyphenol-vanadium oxide system with the EZH2 degrader YM281 PROTAC, encapsulated in methoxy polyethylene glycol-NH2 to enhance biocompatibility. To further facilitate targeted drug delivery to tumors, YM@VBM nano-PROTACs were incorporated into microneedle patches. Our engineered YM@VBM exhibited multiple functionalities, including the peroxidase-like activity to generate reactive oxygen species, depletion of glutathione, and photothermal effects, specifically targeting sarcoma characteristics. YM@VBM significantly enhanced targeting efficacy via inducing potent EZH2 degradation. Most importantly, it can also activate anti-tumor immunity via excluding myeloid-derived suppressor cells, maturing dendritic cells, and forming tertiary lymphoid structures. Hence, we reveal that YM@VBM presents a promising treatment strategy for sarcoma, offering a multifaceted approach to combat this challenging malignancy.

Cell death-based therapies combined with immunotherapy have great potential in cancer therapy. To further explore and apply the combined therapies, the immunogenicity of different cell death modes in colorectal cancer (CRC) was evaluated by a cause-and-effect framework encompassing 12 cell death modes. Results show robust correlations among cuproptosis, immunogenic cell death (ICD) and immunity in CRC, as observed in our in-house and other independent cohorts, which are substantiated by in vitro and in vivo experiments. Subsequent investigations demonstrate that cuproptosis induces endoplasmic reticulum stress, leading to the release of damage-associated molecular patterns from CRC cells and triggering the maturation of antigen-presenting cells. Moreover, for in vivo therapeutic approaches, an in situ cuproptosis-inducing system was devised, which can further strengthen the effects of immune cells. Through the combined analysis including single-cell RNA sequencing, cuproptosis is shown to mobilize cytotoxic T lymphocytes and M1 macrophages within the tumor microenvironment (TME). Additionally, co-treatment with Imiquimod, the TLR7 agonist, augments the anti-tumor immune responses induced by cuproptosis. Overall, we provide compelling evidence that cuproptosis induces ICD thus fostering an inflammatory TME, and the cuproptosis-based delivery system further promotes this inflammatory environment, demonstrating considerable potential for enhancing tumor therapy efficacy.

Precise tumor therapy is essential for improving treatment specificity, enhancing efficacy, and minimizing side effects. Targeting organelles is a key strategy for achieving this goal and is a frontier research area attracting a considerable amount of attention. The concept of organelle targeting has a significant effect on the structural design of the nanodrugs employed. Most notably, the intricate interactions among different organelles in a tumor cell essentially create a unified system. Unfortunately, this aspect might have been somewhat overlooked when existing organelle-targeting nanodrugs were designed. In this review, we underscore the synergistic relationship among the various organelles and advocate for a holistic view of organelle-targeting design. Through the integration of biology and material science, recent advancements in organelle targeting, escaping, and collaborating are consolidated to offer fresh perspectives for the development of antitumor nanomedicines.

The nanomedicine field has progressed enormously in the last couple of decades. From a loose group of liposomologists, polymer scientists, chemical engineers, and experts in metal nanoparticles, mesoporous silica, and other nanomaterials, the field has gradually consolidated and has generated vast amounts of research and clinical data, but, until the development of lipid nanoparticle (LNP)-based vaccinations for Covid-19, has remained with low visibility in the clinic. Applications in the cancer field are the most frequently sought projects in nanomedicine. For the last 45 years, my clinical career has mingled with my research career focusing on ways to formulate drugs in liposomes to improve their safety and efficacy in cancer therapy. In this review, I will discuss my contribution to the development of pegylated liposomal doxorubicin and other cancer nanomedicines from my privileged position as a clinician and scientist.

Immunotherapy is an emerging strategy that awakens the intrinsic immune system for cancer treatment. Generally, successful immunotherapy of malignant tumours relies on the effective production of tumour-associated antigens and their lymph node delivery, antigen processing and presentation for T-cell activation, and the dismantling of the immunosuppressive tumour microenvironment. Toll-like receptor (TLR) agonists are potent stimulants in cancer immunotherapy, which can directly activate antigen-presenting cells (APCs) and further induce T cell activation for antitumour immune response and convert immunosuppressive tumour microenvironment to an immunogenic one for cooperative tumour ablation. However, TLR agonists for effective cancer immunotherapy have encountered essential challenges, such as insufficient immune activation and systemic side effects. In recent years, nano-immunomodulators with TLR agonists have been employed for tumour- and/or lymph node-targeted immune activation to improve the antitumour immune response and alleviate their systemic toxicities, providing a promising strategy for enhanced cancer immunotherapy. Herein, we introduce the recent progress in developing various TLR nano-immunomodulators for cancer immunotherapy via APC activation and tumour microenvironment remodelling. Upon elucidating the rational design principles of nano-immunomodulators, we elucidate the advancement of TLR nanoagonists to break the barriers in effective and safe Toll-like receptor stimulation for potent cancer immunotherapy.

Dendritic cells (DCs) are essential for inducing effective antitumor T cell responses. However, the immunosuppressive tumor microenvironment (TME) hinders DC recruitment and maturation, facilitating tumor progression and spread. This study investigates the synergistic potential of immunogenic cell death (ICD), triggered by chemotherapeutic-derived lipid nanoparticles (LNPs), in combination with Flt3L and CD40L mRNA delivery to enhance DC mobilization and activation, reprogram the TME, and ultimately promote robust antitumor T cell responses. The optimized LNP formulation, GEM5Q7, efficiently delivered mRNA and induced ICD in melanoma cells. Intratumoral administration of GEM5Q7, encapsulating Flt3L and CD40L mRNAs, elevated pro-inflammatory cytokine and chemokine secretion, driving the infiltration and activation of cross-presenting DCs, which are critical for priming T cells. In a subcutaneous melanoma model, this approach led to significant tumor suppression and a 40 % complete response rate. This strategy holds promise for enhancing cancer immunotherapies by reprogramming the TME and inducing durable antitumor T cell immunity.

