Immune checkpoint (IC) pathways, originally identified in T-cell exhaustion in cancer, are increasingly recognized as key modulators of immune tolerance in autoimmune diseases (ADs). In ADs, these molecules function more accurately as inhibitory receptors (IRs) that fine-tune, rather than inducing classical exhaustion phenotypes, autoreactive immune cells. Unlike oncology, where checkpoint blockade enhances immunity, AD therapy aims to restore tolerance through IC agonism or immune reset approaches (e.g., CAR-T cells). This review synthesizes recent advances in targeting CTLA-4, PD-1, LAG-3, TIM-3, and TIGIT. Clinical success with CTLA-4-Ig (abatacept) and emerging efficacy of PD-1 agonists (e.g., peresolimab) provide proof-of-concept that augmenting inhibitory signaling can ameliorate autoimmunity. However, outcomes remain context-dependent, reflecting interplay between effector and regulatory subsets and tissue-specific environments. Mechanistic challenges, including multivalent receptor engagement, ligand complexity, and signaling heterogeneity (e.g., ITIM/ITSM phosphorylation), limit current approaches. Insights from immune-related adverse events (irAEs) highlight shared pathways of dysregulation and inform risk-benefit considerations. A major translational gap persists between acute transplant models and chronic autoimmunity, and validated predictive biomarkers are lacking. Beyond T cells, B cells, dendritic cells, and innate populations expand therapeutic opportunities. Future progress will require multi-omics profiling, biomarker-driven stratification, and next-generation agonist design. IC-targeted strategies hold promises but demand context-aware, mechanistically informed development for broad clinical impact in ADs.

Polycystic ovary syndrome (PCOS) is a prevalent endocrine-metabolic disorder among women of reproductive age, defined by the core features of hyperandrogenism, ovulatory dysfunction, and polycystic ovarian morphology. PCOS is frequently complicated by insulin resistance, obesity, dyslipidemia, and chronic low-grade inflammation, which substantially impair patients' reproductive health, metabolic homeostasis, and quality of life. Although the etiology of PCOS remains incompletely elucidated, accumulating evidence indicates that gut microbiota and their metabolites participate in the pathogenesis and progression of PCOS via metabolic, immune, and neuroendocrine pathways. Focusing on the gut-ovary axis, this review systematically summarizes the molecular mechanisms by which gut microbial metabolites mediate PCOS-related pathological processes, as well as potential intervention strategies.

This article is a narrative review. To ensure comprehensive literature coverage, we searched the PubMed, Embase, Web of Science, and Cochrane Library databases from their inception to June 30, 2026. Search terms included polycystic ovary syndrome, PCOS, gut microbiota, gastrointestinal microbiota, microbial metabolites, short-chain fatty acids, bile acids, lipopolysaccharide, branched-chain amino acids, tryptophan metabolism, gut-ovary axis, probiotics, prebiotics, postbiotics, and fecal microbiota transplantation. Original basic research, clinical observational studies, randomized controlled trials, systematic reviews, meta-analyses, and clinical guidelines related to PCOS and gut microbiota were prioritized for inclusion. Content lacking clear support from primary literature, with evidence limited to other disease models, or involving excessive mechanistic extrapolation was either excluded or interpreted conservatively.

The oral-lung axis describes microbial and inflammatory exchange between the oral cavity and the lower respiratory tract. Its relevance to lung cancer is supported by the detection of oral-associated taxa in lower-airway samples, epidemiological links between periodontal disease and lung cancer risk, and experimental evidence that microbial signals can modify epithelial proliferation and antitumor immunity. This review integrates epidemiological, ecological, mechanistic, and translational evidence while distinguishing oral-associated or source-linked observations from pulmonary and intratumoral mechanisms in which oral origin has not been demonstrated. Particular attention is given to repeated microaspiration, Th17/IL-17 inflammation, NOD2/NF-κB and PI3K/ERK signaling, microbial metabolites, and remodeling of the tumor immune microenvironment. Recent studies of pulmonary nodules, radiotherapy, and immune checkpoint inhibition extend this field from disease association to clinically testable questions. The available evidence is most consistent with context-dependent tumor promotion and treatment-response modulation, rather than independent microbial initiation of human lung cancer. We conclude by defining the source-tracking, analytical, prospective, and interventional studies needed to establish causality and clinical utility.

