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Iron oxide nanoparticles (IONPs) have transitioned from conventional magnetic resonance imaging (MRI) contrast agents into structurally programmable combined imaging/treatment tools, leveraging their superparamagnetism, catalytic activity, and surface engineering versatility to achieve spatiotemporal control over drug delivery and immune modulation. Advances in nanofabrication now yield size-optimized aggregates with enhanced tumor accumulation through the enhanced permeability and retention (EPR) effect, while clinically approved formulations like ferumoxytol demonstrate intrinsic immunomodulatory functionality, positioning IONPs as pivotal tools for precision oncology. Conversely, cancer immunotherapy remains limited by the immunosuppressive tumor microenvironment (TME), where cellular suppression via M2-polarized macrophages and regulatory T cells (Tregs) synergizes with physical exclusion from dense extracellular matrices and metabolic sabotage through lactate-driven acidosis. These barriers establish “immune-cold” phenotypes characterized by deficient CD8⁺ T-cell infiltration and tertiary lymphoid structure formation, driving checkpoint inhibitor resistance with sub-30% response rates in solid tumors. To overcome these constraints, IONPs orchestrate multimodal immunotherapeutic strategies: they reprogram suppressive niches by polarizing macrophages toward M1 phenotypes, activate STING pathways, and induce immunogenic ferroptosis; enable precision delivery via magnetic lymph node targeting and cancer cell membrane-mediated homologous tumor homing; and facilitate real-time theranostics through MRI/magnetic particle imaging (MPI)-monitored immune cell trafficking. Preclinical validation confirms synergistic efficacy, with combinatorial regimens achieving over 50% complete tumor regression by converting immunologically cold microenvironments into inflamed states. This review systematically explores cutting-edge IONP-based innovations—spanning immune cell engineering, biohybrid systems, and energy-amplified therapies—that bridge localized tumor eradication with systemic antitumor immunity, while critically evaluating translational barriers for clinical implementation. Graphical abstract

Osteosarcoma (OS) is the most common primary malignant bone tumor in pediatric populations. Its treatment is complicated by chemotherapy-induced toxicity and limited induction of immunogenic cell death (ICD). To address these challenges, we developed a pH-responsive, multi-component nanoparticle system designed to co-deliver doxorubicin (DOX), monophosphoryl lipid A (MPLA), and a PD-1/PD-L1-targeting peptide, integrated with the immune-modulating polymer PEG-PC7A. The system was optimized using both one-factor-at-a-time (OFAT) and Box-Behnken design (BBD). The optimized nanoparticles had a hydrodynamic size of 110 nm, high encapsulation efficiency (97.15%), and pH-sensitive drug release (91% at pH 6.5). In vitro studies showed enhanced ICD markers, including calreticulin exposure and ATP/HMGB1 release, aswell as synergistic dendritic cell maturation via dual STING/TLR4 pathway activation. In an orthotopic LM8 osteosarcoma model, the nanoparticles significantly suppressed tumor growth, promoted cytotoxic T lymphocyte infiltration, reduced regulatory T cells, and established long-term immune memory. The combination of ICD induction, innate immune activation, and checkpoint blockade reprogrammed the tumor microenvironment, amplifying anti-tumor immune responses. These results demonstrate the potential of this multifunctional nanoparticle platform as an effective immunochemotherapeutic strategy for osteosarcoma, offering enhanced therapeutic efficacy and reduced systemic toxicity.

Glioblastoma (GBM) remains among the most aggressive brain malignancies, necessitating the development of novel therapeutic strategies. In this study, we designed a multifunctional magnetic-targeting nanoassembly (MnBPDF) by chelating Mn²⁺ with a dopamine-modified albumin coat, encapsulating a magnetic core constructed with magnetic Fe₃O₄ and doxorubicin. MnBPDF effectively induces oxidative stress and triggers immunogenic cell death (ICD), thereby releasing damage-associated molecular patterns that prime antigen-presenting cells (APCs) and subsequently activate tumor-specific cytotoxic T lymphocyte (CTL) responses. Moreover, Mn²⁺ simultaneously enhances the activation of cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway, triggering robust type I interferon production and amplifying antitumor immune responses. By boosting antigen presentation by dendritic cells (DCs) in the GBM microenvironment, this system promotes CTL infiltration and inhibits tumor progression. The synergistic effects of magnetic targeting, ICD induction, and enhanced immune activation highlight MnBPDF as a highly effective therapeutic strategy for GBM. Graphical Abstract