Activation of the cyclic GMP-AMP synthase(cGAS)-stimulator of interferon genes (STING) has great potential to promote antitumor immunity. As a major effector of the cell to sense and respond to the aberrant presence of cytoplasmic double-stranded DNA (dsDNA), inducing the expression and secretion of type I interferons (IFN) and STING, cGAS-STING signaling pathway establishes an effective natural immune response, which is one of the fundamental mechanisms of host defense in organisms. In addition to the release of heterologous DNA due to pathogen invasion and replication, mitochondrial damage and massive cell death can also cause abnormal leakage of the body's own dsDNA, which is then recognized by the DNA receptor cGAS and activates the cGAS-STING signaling pathway. However, small molecule STING agonists suffer from rapid excretion, low bioavailability, non-specificity and adverse effects, which limits their therapeutic efficacy and in vivo application. Various types of nano-delivery systems, on the other hand, make use of the different unique structures and surface modifications of nanoparticles to circumvent the defects of small molecule STING agonists such as fast metabolism and low bioavailability. Also, the nanoparticles are precisely directed to the focal site, with their own appropriate particle size combined with the characteristics of passive or active targeting. Herein, combined with the cGAS-STING pathway to activate the immune system and kill tumor tissues directly or indirectly, which help maximize the use of the functions of chemotherapy, photothermal therapy(PTT), chemodynamic therapy(CDT), and radiotherapy(RT). In this review, we will discuss the mechanism of action of the cGAS-STING pathway and introduce nanoparticle-mediated tumor combination therapy based on the STING pathway. Collectively, the effective multimodal nanoplatform, which can activate cGAS-STING pathway for enhanced anti-tumor immunotherapy, has promising avenue clinical applications for cancer treatment.

A significant challenge in the treatment of melanoma with immune checkpoint blockades (ICBs) is the limited T cells response often observed in immunologically "cold" tumors. By leveraging the immunogenicity of immunogenic cell death (ICD), which increases the susceptibility of tumor cells to ICBs, this study investigated the potential of a nucleus-targeted ruthenium(II) complex (Ru1) as an inducer of ICD. Treatment with Ru1 induced DNA damage in melanoma cells, activating the cyclic GMP-AMP synthase-stimulator of the interferon genes (cGAS-STING) pathway. This triggered endoplasmic reticulum (ER) stress, leading to ICD. Ru1-treated dying melanoma cells exhibited characteristics such as cell exposure of calreticulin (CRT) on the cell surface, release of adenosine triphosphate (ATP), and secretion of high-mobility group box 1 (HMGB1). Vaccination with Ru1-treated, dying melanoma cells elicited robust antitumor immune responses, as evidenced by CD8+ T cells activation, reduced Foxp3+ T cells count, and the development of a memory immune response that protected mice from subsequent melanoma challenges. Combining Ru1 with anti-PD-1 therapy significantly promoted T cells infiltration, enhanced dendritic cell activation, and reduced tumor-associated immunosuppressive factors, indicating a reprogramming of the tumor microenvironment. These findings suggest that Ru1 is a promising therapeutic agent for treating "cold" tumors in cancer chemoimmunotherapy.

Ovarian cancer (OV) is a malignant tumor that ranks first among gynecological cancers, thus posing a significant threat to women's health. Immunogenic cell death (ICD) can regulate cell death by activating the adaptive immune system. Here, we aimed to comprehensively characterize the features of ICD-associated genes in ovarian cancer, and to investigate their prognostic value and role in the response to immunotherapy. After analyzing datasets from The Cancer Genome Atlas, we utilized weighted gene coexpression network analysis to screen for hub genes strongly correlated with ICD genes in OV, which was subsequently validated with OV samples from the Gene Expression Omnibus (GEO) database. A prognostic risk model was then constructed after combining univariate, multivariate Cox regression and LASSO regression analysis to recognize nine ICD-associated molecules. Next, we stratified all OV patients into two subgroups according to the median value. The multivariate Cox regression analysis showed that the risk model could predict OV patient survival with good accuracy. The same results were also found in the validation set from GEO. We then compared the degree of immune cell infiltration in the tumor microenvironment between the two subgroups of OV patients, and revealed that the high-risk subtype had a higher degree of immune infiltration than the low-risk subtype. Additionally, in contrast to patients in the high-risk subgroup, those in the low-risk subgroup were more susceptible to chemotherapy. In conclusion, our research offers an independent and validated model concerning ICD-related molecules to estimate the prognosis, degree of immune infiltration, and chemotherapy susceptibility in patients with OV.

This phase 2 study evaluated magrolimab+venetoclax (VEN)+azacitidine (AZA) in untreated, unfit acute myeloid leukaemia (AML) and magrolimab+mitoxantrone+etoposide+cytarabine in relapsed/refractory (R/R) AML.

Endpoints included complete remission rate (CRR), overall response rate (ORR), overall survival (OS) and safety.

Eighteen and 36 patients were enrolled into the unfit and R/R AML arms, respectively. CRR was 38.9% and 25.0%, ORR was 66.7% and 38.9%, and median OS was 15.3 and 10.5 months in the unfit AML and R/R AML arms, respectively. No dose-limiting toxicities or magrolimab-related deaths occurred.

Magrolimab was safely combined with existing AML therapies with no new safety signals.

This trail was registered at www.clinicaltrials.gov as NCT04778410.

