The tumor microenvironment has emerged as a critical orchestrator of cancer progression, therapeutic resistance, and immune evasion, fundamentally reframing cancer as an ecosystem disease. This comprehensive review synthesizes advances in understanding the cellular and acellular architecture of the tumor microenvironment, including cancer-associated fibroblasts, tumor-associated macrophages, vasculature, and extracellular matrix remodeling. The authors examine molecular mechanisms driving immunosuppression and adaptive resistance, encompassing metabolic reprogramming, epigenetic dysregulation, and microbiome interactions. The review highlights innovative therapeutic strategies, including nanotechnology-based delivery systems, advanced immunotherapies such as CAR-T cells and oncolytic viruses, metabolic modulators, stromal normalization, and microbiome interventions. Emerging tools like patient-derived organoids, tumor-on-chip systems, and artificial intelligence-driven multi-omics analysis enable personalized therapeutic prediction, offering promising approaches to overcome intratumoral heterogeneity and therapeutic resistance challenges.

This research explores the engineering and development of exosome-based gene therapies, examining the innovative tools and methodologies employed to optimize these promising therapeutic vehicles. The article addresses critical targets for treatment and integrates artificial intelligence applications to enhance therapy design and efficacy. Exosomes, naturally occurring extracellular vesicles, offer significant advantages as delivery systems for genetic material due to their biocompatibility and capacity to cross biological barriers. The study synthesizes current advances in exosome engineering alongside emerging AI technologies to identify new therapeutic opportunities and improve treatment outcomes across various diseases, positioning these approaches as transformative solutions in precision medicine and regenerative therapeutics.

Dissecting the Tumor Microenvironment in Response to Immune Checkpoint Inhibitors via Single-Cell and Spatial Transcriptomics. Clin. Exp. Metastasis 2024 ...

More specifically, EVs derived from glioblastoma cells have been shown to promote proliferation, stemness, mesenchymal transition, and therapeutic resistance ...

This research article explores intelligent CpG nanoplatforms as innovative therapeutic agents for targeted cancer immunotherapy and immune system remodeling. The study focuses on leveraging CpG oligonucleotides—immune-stimulating molecules—delivered through advanced nanoplatform technology to enhance anti-tumor immune responses. By strategically modulating the tumor immune microenvironment and triggering immunogenic cell death, these intelligent nanoplatforms represent a promising approach to improving cancer treatment efficacy. The research contributes to the expanding field of nanomedicine-based immunotherapy, offering potential clinical applications for more effective and targeted cancer management strategies.

Proteolysis-targeting chimeras (PROTACs) represent a transformative approach to targeted protein degradation, yet their clinical development faces significant obstacles related to physicochemical properties that impede bioavailability and cellular uptake. This review examines chemistry-guided delivery strategies designed to address these limitations by integrating medicinal chemistry with advanced delivery science. Key innovations include prodrug engineering with photo-responsive and enzyme-activated mechanisms, as well as sophisticated delivery vehicles such as lipid-based nanoparticles, polymeric scaffolds, and antibody-conjugate platforms. The emergence of modular self-assembly and membrane-targeting approaches demonstrates progress toward programmable therapeutics that optimize both target selectivity and pharmacokinetic performance, promising to accelerate PROTAC transition into clinical applications.

Glioblastoma remains a devastating malignancy with poor prognosis despite current treatments. Oncolytic viruses represent a promising immunotherapeutic approach, engineered to induce tumor cell death while stimulating antitumor immune responses. However, their clinical efficacy is hampered by delivery challenges, including the blood-brain barrier and complex tumor microenvironment. Hydrogels, composed of natural and synthetic polymers, offer a solution by enabling sustained therapeutic payload delivery and facilitating combination therapies with immune checkpoint inhibitors. This review examines advances and obstacles in oncolytic virus therapy, explores hydrogel-mediated delivery mechanisms, and discusses opportunities for hydrogel-based oncolytic virus and immune adjuvant combinations in treating glioblastoma and other high-grade brain tumors.