Tumor‐derived extracellular vesicles (EVs) are a class of natural nanocarriers with phospholipid bilayers that show great promise as personalized cancer vaccine platforms due to their ability to carry tumor‐specific antigens. However, their immunotherapeutic potential is hindered by limited tissue‐specific targeting. In this study, we engineered tumor cell‐derived EVs using an immunomodulatory peptide, DP7‐C, to generate DP7‐C engineered EVs (DP‐EVs). These DP‐EVs exhibited significantly enhanced accumulation in both lymph nodes and tumor tissues. Additionally, they demonstrated improved cellular uptake and facilitated more efficient endosomal escape. To further enhance the therapeutic efficacy, programmed cell death 1 ligand 1 targeting small interfering RNA (siPD‐L1) was loaded into the DP‐EVs, resulting in DP‐EVs/siPD‐L1. This formulation enabled concurrent suppression of PD‐L1 expression in both dendritic cells (DCs) and tumor cells. In vivo experiments showed that DP‐EVs/siPD‐L1 significantly inhibited tumor growth and prolonged survival in tumor‐bearing mice. The observed antitumor effect was attributed to the immune activation in the lymph nodes and the remodeling of the immunosuppressive tumor microenvironment (TME). Collectively, our findings demonstrate that DP‐EVs/siPD‐L1 functions as an effective therapeutic vaccine, which synergistically activates antitumor immunity and reverses immunosuppression through targeted PD‐L1 blockade. This engineered EV platform represents a promising and translatable strategy for cancer immunotherapy. Simple incubation with DP7‐C enables the generation of extracellular vesicles (DP‐EVs) with enhanced both tumor and lymph nodes targeting properties. DP‐EVs/siPD‐L1 can effectively inhibit tumor growth and greatly prolong the survival of tumor bearing mice through immune response activation and tumor microenvironment reprogramming.

Folate receptors can perform folate transport, cell adhesion, and/or transcription factor functions. The beta isoform of the folate receptor (FRβ) has attracted considerable attention as a biomarker for immunosuppressive macrophages and myeloid-derived suppressor cells, however, its role in immunosuppression remains uncharacterized. We demonstrate here that FRβ cannot bind folate on healthy tissue macrophages, but does bind folate after macrophage incubation in anti-inflammatory cytokines or cancer cell-conditioned media. We further show that FRβ becomes functionally active following macrophage infiltration into solid tumors, and we exploit this tumor-induced activation to target a toll-like receptor 7 agonist specifically to immunosuppressive myeloid cells in solid tumors without altering myeloid cells in healthy tissues. We then use single-cell RNA-seq to characterize the changes in gene expression induced by the targeted repolarization of tumor-associated macrophages and finally show that their repolarization not only changes their own phenotype, but also induces a proinflammatory shift in all other immune cells of the same tumor mass, leading to potent suppression of tumor growth. Because this selective reprogramming of tumor myeloid cells is accompanied by no systemic toxicity, we propose that it should constitute a safe method to reprogram the tumor microenvironment.

Background Patients with epithelial ovarian carcinoma (EOC) are usually diagnosed at an advanced stage with tumour cell invasion. However, identifying the underlying molecular mechanisms and biomarkers of EOC proliferation and invasion remains challenging. Results Herein, we explored the relationship between tumour microenvironment (TME) reprogramming and tissue invasion based on single-cell RNA sequencing (scRNA-seq) datasets. Interestingly, hypoxia, oxidative phosphorylation (OXPHOS) and glycolysis, which have biologically active trajectories during epithelial mesenchymal transition (EMT), were positively correlated. Moreover, energy metabolism and anti-apoptotic activity were found to be critical contributors to intratumor heterogeneity. In addition, HMGA1, EGR1 and RUNX1 were found to be critical drivers of the EMT process in EOC. Experimental validation revealed that suppressing EGR1 expression inhibited tumour cell invasion, significantly upregulated the expression of E-cadherin and decreased the expression of N-cadherin. In cell components analysis, cancer-associated fibroblasts (CAFs) were found to significantly contribute to immune infiltration and tumour invasion, and the accumulation of CAFs was associated with poorer patient survival. Conclusion We revealed the molecular mechanism and biomarkers of tumour invasion and TME reprogramming in EOC, which provides effective targets for the suppression of tumour invasion.

Gallbladder cancer (GBC) is a rare yet highly aggressive malignancy of the biliary tract, characterized by a five-year survival rate of less than 5%. Its asymptomatic onset and the lack of reliable early diagnostic tools contribute to delayed detection and poor clinical outcomes. Although epidemiological and genetic studies have identified numerous risk factors, the molecular mechanisms linking these factors to tumor initiation and progression remain incompletely understood. This review integrates current evidence on the multifactorial etiology of GBC—including geographic variation, genetic predisposition, environmental exposures, chronic inflammation, and infections—with emerging insights into metabolic and molecular dysregulation. Particular focus is placed on metabolic reprogramming as a central driver of carcinogenesis. Altered lipid metabolism, bile acid signaling, and redox imbalance interact with inflammatory and oncogenic pathways, fostering a permissive microenvironment for malignant transformation. Key molecular cascades include inflammation-driven NF-κB activation, bile acid–induced oxidative stress, PI3K/AKT-mediated metabolic remodeling, and DNA damage and repair defects. By consolidating diverse epidemiological and mechanistic data into a unified molecular–metabolic framework, this narrative review identifies new opportunities for biomarker discovery, metabolic imaging, early detection, and targeted therapeutic development, advancing translational research to improve outcomes in this devastating disease. Gallbladder cancer (GBC) is a rare but highly aggressive cancer that is often diagnosed too late for effective treatment. Many factors can increase the risk of developing GBC, including gallstones, chronic infections, lifestyle habits, and inherited genetic changes. This review explains how these different risk factors may work together to trigger cancer through changes in cell metabolism and molecular pathways. We describe how long-term inflammation, bile and lipid imbalance, and exposure to infections or toxins can damage cells and alter key biological processes such as energy use, signaling, and DNA repair. These disruptions can lead to uncontrolled growth and tumor development. By combining evidence from population studies and molecular research, our review highlights possible links between risk factors and metabolic changes that drive cancer. Understanding these connections may help identify early warning biomarkers and develop targeted treatments for GBC in the future.

