Chlorella-based bioactive oxygen generator for sustained tumor hypoxia alleviation and combined-modality tumor therapy.

Mitochondria-targeted carbon monoxide delivery nanoplatform for enhanced cancer immunotherapy through metabolic-immune reprogramming.

Tumor microenvironment and immunometabolic reprogramming in pancreatic ductal adenocarcinoma: Barriers and breakthroughs in immunotherapy.

Chimeric antigen receptor T-cell therapy for solid tumors: A review of the intricate mechanisms and potential strategies.

Rationale: The efficacy of radiotherapy in triple-negative breast cancer (TNBC) is often limited by an immunosuppressive tumor microenvironment (TME), requiring high radiation doses that cause systemic toxicity. There is a critical need for theranostic strategies capable of guiding therapy and amplifying the efficacy of low-dose radiation. Methods: We developed a multifunctional organolutetium nanosensitizer (LSPA) for image-guided, low-dose radioimmunotherapy. Lutetium (Lu) serves as both a contrast agent for CT imaging and a radiosensitizer through the generation of reactive oxygen species (ROS). The LSPA nanoparticles were engineered to selectively accumulate in tumors and release their therapeutic payload in response to the acidic TME. Results: At a low 6 Gy X-ray dose, LSPA synergized with the PARP inhibitor Olaparib to induce extensive DNA damage. This activated the cGAS-STING pathway and remodeled the TME. The treatment promoted immunogenic cell death, dendritic cell maturation, and M1 macrophage repolarization. It also decreased regulatory T cells, leading to increased CD4+ and CD8+ T cell infiltration in both primary and metastatic tumors. Conclusion: This theranostic strategy suppressed primary and distant (abscopal) tumors, prevented recurrence, and established durable immune memory with low-dose irradiation. Our findings present a clinically translatable approach that combines a nanosensitizer with PARP inhibition to turn immunologically "cold" tumors into "hot" ones, thereby enhancing the efficacy of low-dose radioimmunotherapy while limiting systemic toxicity.

Ultrasound-activated piezoelectric BZT Nanocubes mediate direct Piezocatalytic killing and reverse immunosuppressive tumor microenvironment for effective hepatocellular carcinoma therapy.

Chimeric antigen receptor (CAR) T cell therapy has emerged as a promising immunotherapy for central nervous system (CNS) tumors, despite the unique biological barriers posed by the blood-brain barrier (BBB) and immunosuppressive tumor microenvironment (TME). This chapter comprehensively reviews the evolution of CAR designs, gene delivery methods using lentiviral vectors (LVVs), and clinical applications for CNS tumors. We discuss current issues in CAR-T cell therapy for CNS tumors, while highlighting the strategies about new CAR designs and novel delivery methods to overcome these issues.

Targeting DRP1 promotes radiotherapy-induced antitumor immunity via mitochondrial DNA-mediated cGAS-STING signaling in KRAS-mutated colorectal cancer.

Dual PI3Kδ/γ inhibition enhances radiotherapy-induced antitumor immunity via macrophage-dependent cGAS-STING-type I interferon signaling.

Exostosin glycosyltransferase 1 (EXT1) and exostosin glycosyltransferase 2 (EXT2) catalyze heparan sulfate chain elongation and are increasingly implicated in cancer biology, but their roles in gliomas remain incompletely defined. Here, we performed an integrative multi-omics analysis to dissect the transcriptional, epigenetic, and microenvironmental landscape of EXT1 and EXT2 across gliomas. Bulk transcriptomic data from The Cancer Genome Atlas (TCGA) and the Chinese Glioma Genome Atlas (CGGA) revealed that both EXT1 and EXT2 are upregulated in high-grade gliomas and associate with adverse survival, with EXT1 showing the strongest and most consistent prognostic impact. Gene set enrichment analysis (GSEA) and gene set variation analysis (GSVA) indicated that EXT1-high tumors are enriched for DNA damage and replication stress programs, cell cycle progression, inflammatory response, and stromal activation pathways, whereas EXT2 expression is preferentially linked to extracellular matrix remodeling, cytoskeletal organization and angiogenesis-related signaling. Single-cell RNA sequencing and Immune deconvolution using Cell-type Identification By Estimating Relative Subsets Of RNA Transcripts (CIBERSORT) and Estimation of STromal and Immune cells in MAlignant Tumor tissues using Expression data (ESTIMATE) showed that EXT1 correlates with increased stromal and immune scores, and reduced cytotoxic T cell signatures, consistent with an immunosuppressive tumor microenvironment. EXT2 expression is enriched in gliomas with pronounced vascular and mesenchymal features, supporting a complementary role in invasive growth and tissue remodeling. Immunohistochemistry on a glioma tissue microarray validated the upregulation of EXT1 protein in high-grade tumors. The study findings identified EXT1 as a central glycosylation-linked regulator of replication stress tolerance and immune remodeling in gliomas, and suggest that EXT2 contributes to extracellular matrix and cytoskeletal reprogramming. The exostosin axis represents a promising source of prognostic biomarkers and potential therapeutic targets in glioma.

