Boron neutron capture therapy (BNCT) is a novel and emerging form of radiotherapy that combines the advantages of "heavy ion radiotherapy" and "biological targeting". The therapeutic potential of BNCT is ultimately constrained by precise and efficient delivery of boron drugs. In this review, we systematically trace from conventional boron drugs to sophisticated nano-delivery platforms, emphasizing breakthroughs in carrier engineering, targeted delivery strategies, and multifunctional synergistic systems. A dedicated analysis of the biological foundations, such as cell cycle dynamics, tumor microenvironmental interactions, and immunostimulatory effects, provides a crucial framework for understanding mechanism-informed biomaterial design. By synthesizing current advances with an outlook on future challenges, this work aims to chart a course for translating innovative boron-loaded biomaterials from the laboratory into clinical reality, thereby unlocking the full promise of BNCT.

The clinical efficacy of targeted cancer therapies is persistently undermined by the emergence of acquired resistance. While secondary genetic mutations are well-characterized, increasing evidence implicates non-genetic metabolic reprogramming as a primary driver of survival during the initial phase of treatment. This review elucidates the concept of "Metabolic Shapeshifters"-specifically, drug-tolerant persister cells (DTPs) that dynamically adapt their bioenergetic machinery to evade therapeutic stress. We examine the plasticity between the classical Warburg Effect and the Reverse Warburg Effect, describing how DTPs shift from a glucose-addicted proliferative state to a quiescent phenotype strictly reliant on mitochondrial oxidative phosphorylation (OXPHOS) and fatty acid oxidation. Crucially, we highlight a paradigm shift from intracellular reprogramming to intercellular "organelle parasitism." Recent breakthroughs demonstrate that DTPs actively hijack functional mitochondria from infiltrating immune cells and the stromal network via tunneling nanotubes (TNTs). This predatory behavior not only restores the tumor's respiratory capacity but also induces metabolic exhaustion in T cells, thereby orchestrating immune evasion. Finally, we delineate emerging therapeutic strategies designed to dismantle this metabolic fortress. By targeting the "Achilles' heel" of mitochondrial dependency, disrupting the physical infrastructure of organelle hijacking, and revitalizing immunometabolism, we propose a multi-pronged framework to eradicate DTPs and prevent clinical relapse.

Triple negative breast cancer (TNBC) poorly responds to immune checkpoint blockade (ICB) therapy. Dormant tumor cells are recognized as immunotherapy-resistant reservoirs that may lead to tumor relapse, although the underlying mechanisms remain to be fully elucidated.

Public scRNA-seq data was employed to identify dormant tumor cells in TNBC patients receiving ICB therapy. A TetOn-H2BeGFP system was used to label and track dormant tumor cells both in vivo and in vitro. CCK-8, colony formation, and PI staining assay were performed to identify CEBPB as a key factor in tumor dormancy maintenance. The role of CEBPB in immune evasion was evaluated by macrophage and CD8⁺ T cell proportions in tumors, via flow cytometry, immunohistochemistry, and multiplex immunofluorescence assays. RNA-seq and ChIP-seq were further employed to identify downstream targets of CEBPB, and ChIP-qPCR, qPCR, and Western blot were used to further validate these results.

We demonstrated that dormant tumor cells were resistant to ICB and resided within an immunosuppressive niche, characterized by increased M2 macrophages and reduced CD8⁺ T cell infiltration. CEBPB was identified as highly expressed in dormant tumor cells, where it maintained tumor dormancy by transcriptionally activating cell cycle negative regulators, particularly CCNG2. Notably, high CEBPB expression orchestrated a tumor-supportive microenvironment with macrophage recruitment, M2 macrophage polarization, and T cell suppression. Mechanistically, S100A8 was recognized as a key transcriptional target of CEBPB to promote M2 macrophage polarization. Targeting either CEBPB or S100A8 could overcome ICB resistance and remodel the tumor microenvironment.

Our study demonstrate a mechanistic link between tumor dormancy and immune evasion, highlighting the CEBPB-S100A8 axis as a promising therapeutic target to potentiate ICB efficacy in TNBC.

Biomimetic nanovaccines have recently emerged as a frontier in vaccine development. These nanovaccines are designed to structurally and morphologically mimic natural pathogens, including bacteria, viruses, and certain eukaryotic cells. Engineered to replicate pathogenic surface characteristics, these nanoplatforms improve targeted delivery to antigen-presenting cells (APCs) and prolong systemic circulation, which in turn enhances antigen presentation and promotes stronger adaptive immune activation. The preparation process for biomimetic nanovaccines is also highlighted, involving isolating and purifying source cell membrane, encapsulation of synthetic nanoparticle core, and verifying. Additionally, this study offers a thorough evaluation of various biomimetic nanovaccines, particularly those with cell membrane coatings derived from tumor cells, immune cells, or bacteria. Furthermore, we also assess their capabilities when combined with common treatment modalities, including immune checkpoint inhibitors, chemotherapy, and photothermal therapy, to achieve anti-tumor effects. The study also discusses the path to clinical translation and existing challenges in manufacturing, safety, and regulatory approval.