Immune evasion is a characteristic hallmark of cancer. Immunotherapies aim to activate and support the body's immune system to recognize and fight tumor cells. Induction of immunogenic cell death (ICD) and the associated activation of danger signaling pathways can increase the immunogenicity of tumor cells. Therapeutic ICD stimuli activate endoplasmic reticulum stress pathways and apoptosis leading to the cellular expression of damage-associated molecular patterns (DAMPs). The aim of our in vitro study was to investigate whether mistletoe extracts induce characteristics of immunogenic tumor cell death in cancer cell lines.

Three human breast cancer cell lines and one murine melanoma cell line (SKBR3, MDA-MB-231, MCF-7, and B16F10) were treated with aqueous, fermented Viscum album extract (VAE: Iscador Qu spec.) and taxol or tunicamycin as positive controls, respectively. To investigate whether VAE induces ribotoxic stress, we measured the ER stress regulators p-eIF2a, ATF4, and CHOP by Western blot. Cell surface exposure of DAMPs (calreticulin, heat shock proteins hsp70 and hsp90), apoptosis and induction of mitochondrial reactive oxygen species (ROS) were assessed by flow cytometry. HMGB1 and ATP were quantified by ELISA and chemiluminescence assay, respectively.

Treatment with VAE resulted in phosphorylation of eIF2α in all cancer cell lines tested and increased calreticulin (CRT) exposure on the surface of pre-apoptotic SKBR3 breast cancer and B16F10 mouse melanoma cells. VAE exerted a concentration-dependent effect in all cell lines, resulting in a significantly increased exposure of three DAMPs (CRT, hsp70 and hsp90) on the surface of early apoptotic cells. Furthermore, VAE elevated mitochondrial ROS production and the release of ATP. HMGB1 release was not induced by VAE.

In this in vitro study, we demonstrated for the first time the potential of a mistletoe extract to induce surrogate markers of immunogenic cancer cell death. This is a primary step in investigating the potential of VAEs to contribute to ICD-induced tumor-specific immune activation.

Current cancer treatment strategies in practice nowadays often face limitations in effectiveness due to factors such as resistance, recurrence, or suboptimal outcomes. Traditional approaches like chemotherapy often come with severe systemic side effects due to their non-specific action, prompting the development of more targeted therapies. Among these, physical ablation techniques such as radiotherapy (RT) and focused ultrasound (FUS) have gained attention for their ability to precisely target malignant tissues, reduce physical and mental stress for the patients, and minimize recovery time. These therapies also aim to stimulate the immune system through a process referred to as immunogenic cell death (ICD), enhancing the body's ability to fight cancer, explaining abscopal effects. RT has been the most established of the abovementioned techniques for decades, and will not be included in the review. While initially focused on complete tumor ablation, these techniques are now shifting towards milder, more controlled applications that induce ICD without extensive tissue damage. This review explores how physical ablation therapies can harness ICD to boost anticancer immunity, emphasizing their potential to complement immunotherapies and improve outcomes for cancer patients.

Stimulating the immunogenic cell death (ICD) effect is a method of tumor treatment through activating immunity. While conventional approaches including chemotherapy, photothermal therapy (PTT), and chemodynamic therapy (CDT), demonstrate partial ICD induction capabilities, their efficacy in eliciting systemic immune responses remains constrained by the immunosuppressive tumor microenvironment. Herein, a trimetallic nanozyme (Mn/Fe-MIL-101/CuS/DOX@FA) was engineered through the integration of Mn-doped Fe-MOFs, CuS, doxorubicin (DOX, 35.08 mg/g), and folic acid (FA). The design leverages the synergistic effects of Mn(II), Fe(III), and Cu(II), combined with the photothermal performance of CuS, which collectively enhance glutathione peroxidase (GPx)-like and peroxidase (POD)-like activities. This catalytic cascade depletes glutathione and boosts hydroxyl radicals via Fenton-like reactions, thereby disrupting redox balance to amplify chemodynamic therapy. CuS-mediated photothermal effects coupled with pH/GSH-responsive DOX release further augment ICD, effectively reversing immunosuppression. In vivo evaluations demonstrated 57 % inhibition of the primary tumor and 66.7 % inhibition of the distant tumor, confirming its efficacy in tumor treatment and prevention of recurrence/metastasis. Besides, magnetic resonance imaging experiments showed the T1/T2 dual-mode imaging performance. Thereby, a long-term anti-tumor nanoplatform is constructed through dual-mode imaging-guided multimodal therapy, which integrates tumor diagnosis, treatment, and prevention of recurrence and metastasis.

Doxorubicin is a first-line treatment of cancer that works on the mechanism of DNA intercalation and topoisomerase II poisoning. Since the 20th century, Doxorubicin has been used as a promising drug to treat several types of cancer, both solid or metastatic, including breast, thyroid, bladder, ovarian, or gastric cancer, etc. Even though it shows promising effects on cancer cells, it also shows its effects on healthy cells with cancerous cells, which leads to several severe side effects, such as cardiomyopathy, phlebitis, congestive heart failure (CHF), etc., which limits its usage in chemotherapy. Several research has focused on the targeted delivery of doxorubicin to cancerous cells to reduce side effects and improve efficacy. To optimize its anticancer potential, scientists have recently been developing nano-formulations and investigating various conjugations. The structure of doxorubicin consists of two primary functional groups that can be employed for conjugation with a variety of biomolecules, The first is the primary amine group in a sugar moiety, and the other one is the primary hydroxyl group in the aliphatic chain ring. In this paper, we have mentioned several conjugations of doxorubicin such as antibodies, nanoparticles, polymers, and phytochemical conjugations. Different studies regarding these conjugations are also mentioned, which represent promising strategies to optimize cancer treatment by minimizing side effects.