Triple-negative breast cancer is an aggressive, biologically heterogeneous subtype with limited targeted therapies. Immunotherapy improves outcomes in selected patients, but durable benefit is limited by inter- and intratumoral heterogeneity, imperfect biomarkers, and primary or acquired resistance. This review integrates evidence from major positive and negative trials, molecular subgroup studies, predictive biomarkers, and tumor immune microenvironment research to assess current standards and unresolved challenges. Immune checkpoint blockade plus chemotherapy is now standard for high-risk early-stage TNBC and PD-L1-positive metastatic disease, although benefit varies by disease setting, assay, and immune phenotype. Biomarkers such as PD-L1 and tumor-infiltrating lymphocytes provide useful but incomplete guidance because of methodological differences, spatiotemporal heterogeneity, and treatment-induced changes. The central clinical challenge is to identify which patients require intensified immune-based combinations and which are unlikely to benefit from checkpoint blockade alone. We propose a precision immunotherapy framework that integrates TNBC molecular subgroups, validated and dynamic biomarker models, rational combinations, resistance mechanisms, and emerging tools, including single-cell sequencing, spatial transcriptomics, multi-omics, and AI-assisted stratification. This strategy may improve response durability while reducing unnecessary toxicity.

The extracellular matrix (ECM) is a dynamic and functionally active component of the tumor microenvironment that critically regulates immune cell trafficking, activation, and persistence. Rather than serving solely as a structural framework, ECM remodeling through collagen reorganization, proteoglycan-dependent chemokine sequestration, and fibroblast-driven matrix stiffening actively contributes to immune exclusion and evasion in solid tumors. This review integrates emerging mechanistic insights into how ECM composition, architecture, and mechanical properties shape spatial immune exclusion, T cell dysfunction, and immune-checkpoint regulation through mechanotransduction, metabolic reprogramming, and altered cytokine and chemokine signaling. Particular emphasis is placed on the coordinated activities of distinct ECM components and cancer-associated fibroblast subtypes in establishing spatially restricted immunosuppressive niches that limit antitumor immunity and therapeutic responsiveness. ECM-targeted therapeutic strategies are critically evaluated by integrating their mechanistic rationale, preclinical efficacy, clinical trial outcomes, and current stage of translational development. The importance of biomarker-guided patient stratification is also highlighted for identifying tumors most likely to benefit from ECM-directed interventions, particularly in combination with immune-checkpoint blockade and other immunotherapies. Finally, recent advances in spatial transcriptomics, proteomics, matrix imaging, and ECM-derived circulating biomarkers are discussed as tools to refine therapeutic targeting, monitor matrix remodeling, and predict treatment response. By conceptualizing the ECM as an active immunoregulatory network rather than a passive physical barrier, the review provides a mechanistic and translational framework for developing next-generation, ECM-informed cancer immunotherapies.

Liver transplantation has re-emerged as a therapeutic option for unresectable colorectal liver metastases (CRLM), but organ shortage and allocation concerns remain major limitations. The RAPID procedure combines auxiliary liver transplantation with delayed total hepatectomy, allowing small-graft use while the native liver provides temporary metabolic support. We report a modified RAPID transplantation, interpreted as a RAPID-derived staged auxiliary orthotopic liver transplantation (AOLT) strategy, using a whole pediatric graft in a 68-year-old woman with liver-only CRLM and sustained response to chemotherapy. The graft, from a 2-year-old donor (280 g; GRWR 0.4), had been declined by all pediatric centers due to non-standard infectious risk and was authorized by the Italian National Transplant Center within a regulated pathway. Favorable arterial anatomy preserved native right liver perfusion, while portal inflow management combined intentional surgical narrowing of the right portal vein with delayed portal vein embolization (PVE). At pre-PVE CT, graft volume was 350 cc (estimated GRWR 0.5); after PVE, it reached 580 cc (estimated GRWR 0.8), enabling completion hepatectomy at four weeks. At eight months, the patient had normal liver function and no recurrence. To our knowledge, this is the first reported use of a whole pediatric liver graft in modified RAPID transplantation.

Breast cancer is the most common malignancy and the leading cause of cancer-related mortality among women, and resistance to chemotherapy remains a major clinical challenge. Although doxorubicin is widely used, its efficacy is limited by chemoresistance. Neutrophil extracellular traps (NETs), web-like structures composed of DNA and proteins released by activated neutrophils, have been implicated in tumor progression and metastasis; however, their role in chemoresistance remains poorly understood. Here, we investigated the impact of NETs on doxorubicin resistance in human breast cancer cell lines.

NETs were isolated from healthy donor blood and used to treat tumor cell lines (MCF7, T47D, and MDA-MB-231) prior to chemotherapy exposure. Cell viability and clonogenic potential were assessed by MTT and colony formation assays, while apoptotic signaling and AKT activation were evaluated by qPCR and Western blot. Pathway involvement was investigated using pharmacological inhibitors of PI3K, AKT, and NF-κB and siRNA-mediated AKT1 knockdown.