This comprehensive review examines the complex cellular landscape of the tumor microenvironment through single-cell atlas analysis. The article provides detailed insights into specialized cell subtypes and their coordinated network interactions that collectively influence tumor behavior and progression. By integrating single-cell sequencing data, researchers identify previously unknown cellular populations and elucidate their functional roles within tumors. The study emphasizes the immunological aspects of the microenvironment, with particular focus on how understanding these cellular networks can inform and enhance immunotherapy approaches. This open-access publication contributes significantly to advancing precision medicine by mapping cellular heterogeneity and therapeutic vulnerabilities in cancer biology.

This research article explores intelligent CpG nanoplatforms as an innovative approach to targeted cancer immunotherapy and immune microenvironment remodeling. The study, authored by Wang, Zhang, and Zhou, examines how CpG oligonucleotides integrated into nanoplatform systems can enhance immunogenic cell death and strengthen anti-tumor immune responses. By leveraging nanotechnology to deliver immunostimulatory agents directly to tumor sites, these intelligent platforms represent a significant advancement in precision oncology. The work addresses the critical challenge of modulating the tumor immune microenvironment to overcome immunosuppression, thereby improving therapeutic efficacy. This research contributes valuable insights into the development of next-generation cancer treatments that combine nanotechnology with immunological principles.

This article examines nano-immunotherapy strategies targeting tumor-associated macrophages (TAMs), which play a critical role in creating an immunosuppressive tumor microenvironment. Nano-drug delivery systems have emerged as multimodal platforms capable of delivering multiple drugs synergistically while incorporating physical energy interventions, thereby improving drug targeting and biocompatibility. The primary focus of TAM-targeted nano-immunotherapy is the precise regulation and functional remodeling of TAMs to reverse immunosuppression and inhibit cancer progression. The review addresses current knowledge gaps and challenges in this emerging field while exploring recent advances in nano-immunotherapy approaches specifically designed to modulate TAM function.

Researchers have developed innovative smart polymeric nanoparticles that respond to specific tumor microenvironment signals to deliver immunotherapy with precision, addressing a critical challenge in cancer treatment. These nanoparticles activate in response to acidic pH, elevated enzymes, reactive oxygen species, and other tumor-specific markers, triggering controlled drug release directly at cancer sites. The breakthrough converts immunologically 'cold' tumors, which lack immune cell infiltration and resist standard therapies, into 'hot' tumors capable of immune response. This targeted approach significantly enhances antitumor immunity while minimizing systemic toxicity and off-target effects associated with conventional immunotherapies. The advancement promises to extend effective cancer treatment to patient populations previously unresponsive to existing immunotherapy options.

Glioblastoma multiforme remains one of the most challenging brain tumors to treat, with limited drug efficacy largely due to the blood-brain barrier's impermeability and tumor heterogeneity. Despite FDA approval of only a few agents including temozolomide and bevacizumab, therapeutic outcomes remain modest and drug resistance persists. Biomaterial-based delivery systems have emerged as promising alternatives, leveraging their biodegradability and capacity to enhance blood-brain barrier penetration while promoting drug accumulation at tumor sites. This review comprehensively examines natural and synthetic biomaterials, evaluating their physicochemical properties, advantages for fabricating delivery systems, and limitations in preclinical and clinical applications. Additionally, it provides an extensive overview of biomaterials functionalized with therapeutic agents, detailing their composition and delivery strategies to improve glioblastoma treatment efficacy.

Stimuli-responsive nanogels represent an innovative approach to cancer therapeutics, functioning as intelligent drug delivery systems that activate in response to specific tumor microenvironment conditions. These nanocarriers exhibit enhanced precision by releasing anticancer medications only when exposed to targeted stimuli such as pH variations, temperature changes, or enzymatic activity characteristic of malignant tissues. This selective activation mechanism minimizes systemic exposure and reduces adverse effects on healthy cells, thereby improving therapeutic efficacy and patient outcomes. The review comprehensively examines current advancements in nanogel design, synthesis methodologies, and clinical applications, providing valuable insights for oncology and nanomedicine research. The open-access publication facilitates broad accessibility for researchers and practitioners seeking to advance intelligent drug delivery strategies.

This article explores the development of intelligent CpG nanoplatforms as a novel approach to targeted cancer immunotherapy. The research focuses on leveraging CpG oligonucleotides to trigger immunogenic cell death and enhance anti-tumor immune responses. These advanced nanoplatforms are designed to remodel the tumor immune microenvironment, creating conditions unfavorable to cancer cell survival. By combining nanotechnology with immunological principles, this work represents a significant advancement in precision medicine for cancer treatment. The study demonstrates how strategic manipulation of immune pathways through intelligent delivery systems can improve therapeutic efficacy while potentially minimizing systemic side effects associated with conventional cancer treatments.