Photoimmunotherapy has emerged as a promising strategy for cancer therapy due to its increased therapeutic effect, ability to reverse drug resistance, and enhanced immune activation. But there is still a lack of effective nanomaterial-based photothermal therapy (PTT) or photodynamic therapy (PDT) agents in photoimmunotherapy. In this study, photosensitizer hematoporphyrin-modified G5 PAMAM (G5-HP) nanomaterials are synthesized, which exhibit excellent photothermal conversion capability and photodynamic effects under 660 nm irradiation, effectively inducing tumor cell ablation and immunogenic cell death (ICD). Besides, ICD induced by G5-HP can generate tumor-associated antigens, thereby enhancing dendritic cell (DC) maturation and subsequent T cell activation. In addition, G5-HP polymers can bind to Toll-like receptor (TLR) agonists CpG-ODN through electrostatic interaction, forming stable G5-HP/CpG nanoparticles. The incorporation of CpG-ODN as an immunoadjuvant further amplified DC maturation, synergizing with phototherapy to strengthen antitumor immunity. Notably, in vivo studies confirmed that G5-HP/CpG nanoparticles significantly suppressed colorectal tumor growth under laser irradiation, while maintaining excellent biocompatibility. Taken together, the synthesized G5-HP polymers perform excellent PTT and PDT efficacy, and the formed G5-HP/CpG nanoparticles effectively integrate phototherapy with DC-mediated immunotherapy. This study offers a promising strategy for colorectal cancer treatment, leveraging the synergistic effects of phototherapy and immunotherapy to achieve superior antitumor outcomes.

Gene therapy using mRNA has facilitated progress in cancer therapy. However, its application is hindered by a limited tumor-targeted delivery approach, leading to off-target effects and safety concerns. Chimeric antigen receptor (CAR) molecules enable T cells to recognize specific antigens in a major histocompatibility complex-unrestricted manner. CAR approaches provide an "off-the-shelf" solution for introducing additional targeting functionality to a cell membrane. Cancer cell membrane-coated nanoparticles with homotypic tumor-targeted properties provide a readily accessible platform for gene engineering and membrane extraction. Herein, we demonstrate a CAR-inspired cancer cell membrane-coated platform for delivering an mRNA formulation through a dual tumor-targeted mechanism. The simplified human epidermal growth factor receptor 2 (HER2)-specific CAR molecule (comprising an extracellular HER2-binding domain, a hinge, and a transmembrane domain) was engineered on the cell membrane of cancer cells to establish CAR-CT26 cells. The extracted CAR-CT26 membrane (CARM) was subsequently coated onto the lipid nanoparticle (LNP)-mRNA surface to form a CARM@LNP-mRNA complex. In vitro, the CARM-coated nanoparticles exhibited enhanced mRNA transfection efficiency toward CT26 cells overexpressing target HER2 antigens. Systemic administration of the CARM@LNP-mRNA formulation resulted in stronger tumor-targeting ability and tumor suppression in HER2+ CT26 subcutaneous tumors and peritoneal cavity metastasis models than that observed with the CT26 cell membrane-coated version. Our data suggest that CARM@LNP is a feasible choice for mRNA-based gene therapy. These results provide evidence for the systemic administration of CARM@LNP-mRNA as a promising tumor-targeted therapeutic strategy.

The phagocytosis of macrophages to tumor cells represents an alluring strategy for cancer immunotherapy; however, its effectiveness is largely hindered by the detrimental upregulation of anti-phagocytic signals and insufficient expression of pro-phagocytic signals of tumor cells. Here, a pro-phagocytic polymer-based nanocomplex is designed to promote the macrophage engulfment of tumor cells through concurrent modulation of both the "eat me" and "don't eat me" signals. The nanocomplex MNCCD47i-CALRt is formed by complexing a synthetic PAMAM derivative (G4P-C7A) that is capable of intrinsically inducing the exposure of calreticulin (CALR, a crucial pro-phagocytic protein) and a small inference RNA that can inhibit the expression of CD47 (a primary anti-phagocytic protein). MNCCD47i-CALRt can significantly delay tumor growth and prolong the survival of tumor-bearing mice with negligible hematopoietic toxicity in multiple murine colorectal cancer models. Furthermore, the pro-phagocytic capacity of MNCCD47i-CALRt is validated in the patient-derived tumor organoid model. Collectively, the phagocytosis-promoting nanocomplex provides a simple and potent strategy for boosting macrophage-mediated cancer immunotherapy.

External beam radiation therapy (RT) is a cornerstone of modern cancer management, being utilized in both curative and palliative settings due to its safety, efficacy, and widespread availability. A primary biological effect of RT is DNA damage, which leads to significant cytostatic and cytotoxic effects. Importantly, malignant cells possess a limited capacity for DNA repair compared to normal cells, and when combined with irradiation techniques that minimize damage to healthy tissues, this creates an advantageous therapeutic window. However, the clinical effectiveness of RT also appears to involve both direct and indirect interactions between RT and non-transformed components of the tumoral ecosystem, particularly immune cells. In this review, we describe the molecular and cellular mechanisms by which irradiated cancer cells modify the immunological tumor microenvironment and how such changes ultimately impact tumor growth.