Metabolic reprogramming is a k`ey hallmark of tumors, developed in response to hypoxia and nutrient deficiency during tumor progression. In both cancer and immune cells, there is a metabolic shift from oxidative phosphorylation (OXPHOS) to aerobic glycolysis, also known as the Warburg effect, which then leads to lactate acidification, increased lipid synthesis, and glutaminolysis. This reprogramming facilitates tumor immune evasion and, within the tumor microenvironment (TME), cancer and immune cells collaborate to create a suppressive tumor immune microenvironment (TIME). The growing interest in the metabolic reprogramming of the TME, particularly its significance in colorectal cancer (CRC)—one of the most prevalent cancers—has prompted us to explore this topic. CRC exhibits abnormal glycolysis, glutaminolysis, and increased lipid synthesis. Acidosis in CRC cells hampers the activity of anti-tumor immune cells and inhibits the phagocytosis of tumor-associated macrophages (TAMs), while nutrient deficiency promotes the development of regulatory T cells (Tregs) and M2-like macrophages. In CRC cells, activation of G-protein coupled receptor 81 (GPR81) signaling leads to overexpression of programmed death-ligand 1 (PD-L1) and reduces the antigen presentation capability of dendritic cells. Moreover, the genetic and epigenetic cell phenotype, along with the microbiota, significantly influence CRC metabolic reprogramming. Activating RAS mutations and overexpression of epidermal growth factor receptor (EGFR) occur in approximately 50% and 80% of patients, respectively, stimulating glycolysis and increasing levels of hypoxia-inducible factor 1 alpha (HIF-1α) and MYC proteins. Certain bacteria produce short-chain fatty acids (SCFAs), which activate CD8+ cells and genes involved in antigen processing and presentation, while other mechanisms support pro-tumor activities. The use of immune checkpoint inhibitors (ICIs) in selected CRC patients has shown promise, and the combination of these with drugs that inhibit aerobic glycolysis is currently being intensively researched to enhance the efficacy of immunotherapy.

Epigenetic mechanisms play vital roles not only in cancer initiation and progression, but also in the activation, differentiation and effector function(s) of immune cells. In this review, we summarize current literature related to epigenomic dynamics in immune cells impacting immune cell fate and functionality, and the immunogenicity of cancer cells. Some important immune-associated genes, such as granzyme B, IFN-γ, IL-2, IL-12, FoxP3 and STING, are regulated via epigenetic mechanisms in immune or/and cancer cells, as are immune checkpoint molecules (PD-1, CTLA-4, TIM-3, LAG-3, TIGIT) expressed by immune cells and tumor-associated stromal cells. Thus, therapeutic strategies implementing epigenetic modulating drugs are expected to significantly impact the tumor microenvironment (TME) by promoting transcriptional and metabolic reprogramming in local immune cell populations, resulting in inhibition of immunosuppressive cells (MDSCs and Treg) and the activation of anti-tumor T effector cells, professional antigen presenting cells (APC), as well as cancer cells which can serve as non-professional APC. In the latter instance, epigenetic modulating agents may coordinately promote tumor immunogenicity by inducing de novo expression of transcriptionally repressed tumor-associated antigens, increasing expression of neoantigens and MHC processing/presentation machinery, and activating tumor immunogenic cell death (ICD). ICD provides a rich source of immunogens for anti-tumor T cell cross-priming and sensitizing cancer cells to interventional immunotherapy. In this way, epigenetic modulators may be envisioned as effective components in combination immunotherapy approaches capable of mediating superior therapeutic efficacy.

Glioma is one of the most common malignant tumors of the central nervous system and is characterized by extensive infiltrative growth, neovascularization, and resistance to various combined therapies. In addition to heterogenous populations of tumor cells, the glioma stem cells (GSCs) and other nontumor cells present in the glioma microenvironment serve as critical regulators of tumor progression and recurrence. In this review, we discuss the role of several resident or peripheral factors with distinct tumor-promoting features and their dynamic interactions in the development of glioma. Localized antitumor factors could be silenced or even converted to suppressive phenotypes, due to stemness-related cell reprogramming and immunosuppressive mediators in glioma-derived microenvironment. Furthermore, we summarize the latest knowledge on GSCs and key microenvironment components, and discuss the emerging immunotherapeutic strategies to cure this disease.