NETs were not cytotoxic but significantly increased clonogenic capacity and conferred resistance to doxorubicin. This effect was independent of the DNA scaffold and abolished by heat denaturation, implicating heat-labile, NET-associated components (most likely proteins) rather than the DNA backbone. NET exposure downregulated the pro-apoptotic factor BAX and upregulated the anti-apoptotic factor BCL2, indicating modulation of apoptosis-related factors toward a pro-survival profile. NETs induced AKT phosphorylation in the luminal cell lines and engaged the PI3K/AKT/NF-κB signaling axis, consistent with the modulation of downstream apoptotic factors. Inhibition of this pathway or AKT1 knockdown reversed the NET-induced chemoresistant phenotype, restoring chemosensitivity and apoptotic gene expression.

Collectively, these findings identify heat-labile, NET-associated components as mediators of breast cancer chemoresistance and support targeting NETs or their downstream signaling pathways to improve chemotherapy response.

Epithelioid hemangioendothelioma (EHE) is a rare low-grade malignant vascular neoplasm characterized by local aggressiveness and metastatic potential. Clinically, EHE may involve multiple anatomical sites-including the lungs, liver, bones, and soft tissues-either synchronously or metachronously. Its non-specific clinical manifestations often complicate early diagnosis. Given the extreme rarity of documented cases in the literature, we report a rare case of right atrial EHE with concurrent bilateral pulmonary and extensive systemic metastases. Furthermore, we present a comprehensive literature review to explore the diagnostic and therapeutic challenges associated with this disease. We particularly emphasize the necessity of a thorough diagnostic evaluation encompassing both pathological and imaging modalities to ensure accurate characterization and diagnosis of the tumor in this case.

Mammary tumors are among the most common neoplasms affecting female dogs and are typically diagnosed in middle-aged or older animals. The occurrence of malignant mammary tumors in very young dogs is uncommon and may present diagnostic and clinical management challenges. This case report describes a young female dog presenting with multiple mammary nodules accompanied by persistent hyperglycemia detected approximately one to 2 weeks before the onset of estrus. Clinical examination, hematological and biochemical testing, cytological evaluation, surgical excision of the mammary lesions, and histopathological analysis were performed. Histopathology confirmed the presence of multiple mammary carcinomas with different histological patterns. Despite surgical removal of the tumors, blood glucose concentrations remained elevated. Two weeks later, the patient underwent ovariohysterectomy, after which glycemic values gradually decreased and returned to normal within the following weeks. The temporal association between reproductive hormonal status and the observed metabolic alteration suggests a possible hormone-related insulin resistance rather than a direct metabolic effect of the tumors themselves. This case highlights the potential interaction between mammary neoplasia, reproductive hormonal status, and glucose metabolism in dogs and emphasizes the importance of comprehensive clinical and metabolic evaluation in young patients presenting with mammary tumors.

Air pollutants are implicated in carcinogenesis, but their relevance to gastric cancer (GC) across prognosis, tumor organization and cell behavior remains unclear. We integrated evidence to evaluate pollutant-prioritized GC candidates.

Seven pollutants were integrated with GeneCards/OMIM GC genes using toxicology and candidate-prioritization resources. Robustness analyses used alternative disease definitions, Fisher's tests, 5,000 degree- and annotation-matched null sets, enrichment and protein-protein interaction networks. TCGA-STAD supported nested evaluation of 117 survival pipelines and a five-gene neural network, with locked external testing in GSE84437 and GSE54129. Single-cell, donor-aware macrophage, CellChat, Monocle2, multiplex immunofluorescence and cell2location-guided Visium analyses resolved tissue context. Docking, 100-ns molecular dynamics and bibliometrics examined GSK-3β-centered hypotheses. AGS cells underwent benzene/toluene dose screening followed by CCK-8, colony formation, Transwell and wound-healing assays.

Among 176 genes, 63 overlapped with GC beyond matched-null expectations (empirical P = 0.012), with enrichment in inflammation, hypoxia, apoptosis, metabolism and carcinogenesis. APRGSig (DNMT1, GSK3B, HNF4A, MMP9 and TERT) remained associated with overall survival after age/T/N/M adjustment (HR per 1-SD increase, 2.31; 95% CI, 1.98-2.71) and achieved a locked external C-index of 0.701; exploratory GC-ANN achieved an external AUC of 0.962. Score-defined APRGSig-high macrophages showed broader predicted crosstalk, whereas donor-aware analysis identified an inflammatory/stress-associated MALAT1-high state. Multiplex immunofluorescence provided representative compartment-level localization of APRGSig-encoded proteins; four Visium sections showed directionally consistent positive spatial concordance between APRGSig scores and inferred MALAT1-high abundance. Formal GSK-3β-benzene/toluene models yielded Vina scores of -7.1/-7.4 kcal/mol and remained numerically persistent over 100 ns; bibliometrics of 311 publications highlighted proliferation, invasion and metastasis. At 2.5 mM benzene and 20 μM toluene, both exposures increased AGS clonogenic capacity, Matrigel traversal and wound closure (all P < 0.05).

This framework integrates predictive, tissue-resolved, structural and phenotype-level evidence to prioritize exposure-linked molecular and immune hypotheses in GC.