Transcatheter arterial chemoembolization (TACE) stands as the frontline strategy for unresectable hepatocellular carcinoma (HCC), effectively eliminating cancer cells through direct cytotoxicity and immunogenic cell death (ICD). However, TACE triggers rapid tumor apoptosis, which promotes the release of intracellular ATP into the extracellular space. This ATP is sequentially hydrolyzed to adenosine (ADO) by ectonucleotidases (CD39 and CD73) overexpressed in the tumor microenvironment (TME), resulting in ADO accumulation. The ensuing ADO pathway-mediated immunosuppression via adenosine 2A receptors (A2AR) signaling severely limits TACE-induced ICD efficacy, resulting in poor prognosis. To address this, we developed gelatin microspheres co-loaded with doxorubicin (DOX) and the A2AR antagonist SCH-58,261, in which SCH-58,261 was loaded into solid lipid nanoparticle (SLNP) due to its poor water solubility. The microspheres (SLNP-SCH/DOX@MS) showed an average size of 49 ± 13 μm, with the capable of complete tumor vascular embolization, and sustained release profiles of both DOX and SCH-58,261 over 30 days. In vitro and in vivo studies indicated that SLNP-SCH/DOX@MS not only enhanced tumor cell apoptosis but also amplified ICD-mediated dendritic cell maturation and antigen presentation. Moreover, SCH-58,261 counteracted TACE-triggered ADO accumulation by competitively binding to A2AR on immune cells, thereby reversing dendritic cell dysfunction and CD8+T cell exhaustion. This dual-action strategy synergized ICD-driven immunostimulation with ADO pathway blockade, reshaping the TME. Our findings highlight the potential of SLNP-SCH/DOX@MS to address the delicate equilibrium between ICD-induced immunity and ADO-mediated immunosuppression for improved HCC treatment. STATEMENT OF SIGNIFICANCE: This study introduces a approach to improve transcatheter arterial chemoembolization (TACE) for unresectable hepatocellular carcinoma (HCC) by addressing the adenosine (ADO) pathway, a known barrier to effective immunogenic cell death (ICD). We developed gelatin microspheres co-loaded with doxorubicin (DOX) and the A2AR antagonist SCH-58,261, which significantly enhance TACE-induced immunity by promoting ICD and counteracting ADO-mediated immunosuppression. In vitro and in vivo results demonstrate robust dendritic cell maturation and amplified tumor-specific immune responses, indicating improved antitumor efficacy. This work provides a promising strategy to optimize TACE for HCC treatment, offering our readership a therapeutic solution that bridges cancer treatment and immunomodulation.

Pyroptosis, a programmed cell death mechanism that bypasses apoptosis resistance and triggers tumor-specific immune responses, has gained much attention as a promising approach to cancer therapy. Despite enhancing tumor accumulation and extending the circulation of small-molecule drugs, nanomedicines still face significant challenges, including poor tissue penetration, tumor resistance, and hypoxic microenvironments. To overcome these challenges, a novel near-infrared II (NIR-II) J-aggregate-based nanomedicine is designed, leveraging an in situ secondary self-assembly strategy to fabricate highly targeted nanoparticles (MSDP NPs). These nanomedicines trigger pyroptosis by generating type I reactive oxygen species, especially superoxide anions, while simultaneously activating photoimmunotherapy. In vivo studies demonstrate that MSDP NPs achieve efficient tumor penetration and prolong tumor retention, which is facilitated by the J-aggregate-driven formation of microscale spindle-shaped fibrillar bundles through in situ secondary self-assembly at the tumor site. This unique structural transformation enhances nanomedicine accumulation in tumor tissues, enabling robust NIR-II fluorescence imaging and improving therapeutic efficacy even in hypoxic tumor microenvironments. This study provides an innovative phototheranostic strategy that utilizes the in situ secondary self-assembly of NIR-II J-aggregates to induce tumor pyroptosis, offering a potential solution to the limitations of current nanomedicines in cancer therapy.

To investigate whether Thrombospondin-1 (TSP-1) induces immunogenic cell death (ICD) in human mucoepidermoid carcinoma (MC-3) cells and explore its potential to induce calreticulin (CRT) exposure via the PERK/eIF2α signaling pathway.

The MC-3 cell line was used as the research model. The CCK-8 assay was performed to determine the optimal seeding density, TSP-1 concentration, and treatment time. Annexin V/PI double staining combined with flow cytometry was used to assess apoptosis across different experimental groups (blank control, TSP-1, paclitaxel (PTX), TSP-1 + PTX). Cells were divided into groups: blank control, PTX, TSP-1, TSP-1 + ISRIB (ISRIB: Integrated Stress Response Inhibitor), and TSP-1 + PTX, and CRT expression was detected by flow cytometry. Immunofluorescence, Western blot, and qPCR were used to detect the expression of PERK (Protein Kinase R-like Endoplasmic Reticulum Kinase), eIF2α (eukaryotic Initiation Factor 2α), and CRT. All experiments were performed in triplicate, and data were analyzed using GraphPad Prism 8.0 software. Statistical significance was set at P < 0.05.

At a seeding density of 2 × 104/mL, MC-3 cells reached the growth plateau by day six. The optimal concentration and duration of TSP-1 treatment were 0.1 μmol/L and 72 h, respectively. Flow cytometry, immunofluorescence, Western blot, and qPCR results revealed that TSP-1 significantly induced CRT exposure in MC-3 cells (P < 0.05), accompanied by the upregulation of PERK and eIF2α expression (P < 0.05). Co-treatment with PTX further enhanced these effects, while the addition of ISRIB reduced the expression of PERK, eIF2α, and CRT (P < 0.05).

TSP-1 induces ICD in MC-3 cells, accompanied by CRT exposure, potentially mediated through the activation of the PERK/eIF2α signaling pathway. These findings suggest that TSP-1 may have potential as an adjunct to chemotherapy for enhancing tumor immunotherapy.

Radiotherapy is a standard cancer treatment that involves the induction of DNA damage. DNA damage repair (DDR) pathways maintain genomic integrity and make tumors resistant to radiotherapy and certain chemotherapies. In turn, DDR dysfunction results in cumulative DNA damage, leading to increased sensitivity for antitumor treatment. Moreover, radiotherapy has been shown to trigger antitumor immunity. Currently, immunotherapy has become a new and widely used standard strategy for treating a broad spectrum of tumor types. Notably, recent studies have demonstrated that DDR pathways play important roles in driving the response to immunotherapy. Herein, we review and discuss how DDR affects antitumor immunity induced by radiotherapy. Furthermore, we summarize the development of strategies for combining DDR inhibitors with radiotherapy and/or immunotherapy to enhance their efficacy against cancers.

