The gasdermin (GSDM) family of proteins has emerged as the central executioner of pyroptosis, a form of inflammatory cell death characterized by plasma membrane rupture and the release of pro-inflammatory cytokines such as interleukin-1β (IL-1β), IL-18 and high mobility group protein B1 (HMGB1). Emerging evidence indicates that GSDMs exert diverse functions in health and various disease contexts, which can be either dependent on or independent of pyroptosis, including facilitating mucus secretion, regulating bone resorption, and modulating mitochondrial metabolism. This review provides a comprehensive overview of the GSDM family, detailing the molecular mechanisms of activation, regulation, pore formation, cell rupture and membrane repair. We explored the extensive crosstalk between GSDMs and other cell death modalities, including apoptosis, necroptosis, NETosis, and PANoptosis. Furthermore, we systematically discuss GSDMs' 'double-edged sword' roles in diverse pathologies, ranging from host defense in infectious diseases and chronic inflammation in autoimmune disorders to their complex, context-dependent function in cancer progression and immunity. Finally, we evaluate emerging therapeutic strategies, encompassing small-molecule inhibitors such as disulfiram (DSF), necrosulfonamide (NSA) and dimethyl fumarate (DMF), as well as novel material-based delivery systems. Collectively, these advances underscore the therapeutic potential of targeting GSDMs for precise clinical intervention to treat both inflammatory and non-inflammatory diseases, as well as to enhance cancer immunotherapy.

A systematic mapping of nonsurgical, lower-cost primary prevention strategies for women at high risk of breast cancer remains limited.

To identify and summarize lower-cost (i.e., lower economic cost relative to surgical and pharmaceutical alternatives; not dependent on expensive equipment, patented drugs, or complex medical procedures; implementable through community, family, or self-management models), nonsurgical primary prevention strategies for women at high risk of breast cancer, providing empirical evidence to inform clinical practice, health education, and public health policy.

Following the Joanna Briggs Institute (JBI) methodology for scoping reviews and the Participants, Concept, and Context (PCC) framework, we systematically searched 9 Chinese and English databases. Search terms covered "breast cancer," "high-risk women," "primary prevention," and various nonsurgical strategies. Two independent reviewers performed literature screening and data extraction.

Seventeen studies were included, and six prevention strategy categories were identified: nutritional dietary interventions, physical activity interventions, comprehensive lifestyle interventions, chemoprevention, digital health interventions, and health education with self-management. Comprehensive lifestyle intervention emerged as the core strategy with robust evidence and manageable costs. Nutritional interventions have shifted from single nutrients to overall dietary patterns. Chemoprevention, limited by cost and side effects, is more suitable for very high-risk women. Digital health interventions and health education offer advantages in medically underserved areas.

This scoping review systematically maps lower-cost, nonsurgical primary prevention strategies for women at high risk of breast cancer, identifying six categories of promotable interventions. Comprehensive lifestyle intervention represents the most evidence-supported and economically manageable core strategy. For the first time from the dual perspectives of "nonsurgical" and "lower cost," this review provides practical references for primary healthcare systems, clinical education, and public health policy, with particular relevance for resource-limited settings.

Antibody-drug conjugates (ADCs) have transformed the treatment landscape of breast cancer and redefined the conceptual distinction between targeted therapy and conventional chemotherapy. Originally conceived as "magic bullets" that selectively deliver cytotoxic warheads to antigen-expressing tumor cells, clinical and mechanistic evidence indicates that ADC activity depends on a broader interplay of target-dependent and target-independent mechanisms, including extracellular payload release, bystander killing, off-tumor uptake, and immune modulation. Here, we examine ADCs in breast cancer as a distinct therapeutic paradigm. We discuss how antigen biology, linker chemistry, payload features, and drug-to-antibody ratio collectively determine efficacy, toxicity, and therapeutic index. We then compare currently approved and emerging HER2- and TROP2-directed ADCs, highlighting how differences in linker stability, payload pharmacology, and bystander capacity can affect clinical outcomes in ADCs sharing the same target. We further discuss the biological basis and translational challenges of de novo and acquired resistance related to targets, payloads, and tumor microenvironmental constraints, as well as the implications of these mechanisms for biomarker development, sequencing rationales, and combination strategies with immune checkpoint inhibitors and DNA repair-targeting therapies. Finally, we outline future directions of ADC development, including expansion of the target space, novel payload modalities, and next-generation antibody and conjugation engineering.