Triple-negative breast cancer (TNBC) poses major treatment difficulties because of its aggressive behavior, the absence of targetable receptors, resistance to chemotherapy, and an immunosuppressive tumor microenvironment (TME) promotes that metastasis....

In situ cancer vaccination mediated by sonodynamic therapy (SDT) has demonstrated considerable potential, however its efficacy is often suboptimal by low immunogenicity of tumor and the immunosuppressive tumor microenvironment. Herein,...

Polymer-based nanomedicines: Supporting multimodal approaches to glioblastoma multiforme treatment.

Rationale: Radiotherapy is a principal modality in cancer treatment, effectively controlling local tumor growth and possessing the potential to enhance the immunogenicity of tumor cells, thereby improving the antitumor immunity. However, its efficacy is often limited by insufficient production of reactive oxygen species (ROS), tumor hypoxia, and the immunosuppressive tumor microenvironment (TME). Therefore, developing strategies to amplify ROS and reshaping the hypoxic, immunosuppressive TME is crucial for advancing radiotherapy.Methods: In this study, we designed a polyethylene glycol (PEG)-modified gold@manganese dioxide core-shell nanoparticle (GMCN@PEG) that is responsive to the acidic TME. We then investigated its ability to enhance radiotherapy and magnetic resonance-computed tomography (MR-CT) dual-modality imaging both in vivo and in vitro.Results: GMCN@PEG exhibits good biocompatibility under neutral physiological conditions and, upon exposure to the acidic TME, it alleviates tumor hypoxia and amplifies ROS production. This leads to enhanced radiotherapy sensitivity and the induction of immunogenic cell death (ICD). Furthermore, GMCN@PEG activates the cGAS-STING signaling pathway, promoting dendritic cells (DCs) maturation, macrophages M1 polarization, and T cells infiltration, effectively counteracting the immunosuppressive state within the TME. Additionally, GMCN@PEG enhances dual-modality imaging through MR-CT, achieving the integration of diagnosis and therapy.Conclusion: In summary, GMCN@PEG as a multifunctional nanosensitizer, demonstrate significant potential and promise in improving the efficacy of radiotherapy, reshaping the tumor microenvironment, promoting antitumor immunity, and biomedical imaging enhancement.

Histological Categorization of Desmoplastic Reaction in Triple-Negative Breast Cancer: Its Relevance to Neoadjuvant Chemoimmunotherapy Response and Tumor Biology.

Over the past decade, CAR-T cell therapy has achieved remarkable success in treating hematological malignancies. However, traditional CAR-T cell engineering employs viral vectors, which has several limitations. Additionally, the immunosuppressive tumor microenvironment, particularly mediated by the PD-1/PD-L1 pathway, significantly restricts CAR-T cell efficacy. CRISPR/Cas9-mediated PD-1 knockout can enhance CAR-T cell anti-tumor activity, but traditional electroporation (EP) method often damages T cells. Herein, a novel lipid nanoparticles (LNPs)-mediated delivery technology are introduced to engineer CAR-T cells. The LNPs platform enables the simultaneous expression of CAR cassette and CRISPR/Cas9 gene editor in T cells via co-delivery of multiplex RNAs (CD19 CAR mRNA+Cas9 mRNA+sgRNA targeting PD-1). Importantly, LNPs exhibit higher transfection efficiency and superior cell viability compared to traditional electroporation method. The engineered CAR-T cells with PD-1 knockout, which express anti-CD19 CAR, can specifically kill CD19+ Nalm-6 tumor cells in vitro and display enhanced anti-tumor activity in vivo. Furthermore, LNPs-mediated co-delivery of Cas9 mRNA and sgRNAs targeting PD-1, TRAC, and B2M enables triple-knockout of T cells with high editing efficiencies (76% for PD-1, 86% for TRAC, and 80% for B2M), highlighting the ability for multiplex gene editing. This LNP-mediated delivery strategy has great potentials for the development of safer and more efficacious CAR-T cells.

Lung cancer remains one of the most lethal malignancies worldwide. Despite recent advances, current immunotherapies are often limited by the immunosuppressive tumor microenvironment and insufficient local immune activation. Herein, we...

A controllable self-amplifying oxidative stress strategy for boosting noninvasive sonodynamic therapy and synergistic immunotherapy.

Gold-embedded yolk-shell mesoporous organosilica nanocomposite for microwave-enhanced targeted chemotherapy and immune modulation in hepatocellular carcinoma.

Molecular regulation and therapeutic targeting of programmed cell death in hepatocellular carcinoma.