Oxidation of lipids, excessive cell death, and iron deposition are prominent features of human atherosclerotic plaques. While extensive research has established the detrimental roles of lipid oxidation and apoptosis in atherosclerosis development, the involvement of iron in atherogenesis is not yet fully understood. With the emergence of an iron-dependent form of cell death termed ferroptosis, new attention has been brought to the complex inter-play among iron, ferroptosis, and atherosclerosis. Mechanistically, ferroptosis is caused by the lethal accumulation of iron-mediated lipid peroxides. Emerging studies have underscored ferroptosis as a contributor to worsened atherosclerosis. Herein, we review the evidence that oxidative damage and iron overload in the context of atherosclerosis may promote ferroptosis within plaques. Furthermore, we summarize recent findings of lipid peroxidation, thereby potentially ferroptosis, in various plaque cell types-such as endothelial cells, macrophages, dendritic cells, T cells, and vascular smooth muscle cells-across different stages of atherosclerosis. Understanding how these processes influence atherosclerotic plaque progression may permit targeting stage-dependent ferroptosis in each cell population and could provide a rationale for developing cell type-specific intervention strategies to mitigate atherogenic ferroptosis effectively.

Immunogenic cell death (ICD) is a promising cancer therapy where dying tumor cells release damage-associated molecular patterns (DAMPs) to activate immune responses. Recent research highlights the critical role of metabolic reprogramming in tumor cells, including the Warburg effect, oxidative stress, and lipid metabolism, in modulating ICD and shaping the immune microenvironment. These metabolic changes enhance immune activation, making tumors more susceptible to immune surveillance. This review explores the molecular mechanisms linking ICD and metabolism, including mitochondrial oxidative stress, endoplasmic reticulum (ER) stress, and ferroptosis. It also discusses innovative therapeutic strategies, such as personalized combination therapies, metabolic inhibitors, and targeted delivery systems, to improve ICD efficacy. The future of cancer immunotherapy lies in integrating metabolic reprogramming and immune activation to overcome tumor immune evasion, with multi-omics approaches and microbiome modulation offering new avenues for enhanced treatment outcomes.

Immunogenic cell death (ICD) has attracted enormous attention over the past decade due to its unique characteristics in cancer cell death and its role in activating innate and adaptive immune responses against tumours. Many efforts have been dedicated to screening, identifying and discovering ICD inducers, resulting in the validation of several based on metal complexes. In this review, we provide a comprehensive summary of current metal-based ICD inducers, their molecular mechanisms for triggering ICD initiation and subsequent protective antitumour immune responses, along with considerations for validating ICD both in vitro and in vivo. We also aim to offer insights into the future development of metal complexes with enhanced ICD-inducing properties and their applications in potentiating antitumour immunity.

Current tumor vaccines suffer from inadequate immune responsive due to the insufficient release of tumor antigens, low tumor infiltration, and immunosuppressive microenvironment. DNA nanostructures with their ability to precisely engineer, controlled release, biocompatibility, and the capability to augment the immunogenicity of tumor microenvironment, have gained significant attention for their potential to revolutionize vaccine designing. This review summarizes various applications of DNA nanostructures in the construction of in situ cancer vaccines, which can generate tumor-associated antigens directly from damaged tumors for cancer immune-stimulation. The mechanisms and components of cancer vaccines are listed, the specific strategies for constructing in situ vaccines using DNA nanostructures are explored and their underlying mechanisms of action are elucidated. The immunogenic cell death (ICD) induced by chemotherapeutic agents, photothermal therapy (PTT), photodynamic therapy (PDT), and radiation therapy (RT) and the related cancer vaccines building strategies are systematically summarized. The applications of different DNA nanostructures in various cancer immunotherapy are elaborated, which exerts precise, long-lasting, and robust immune responses. The current challenges and future prospectives are proposed. This review provides a holistic understanding of the evolving role of DNA nanostructures for in situ vaccine development.

Photodynamic immunotherapy presents a non-invasive strategy characterized by spatiotemporal control and minimal side effects to induce immunogenic cell death (ICD). This approach significantly enhances the release of tumor-associated antigens and damage-associated molecular patterns, thereby improving cancer immunotherapy outcomes. However, hypoxia and antioxidant defenses at tumor sites considerably diminish the efficacy of photodynamic immunotherapy. In this work, a covalent warhead, alkyneamide, is introduced into an AIE photosensitizer to develop a novel covalent photosensitizer, MBTP-PA, which targets redox systems and facilitates ferroptosis- and pyroptosis-mediated photodynamic immunotherapy by thiol-yne click reactions. The covalent photosensitizer interacts with intracellular thiol compounds such as cysteine and glutathione, disrupting the intracellular antioxidant system and alleviating hypoxia. This results in enhanced photodynamic therapy (PDT) efficacy compared to the non-covalent photosensitizer MBTP-A. Furthermore, in conjunction with PDT, this reaction therapy can activate ICD through ferroptosis and pyroptosis, thereby enhancing anti-tumor immunity. Notably, in vivo injection of MBTP-PA nanoparticles at the tumor site led to the elimination of primary tumors, inhibiting distal tumors and exhibiting minimal side effects. Therefore, this work not only integrates the thiol-yne click reactions into cellular systems, significantly enhancing the efficacy of photodynamic immunotherapy but also paves the way for developing novel photosensitizers.