Despite growing recognition of invasive lobular carcinoma (ILC) as a biologically and clinically distinct subtype of breast cancer, ILC remains understudied. Most contemporary therapeutic trials continue to enroll patients predominantly with invasive ductal carcinoma/invasive carcinoma of no special type and rarely stratify by histology. As a result, ILC's unique disease biology, characteristic loss of E-cadherin function, diffuse growth pattern, and distinct metastatic tropism remain underrepresented in evidence that guides systemic therapy recommendations. In this Review, we examine key molecular alterations and emerging therapeutic targets in ILC, emphasizing recent preclinical discoveries that identify subtype-specific therapeutic vulnerabilities and guide the development of histology-specific treatment approaches for this unique disease. In combination with endocrine therapies, effective targeting in ILC may require a multilayered strategy that extends beyond genomic alterations to leverage ILC's specific estrogen receptor-associated proteins, metabolism, and tumor microenvironment. Future clinical trial frameworks incorporating prespecified ILC cohorts, tailored endpoints, and coclinical approaches enabling parallel testing in patients and patient-derived models could help accelerate the development and evaluation of ILC-targeted therapeutics.

Homologous recombination repair deficiency (HRD) occurs in approximately 10% of breast tumors and represents a major targetable vulnerability across multiple cancer types. Impairment of the homologous recombination DNA repair pathway - arising through somatic and germline mutations in homologous recombination repair genes, epigenetic mechanisms, and transcriptomic changes - leads to genomic instability and a reliance on error-prone repair mechanisms. Poly (ADP-ribose) polymerase (PARP) inhibitors harness the synthetic lethality of HRD and PARP inhibition, with current approvals encompassing both early-stage and advanced breast cancer in patients with germline BRCA1/2 (gBRCA1/2) mutations. However, emerging evidence suggests efficacy of PARP inhibitors beyond gBRCA1/2-mutated breast cancer to tumors with other homologous recombination repair defects that confer a "BRCAness" phenotype. This Review examines opportunities to broaden the use of PARP inhibitors in breast cancer and underscores the importance of innovative biomarkers, combination strategies, and next-generation agents to maximize therapeutic impact.

γ-Secretase is a transmembrane protease complex that cleaves multiple type I transmembrane proteins, including amyloid precursor protein and neurogenic locus notch homolog protein (NOTCH). Although numerous γ-secretase inhibitors and modulators targeting Notch-dependent cancers have been developed in recent decades, their clinical translation has been hampered by low substrate specificity and on-target gut toxicity. Using a proteomics-based screening approach, we identified dedicator of cytokinesis protein 2 (DOCK2) as an interactor of the γ-secretase subunit nicastrin (NCSTN). We further demonstrate that DOCK2 regulates mannosylation of NCSTN N-glycans, which in turn modulates γ-secretase activity toward NOTCH receptors. Both genetic depletion of DOCK2 and pharmacological inhibition of NCSTN mannosylation with kifunensine attenuated Notch-dependent leukemia progression in vivo. Collectively, these findings uncover a regulatory mechanism underlying substrate-specific activation of γ-secretase and suggest a promising therapeutic strategy for Notch-related diseases.

Immunotherapy has revolutionized the therapeutic landscape for many cancers, but its application in solid tumors has lagged. There is now evidence that immunotherapy can improve outcomes in triple-negative breast cancer, but hormone receptor-positive (HR+) breast cancer has traditionally been considered immunologically cold. However, emerging evidence challenges this binary paradigm, suggesting that a biologically relevant subset of HR+/human epidermal growth factor receptor 2-negative (HER2-) tumors exhibit meaningful immunogenic features and clinically relevant sensitivity to immune-based treatment. In this Review we summarize the current understanding of immunogenicity and clinical use of immune-based treatments across breast cancer subtypes. We argue for a broader view of a spectrum of breast cancer immunogenicity and highlight the importance of host factors, including parity and lactation history, in shaping antitumor immunity. Improved identification of immunologically active subsets and deeper mechanistic insight will be essential to expand the therapeutic benefit of immunotherapy to broader patient cohorts and to refine care of patients with breast cancer.