Gallbladder cancer (GBC) has poor prognosis, is primarily treated with gemcitabine-based chemotherapy, which is limited by gemcitabine correlates with GBC progression. This study investigate the role of Globo H ceramide (GHCer) in GR and explore whether targeting Glob H could overcome resistance.

Globo H expression was assessed by immunohistochemistry in 81 GBC samples. GHCer-induced GR and ABCG2 upregulation were assessed in GBC cell lines, patient-derived xenograft (PDX), and a thioacetamide (TAA)-induced rat cholangiocarcinoma model. A2AR/cAMP/PKA signaling involvement was examined using inhibitors and siRNA. The efficacy of anti-Globo H antibody (mAb VK9) or vaccine (OBI-833/OBI-821) combined with gemcitabine was evaluated in vitro and in vivo. Immune responses were assessed by ELISA and multiplex immunohistochemistry.

High Globo H expression correlated with shorter survival in GBC patients receiving gemcitabine. GHCer promoted GR via A2AR/cAMP/PKA-mediated ABCG2 upregulation, which was reversed by mAb VK9 or pathway inhibition. mAb VK9 or OBI-833/821 enhanced gemcitabine efficacy in GBC PDX and TAA cholangiocarcinoma models. OBI-833/821 induced anti-Globo H IgG/IgM, reduced Foxp3⁺ Tregs, and increased CD161⁺ NK cells in TAA model. A compassionate clinical use of 833/821 led to stable disease.

GHCer promotes GR by upregulating ABCG2 via A2AR/cAMP/PKA signaling. Targeting Globo H may improve chemotherapy response in GBC.

Therapy resistance remains a critical challenge in colon adenocarcinoma (COAD). The dysregulation of programmed cell death (PCD) pathways significantly influences therapeutic response, but its integrated role in shaping the tumor microenvironment (TME) and driving clinical heterogeneity in COAD is poorly defined.

We established a Programmed Cell Death-related Subtype (PCDS) classification by integrating 12 PCD pathways across transcriptomic data from 1,140 COAD patients using non-negative matrix factorization (NMF). The subtypes were validated in independent RNA-sequencing cohorts. We characterized the genomic, TME, and therapeutic features of each PCDS using multi-omics data analysis, and computational drug repositioning. Molecular docking and in silico drug sensitivity analyses were employed to evaluate candidate drugs.

We identified three robust subtypes, including PCDS1 (immune-activated), PCDS2 (WNT and TP53 signaling activation), and PCDS3 (mesenchymal and T-cell dysfunction/exclusion). PCDS3, enriched with inflammatory cancer-associated fibroblasts (iCAFs), exhibited the poorest prognosis and dual resistance to both chemotherapy and immunotherapy (>80% non-response). Analysis of single-cell and spatial transcriptomics data revealed the activation of MDK-SDC2 ligand-receptor axis between tumor cells and fibroblasts in PCDS3, spatially associated with T-cell dysfunction and exclusion. Computational drug repositioning identified the sunitinib as having selective potency against PCDS3 tumors, showing significantly lower IC50 values and high-affinity binding to SDC2 in molecular docking.

This study defines a novel molecular subtype for COAD, linking PCD dysregulation to distinct TME remodeling and therapeutic outcomes. Targeting the MDK-SDC2 axis with agents such as sunitinib may offer a promising strategy to overcome stromal-mediated immunotherapy resistance in the most lethal PCDS3 tumors.

Traditional cancer vaccines that utilize peptides or proteins often exhibit limited efficacy as a result of mutations in cancer antigenic epitopes, also known as antigenic drift, which reduce the ability of traditional vaccines to target tumor antigens and elicit robust immune response.

To address these challenges, we propose an innovative and universal strategy for dendritic cell (DC)-targeted neoepitope delivery via proximity-induced conjugation (PIC). This approach enables the site-specific crosslink of a broad spectrum of neoepitopes tailored to diverse cancer types, thereby increasing both vaccine flexibility and applicability. The PIC method involves the use of recombinant Fc-affinity peptides that are modified with two distinct unnatural amino acids: the photoreactive amino acid p-benzoyl-L-phenylalanine (pBPA) and the bioorthogonal reactive amino acid 4-fluorophenyl carbamate lysine (FPheK). These modified peptides allow for the precise conjugation of neoepitopes through ultraviolet (UV) irradiation or mild incubation, thereby achieving controlled antigen coupling.