Necroptosis plays a crucial role in the progression of various diseases and has gained substantial attention for its potential to activate antitumor immunity. However, the complex signaling networks that regulate necroptosis have made it challenging to fully understand its mechanisms and translate this knowledge into therapeutic applications. To address these challenges, an optogenetically activatable necroptosis system is developed that allows for precise spatiotemporal control of key necroptosis regulators, bypassing complex upstream signaling processes. The system, specifically featuring optoMLKL, demonstrates that it can rapidly assemble into functional higher-order "hotspots" within cellular membrane compartments, independent of RIPK3-mediated phosphorylation. Moreover, the functional module of optoMLKL significantly enhances innate immune responses by promoting the release of iDAMPs and cDAMPs, which are critical for initiating antitumor immunity. Furthermore, optoMLKL exhibits antitumor effects when activated in patient-derived pancreatic cancer organoids, highlighting its potential for clinical application. These findings will pave the way for innovative cancer therapies by leveraging optogenetic approaches to precisely control and enhance necroptosis.

Disulfidptosis is a recently identified form of cell death characterized by the aberrant accumulation of cellular disulfides. This process primarily occurs in glucose-starved cells expressing higher levels of SLC7A11 and has been proposed as a therapeutic strategy for cancers with hyperactive SCL7A11. However, the potential for inducing disulfidptosis through other mechanisms in cancers remains unclear. Here, we found that inhibiting thioredoxin reductase 1 (TrxR1), a key enzyme in the thioredoxin system, induces disulfidptosis in glioblastoma (GBM) cells. TrxR1 expression is elevated in GBM with activated transcriptional coactivator with PDZ-binding motif (TAZ) and correlates with poor prognosis. TrxR1 inhibitors induced GBM cell death that can be rescued by disulfide reducers but not by ROS scavengers or inhibitors of apoptosis, ferroptosis, or necroptosis. Glucose-starved cells, but not those deprived of oxygen or glutamine, increased TrxR1 expression in an NRF2-dependent manner and were more sensitive to TrxR1 inhibition-induced cell death. The dying cells initially exhibited highly dynamic lamellipodia, followed by actin cytoskeleton collapse. This process involved the accumulation of cytosolic peroxisomes and micropinocytic caveolae, as well as small gaps in the plasma membrane. Depletion of the WAVE complex component NCKAP1 partially rescued the cells, whereas Rac inhibition enhanced cell death. In an orthotopic xenograft GBM mouse model, TrxR1 depletion inhibited tumor growth and improved survival. Furthermore, cells undergoing TrxR1 inhibition exhibited features of immunogenic cell death. Therefore, this study suggests the potential of targeting TrxR1 as a therapeutic strategy in GBM.

Glioblastoma multiforme (GBM) is one of the most lethal malignant brain tumors in the central nervous system. Patients face many challenges after surgery, including tumor recurrence, intracranial pressure increase due to cavitation, and limitations associated with immediate postoperative oral chemotherapy. Here an injected peptide gel with in situ immunostimulatory functions is developed to coordinate the regulation of glutamine metabolism and chemodynamic therapy for overcoming these postoperative obstacles. The methodology entails crafting injectable gel scaffolds with short peptide molecules, incorporating the glutaminase inhibitor CB-839 and copper peptide self-assembled particles (Cu-His NPs) renowned for their chemodynamic therapy (CDT) efficacy. By fine-tuning glutamic acid production via metabolic pathways, this system not only heightens the therapeutic prowess of copper peptide particles in CDT but also escalates intracellular oxidative stress. This dual mechanism culminates in augmented immunogenic cell death within glioblastoma multiforme cells and improves a conducive immune microenvironment. Based on the concept of metabolic reprogramming, this treatment strategy has great potential to significantly reduce GBM tumor recurrence and prolong median survival in murine models.

Triple-negative breast cancer (TNBC) is a particularly aggressive subtype of breast cancer due to poor immunogenicity and limited immune cell infiltration, efficient therapeutics are still deficiency. Ferroptosis, a reactive oxygen species (ROS)-reliant cell death, can enhance cellular immunogenicity and then active immune system. To sustain a long-term "hot" tumour immune microenvironment (TIME), an immune-modulator is indispensable. Metformin (MET), a commonly used oral drug for type 2 diabetes, has played a vital role in fostering an immunostimulatory environment. Herein, we confirm the TIME can be remodeled by MET and further promotes ferroptosis via upregulating cellular concentration of l-Glutamine. In light of this, we have design a self-assembled MET-loaded Fe3+-doped polydopamine nanoparticle (Fe-PDA-MET NP) that can disorder the cellular redox homeostasis and induce robust ferroptosis under 808 nm irradiation, resulting in a strong immune response. Based on the function of MET, there is a marked increase in the infiltration of activated CD8+ T cells and NK cells, which subsequently augments ferroptosis to a greater extent. Taken together, Fe-PDA-MET NPs activate a ferroptotic positive-feedback loop for effectively control TNBC progression, which offers a promising therapeutic modality to enhance the immunogenicity and reshape the TIME.

The results of stereotactic body radiation therapy (SBRT) for parenchymal lesions in the setting of oligometastatic ovarian cancer are reported in the context of the prospective multicenter phase 2 MITO-RT3/RAD trial (NCT04593381).

The primary endpoint was the complete response (CR) rate, secondary endpoints included local control (LC), progression-free survival, overall survival, treatment-free interval, and toxicity rates. Sample size was based on a previous study reporting an average 40.0% CR with SBRT. The study was powered to detect an improvement in the CR rate from 40.0% to 55.0%, with an α error of 0.05 (one-side) and a β error of 0.1.