Juvenile nasopharyngeal angiofibroma (JNA) is a rare, benign but locally aggressive vascular tumor affecting adolescent males. While endoscopic resection with preoperative embolization remains the treatment of choice, recurrence remains a challenge, often driven by incomplete excision or poor follow-up adherence.

We report two cases of recurrent JNA in adolescent males, each highlighting a different modifiable risk factor for recurrence. Case 1 involved a 21-year-old with prior resection and poor postoperative follow-up, who re-presented with Radkowski Stage IIIA disease involving the central skull base. Case 2 involved an 18-year-old initially misdiagnosed with a nasal polyp, later confirmed as JNA after recurrence within 4 months of surgery. Both patients underwent preoperative embolization followed by endoscopic endonasal resection using a transnasal-transpterygoid approach. Histopathology confirmed recurrent JNA in both cases. Postoperative MRI at 3 months showed no evidence of residual or recurrent disease.

These cases underscore the critical role of accurate initial diagnosis, proper staging, and structured postoperative surveillance in reducing recurrence risk in JNA. Multidisciplinary care, patient education, and imaging-guided follow-up protocols are essential, especially in resource-constrained settings where diagnostic delays and adherence challenges are prevalent.

Renal cell carcinoma (RCC) is a common malignant neoplasm of the urinary system, characterized by the difficulty of early diagnosis and the frequent emergence of therapeutic resistance in advanced stages, both of which profoundly compromise patient prognosis. Exosomes, as nanoscale vesicles secreted by cells, are capable of transporting bioactive molecules such as proteins and nucleic acids, thereby mediating communication within the tumor microenvironment and offering novel avenues for the noninvasive diagnosis and treatment of RCC. This article reviews recent advances in exosome research in RCC. It first outlines the biogenesis, structure, and biological functions of exosomes; it then systematically examines their pivotal roles in RCC invasion and metastasis, epithelial-mesenchymal transition, immune evasion, angiogenesis, and therapeutic resistance. Furthermore, it explores the potential of exosomes as biomarkers for the early diagnosis and prognostic assessment of RCC, as well as their promising applications in therapy as drug delivery vehicles and tumor vaccines. Finally, the review summarizes the current challenges confronting exosome research, including the lack of standardized isolation techniques and insufficient clinical validation, and considers future directions for promoting their clinical translation through the integration of multi-omics approaches and artificial intelligence. This review provides a theoretical foundation and valuable reference for the precise diagnosis and treatment of RCC.

Cutaneous melanoma is the deadliest type of skin cancer, with increasing incidence and mortality rates. Therefore, primary and secondary prevention are of utmost importance.

The objective is to evaluate new recent evidence on primary and secondary prevention strategies for cutaneous melanoma.

Search of PubMed, Web of Science and EBSCOhost databases retrieved studies from February 2020 to January 2026, on prevention at both primary and secondary levels and that followed the PICO criteria selection process in the PRISMA method for a systematic review. Different assessment tools were used to evaluate methodological quality.

A total of 404 citations were analysed, of which 24 studies met the inclusion criteria: 3 addressed primary prevention and 21 secondary prevention. Primary prevention found a possible chemopreventive agent and the possibility of a genetic control of the mechanisms of nevi fluctuation in life associated with height. The secondary prevention studies evaluated population-based screening strategies and emerging diagnostic tools, artificial intelligence (AI)-assisted tools included, and found a new wearable microneedle biosensor for in situ tyrosinase activity detection as a new approach for early cutaneous melanoma detection. It is clearly a limited primary prevention publication that shows poor new evidence for conclusions.

Two new primary prevention approaches were identified, but both require further research before clinical implementation: aspirin as a potential chemoprotective agent and a possible genetic association between height and age-related nevus regression. Both require further study. Emerging diagnostic technologies, including AI-assisted tools and wearable biosensors for in situ tyrosinase detection, demonstrated high sensitivity but variable specificity, requiring further validation before routine clinical use. Population-based screening, patient education and risk-stratified surveillance improved early melanoma detection, particularly among high-risk populations. Most studies achieved moderate to high methodological quality, but diagnostic accuracy studies revealed some issues showing that require relevant improvements in diagnostic accuracy and standardization. The use of biomarkers is a promising new tool for early diagnosis.