Extracellular vesicles as drug and gene delivery vehicles in central nervous system diseases. Sci. 2025, 13, 1161–1178. https://doi.org/10.1039/D4BM01394H.

Pharmaceutical science is advancing toward precision medicine through the development of stimuli-responsive drug delivery systems that overcome limitations of conventional formulations, including poor bioavailability and non-specific distribution. These intelligent systems, composed of functional polymers, lipids, and nanostructures, dynamically adjust their physicochemical properties in response to endogenous or exogenous stimuli such as pH, temperature, and glucose levels. By mimicking biological feedback mechanisms, stimuli-responsive delivery systems enable targeted, on-demand drug release particularly beneficial for cancer treatment, endocrinology, and regenerative medicine. This bioresponsive approach represents a significant paradigm shift in controlled drug delivery, offering programmable release kinetics that enhance therapeutic efficacy and patient outcomes through intelligent, adaptive formulation design.

Researchers have developed AI-designed protein-lipid hybrid nanoparticles (PLHNs) to address limitations of conventional cancer therapies, including poor drug specificity and systemic toxicity. These innovative nanoparticles combine the biocompatibility and drug-loading capacity of lipid carriers with the biological recognition capabilities of proteins, offering improved stability and controlled drug release. Artificial intelligence optimizes PLHN design by predicting ideal lipid-protein combinations, particle characteristics, and targeting ligand selection, eliminating inefficient trial-and-error experimentation. The hybrid systems employ both passive targeting through the enhanced permeability and retention effect and active targeting via protein-mediated receptor recognition, enabling precise therapeutic delivery to cancer cells while extending applications to other complex diseases.

Quantum nanomaterials are transforming precision medicine through their unique optical, electronic, and magnetic properties derived from quantum confinement effects. Semiconductor quantum dots, carbon quantum dots, and graphene-based nanostructures demonstrate exceptional characteristics including size-dependent fluorescence, sharp emission spectra, and ultra-high sensitivity. These properties enable critical applications in bioimaging, biosensing, targeted drug delivery, and theranostic platforms. In diagnostics, quantum dots provide superior sensitivity for detecting disease biomarkers, facilitating early diagnosis and personalized medicine approaches. Therapeutically, these nanomaterials function as drug and gene carriers, photodynamic agents, and multifunctional platforms that seamlessly integrate imaging with therapeutic modalities, advancing integrated treatment strategies.

Researchers have developed a novel vitamin B12-based therapy called nitrosylcobalamin (NO-Cbl) that demonstrates promising tumor-targeting potential against glioblastoma multiforme, one of the most lethal and treatment-resistant brain cancers. The breakthrough addresses a critical challenge in glioblastoma treatment: the blood-brain barrier's impermeability to most anticancer drugs. Through comprehensive pharmacokinetic studies and cell line experiments, scientists found that NO-Cbl selectively penetrates the blood-brain barrier and effectively targets glioblastoma tissue. Notably, the therapy exhibited synergistic effects when combined with existing treatments including TRAIL and temozolomide, suggesting enhanced anticancer activity. These findings offer significant clinical potential, as current glioblastoma patients typically survive fewer than fifteen months despite aggressive multimodal treatment approaches.

Gliomas, particularly glioblastoma, secrete extracellular vesicles that mediate tumor microenvironment communication and drive immunotherapeutic resistance. These vesicles carry immunosuppressive cargoes including PD-L1, non-coding RNAs, and metabolic regulators, capable of crossing the blood-brain barrier to modulate both local and systemic immunity. Glioma-derived extracellular vesicles promote myeloid-derived suppressor cell expansion, polarize tumor-associated macrophages toward immunosuppressive phenotypes, impair dendritic cell antigen presentation, and induce T-cell dysfunction. Enriched non-coding RNAs within these vesicles regulate critical signaling pathways involved in immune suppression. Understanding these EV-mediated mechanisms offers potential therapeutic targets for overcoming immunotherapeutic resistance in glioma patients through combined immune and metabolic intervention strategies.