The study met its primary endpoint of a statistically significant improvement of CR. A total of 88 patients with 127 lesions were enrolled across 15 institutions from May 2019 to November 2023. CRs were observed in 71 lesions (55.9%), partial response in 37 (29.1%), stable disease in 14 (11.0%), and progressive disease in 5 lesions (4.0%). The objective response rate was 85.0%, with an overall clinical benefit rate of 96.0%. The overall 12-month LC was 81.6%, with CR lesions exhibiting a significantly higher rate than partial or not responding lesions (12-month LC: 96.3% vs 61.4%, P < .001). The 12-month actuarial rates for progression-free survival and for overall survival were 34.9% and 91.5%, respectively. The median actuarial treatment-free interval was 9 months (range, 2.5-15.4 months), whereas the 12-month actuarial rate was 44.1%. No grade 3 or higher toxicity was reported. In particular, 15 (20.5%) patients experienced mild acute toxicity (≤grade 2). There were 12 grade 1 events and 6 grade 2 events, the latter mostly represented by pain flare (N = 2). Late toxicity was reported in 4 patients (4.5%) accounting for 4 events, mostly grade 1, except for one case of moderate asthenia (grade 2).

Parenchymal oligometastatic lesions showed a high rate of CR and encouraging long-term outcomes for patients achieving CR, including a substantial period of systemic therapy-free survival after radiation therapy. The observed toxicity was minimal, strengthening the safety of ablative SBRT as a noninvasive alternative to surgical resection for parenchymal metastases in high-risk areas.

Immunogenic cell death (ICD), a type of regulatory cell death, plays an important role in activating the adaptive immune response. Activation of the tumor-specific immune response is accompanied by the cell surface exposure of calreticulin and heat-shock proteins, the secretion of adenosine triphosphate, and the release of high mobility group box-1. In this review, we summarize and classify the latest types of ICD inducers and their molecular mechanisms, and discuss the effects and potential applications of inducing ICD by chemotherapy drugs, targeted drugs, and oncolytic viruses in clinical research. We also explore the potential role of epigenetic modifiers in the induction of ICD, and clarify the synergistic anti-tumor effects of nano-pulse stimulation, radiosensitizers for radiotherapy, photosensitizers for photodynamic therapy, photothermal therapy, and other physical stimulation, combined with radiotherapy and chemotherapy induced-ICD, in multimodal immunotherapy. In addition, we elucidate the molecular mechanism of ICD in detail, including the calcium imbalance, mitochondrial stress, and the interactions in the tumor microenvironment. Ultimately, this review aims to offer deeper insight into the factors and mechanisms of ICD induction and provide a theoretical basis for the future development of ICD-based immunotherapy.

Immunogenic cell death (ICD) is a regulated form of cell death that activates an immune response through the release of danger-associated molecular patterns (DAMPs), including calreticulin, ATP, and HMGB1. Gold complexes are known to induce ICD, but the ICD-inducing potential of palladium complexes remains largely unexplored. We report the first examples of palladium compounds capable of inducing ICD, specifically allyl palladates bearing bis(imino)acenaphthene-NHC (BIAN-NHC) ligands. Cytotoxicity tests on human cancer cell lines revealed that allyl palladates outperform their cinnamyl analogues and gold(i)/copper(i) BIAN-NHC complexes. Notably, [BIAN-IMes·H][PdCl2(allyl)] 2a showed excellent TrxR inhibition, reducing activity by 67% and surpassing auranofin. This inhibition strongly correlates with ICD induction, as evidenced by enhanced DAMP marker expression, including superior ATP and HMGB1 release compared to doxorubicin. These findings establish allyl palladates as a novel class of ICD inducers with dual anticancer activity and immune activation potential.

Despite ongoing advancements, cancer remains a significant global health concern, with a persistent challenge in identifying a definitive cure. While various cancer therapies have been developed and approved, offering treatments for smaller neoplasms, their efficacy diminishes in solid tumors and hypoxic environments, particularly for chemotherapy and radiation therapy. A novel approach, Clostridium-based therapy, has emerged as a promising candidate for current solid tumor treatments due to its unique affinity for the hypoxic tumor microenvironment. This review examines the potential of Clostridium in cancer treatment, encompassing direct tumor lysis, immune modulation, and synergistic effects with existing cancer therapies. Advancements in synthetic biology have further enhanced its potential through genetic modifications, such as the removal of alpha toxin gene from Clostridium novyi-NT, the implementation of targeted approaches, and reduction in systemic toxicity. Although preclinical and clinical studies have demonstrated that Clostridium-based treatments combined with other therapies hold promise for complete cancer eradication, challenges persist. Through this review, we also propose that the integration of various methods and technologies together with Clostridium-based therapy may lead to the complete eradication of cancer in the future.

Gene electrotransfer (GET) has recently emerged as an effective nonviral approach for plasmid DNA (pDNA) delivery in gene therapy for several pathologies, including cancer. Multiple mechanisms have been identified that influence cell biology after GET, as electroporation significantly increases pDNA uptake and immunogenicity, which may directly influence target cell death. However, the molecular effects of in vivo electroporation-mediated DNA delivery have yet to be fully elucidated. In this study, we evaluated the transcriptomes of murine colorectal tumors treated with two protocols, short- and high-voltage (SHV) electric pulses or an adapted high-voltage-low-voltage (HV-LV) pulse protocol, both of which are used for reversible electroporation. Although no significant differences in clinical outcomes were observed, variations in intratumoral macrophage infiltration were reported between the two treatment methods. Transcriptomic analysis revealed that apoptosis is a predominant mode of cell death after GET by SHV pulses, whereas GET by HV-LV pulses is associated with immunogenic necrotic pathways as well as the activation of both the innate and adaptive immune response. We demonstrated that specific pulse parameters can induce distinct immunomodulatory profiles in the tumor microenvironment; therefore, these aspects should be considered carefully when selecting the most suitable GET-based approach for antitumor immunization.