Through optimization of this strategy, we observed a substantial increase in DCs mediated antigen uptake and processing, leading to enhanced T cell activation, a robust cytotoxic immune response, and significant improvements in antitumor efficacy. Moreover, the DC-targeted vaccine exhibited promising synergistic effects with an immune checkpoint inhibitor (ICI), resulting in a marked reduction in tumor growth and prolonged survival in preclinical models.

These findings underscore the potential of the PIC-based DC-targeted vaccine system to augment the immunogenicity, versatility, and therapeutic efficacy of cancer vaccines. This strategy offers a compelling solution to the challenges posed by antigenic drift and mutation, thereby improving clinical outcomes across a broad range of cancers.

Clear cell renal cell carcinoma (ccRCC) is predominantly treated with anti-angiogenic therapies (AATs), such as sunitinib and axitinib. While these therapies initially improve outcomes, resistance frequently emerges, limiting long-term efficacy. Understanding the molecular mechanisms underlying AAT resistance is essential to optimize treatment strategies.

To identify factors involved in AAT resistance, we performed integrated transcriptomic and proteomic analyses on ccRCC cell lines subjected to either transient AAT treatment or with established acquired resistance. Functional validation was performed using in vitro assays (proliferation, migration, invasion) and in vivo zebrafish models. Plasma levels of candidate proteins were also measured in ccRCC patients and correlated with clinical outcomes.

Connective Tissue Growth Factor (CTGF) was consistently upregulated following treatment and in resistant cell lines. CTGF, a secreted protein regulated by Yes-associated protein (YAP) in the Hippo pathway, is known to promote angiogenesis, fibrosis, and tumor progression. Functionally, CTGF enhanced tumor cell aggressiveness in vitro and in vivo. Patient-derived samples also exhibited elevated CTGF levels in resistant tumors. Crucially, higher plasma CTGF levels were associated with shorter progression-free survival in ccRCC patients receiving AATs.

CTGF is a key mediator of resistance to AATs in ccRCC, by promoting tumor progression and remodeling the tumor microenvironment. CTGF may thus serve as both a predictive biomarker and a therapeutic target. These findings support further investigation of CTGF inhibition as a strategy to overcome AAT resistance and improve treatment outcomes in ccRCC patients.

Metal-organic frameworks (MOFs) are a unique class of porous materials constructed from metal-containing nodes, known as secondary building units (SBUs) and organic ligands. Their highly tunable structures enable the encapsulation of a broad range of therapeutic agents, spanning small-molecule chemotherapeutics to biomacromolecules such as proteins, DNA, and RNA. By rational selection of metal ions and organic linkers, diverse functionalities, including molecular imaging and phototherapeutic capabilities, can be included into MOFs, rendering them promising nanoscale platforms of nanomedicines. In this review, we summarize recent advances of MOFs for drug delivery, cancer imaging and theranostics. We discuss the progress in regulating the morphology and functions of MOFs through diverse synthetic strategies and surface modification approaches. We further systematically analyzed and discussed MOFs in the applications of drug delivery, molecular imaging, and cancer theranostics, with recent strategies. Finally, key limitations associated with the clinical translation of MOFs are discussed, along with the corresponding bottlenecks, future challenges, and emerging opportunities.

Ovarian cancer (OC), particularly high-grade serous ovarian cancer (HGSOC), is among the most lethal gynecologic malignancies, with its therapeutic challenges primarily stemming from a distinctly immunosuppressive tumor immune microenvironment (TIME). Neoadjuvant chemotherapy (NACT) has emerged as a crucial treatment strategy for advanced ovarian cancer; nevertheless, its impact on the tumor microenvironment-especially on tumor-infiltrating lymphocytes (TILs)-is not yet fully understood. As central mediators of antitumor immune responses, the density, composition, and dynamic changes of TILs are strongly associated with chemotherapy response and patient prognosis. Notably, spatial omics studies further revealed that, after NACT, a subset of CD8+ T cells can be confined within "myelonets" microdomains organized by myeloid cells, where interactions such as NECTIN2-TIGIT impose spatial restriction and induce functional exhaustion of T cells, thereby compromising their effective tumor killing. This review aims to systematically summarize the baseline characteristics and heterogeneity of lymphoid- and myeloid-derived TILs in ovarian cancer, elucidate the mechanisms underlying immune remodeling induced by NACT and their complex relationships with clinical outcomes, and further discuss combination therapeutic strategies and biomarker development based on dynamic TIL changes to enhance the clinical application of precision immunotherapy.