Antibody-drug conjugates (ADCs) have become a major therapeutic class in breast cancer, but their clinical performance cannot be predicted by antigen expression alone. This review uses therapeutic-window engineering as a unifying framework to connect ADC molecular architecture with tumor heterogeneity, clinical positioning, resistance, immune effects, and toxicity. We examine how target selection, antibody properties, linker stability, payload mechanism and membrane permeability, drug-to-antibody ratio (DAR), conjugation homogeneity, and intratumoral delivery jointly determine efficacy and safety. We then distinguish established clinical uses from investigational strategies across HER2-positive, HER2-low/ultralow, hormone receptor-positive/HER2-negative, and triple-negative breast cancer, reflecting the rapid movement of ADCs into earlier treatment lines and selected early-stage settings. Rather than treating ADCs as a homogeneous class, we critically assess how payload class, linker behavior, bystander killing, Fc-mediated activity, and baseline immune context may favor or limit combinations with immune checkpoint inhibitors. We also map resistance along the delivery-to-kill cascade and integrate practical safety considerations, including interstitial lung disease/pneumonitis, hematologic toxicity, ocular events, and overlapping toxicities in combination regimens. Three principles emerge: ADC efficacy is a systems property; strategies that broaden tumor coverage may also increase normal-tissue exposure; and successful combinations require platform-specific rather than class-wide rationale. Future progress will depend on biomarker-guided sequencing, rational platform selection, and safety-adapted optimization of the therapeutic window.

Resistance to cancer immunotherapy is frequently sustained by immune exclusion, suppressive myeloid and stromal programs, abnormal tumor vasculature, and inhibitory checkpoint-ligand expression within the tumor microenvironment. Activation of the cGAS-STING (cyclic GMP-AMP Synthase)- (Stimulator of Interferon Genes) pathway has emerged as a context-dependent strategy to modulate the cancer immunity cycle and remodel resistant tumor ecosystems, with the potential to convert selected poorly inflamed immune-excluded tumors into immune-reactive lesions. However, STING activation does not simply "turn on" antitumor immunity. By reprogramming the tumor microenvironment, it can generate both therapeutic opportunity and compensatory resistance, including the induction of PD-L1 and PD-L2 on tumor, immune cells, stroma, and endothelial compartments. Recent evidence suggests that this adaptive response may be therapeutically exploited rather than merely counteracted. STING-driven remodeling may sensitize non-malignant tumor microenvironment compartments, including endothelial and myeloid cells, to Fc-engineered antibodies targeting PD-L1 and PD-L2. This Perspective discusses STING agonism as a broad immuno-oncology priming strategy and reframes inducible PD-L1/PD-L2 expression from an adaptive escape mechanism to an emergent transient, spatially organized, and therapeutically actionable cancer selective target. We propose that rational combinations of STING agonists with Fc-engineered PD-L1/PD-L2-targeting antibodies, guided by dynamic and spatial biomarkers, could overcome resistance to conventional immune checkpoint blockade in tumors with minimal T-cell infiltration but targetable tumor vasculature. Emerging delivery platforms, including antibody-conjugated STING agonists, may further improve the therapeutic index of this approach by concentrating innate immune activation within antigen-defined tumor niches and reducing off-tumor inflammatory activation.

Insulinoma is a rare endocrine tumor that is clinically characterized by the Whipple's triad and can be part of multiple endocrine neoplasia syndrome type 1 (MEN1). Most insulinomas are less than 2 cm, but the smaller the tumor diameter, the lower the imaging sensitivity. Here we present a case of recurrent asymptomatic hypoglycemia with unremarkable contrast-enhanced CT and MRI imaging that led to the delayed identification of an insulinoma. The tumor was localized with the invasive selective arterial calcium stimulation test (SACST).

A 59-year-old female presented with asymptomatic hypoglycemia detected in preoperative screening on two occasions over the past year. She had no classic symptoms of hypoglycemia such as dizziness, weakness, blackouts, anxiety, palpitations, tremors, or profuse sweating. Detailed history taking revealed that she has had two episodes of sudden irritability, personality changes, and abnormal violent behavior that were relieved with food. After extensive endocrine hormone testing and imaging to exclude the possibility of MEN1, she was diagnosed with a 1.5-cm insulinoma in the pancreatic tail. Her blood glucose, insulin and C-peptide levels returned to normal after tumor excision.

Hypoglycemia unawareness develops after recurring episodes of hypoglycemia and increases the risk of life-threatening hypoglycemia. This case highlights the importance of identifying the underlying cause of hypoglycemia and implementing timely intervention.

Immune checkpoint inhibitor (ICI)-associated transverse myelitis (TM) is a rare and severe neurological immune-related adverse event (n-irAE) with an incidence of < 0.01%, and the clinical management of steroid-unresponsive cases remains extremely challenging. This article reports the case of a 37-year-old male patient with biphasic pleural mesothelioma who developed ICI-associated TM after treatment with nivolumab combined with ipilimumab. Initial treatment with high-dose glucocorticoids plus intravenous immunoglobulin (IVIg) was ineffective. After mycophenolate mofetil (MMF) was added in combination with steroids for 1 month, the patient's neurological function showed slight improvement, and intramedullary contrast-enhanced signals on spinal MRI showed partial reduction. However, spinal cord cystic or myelomalacic changes suggested potentially irreversible parenchymal injury. Currently, the patient has restarted pemetrexed combined with carboplatin chemotherapy, and the disease status is stable. Based on recently published case series, case reports, and systematic reviews, this article discusses the second-line treatment strategies for steroid-unresponsive ICI-associated TM, aiming to provide a reference for clinical practice in managing such rare cases.

Major glossectomy frequently results in profound speech impairment. We investigated whether a patient's voice could be captured preoperatively and reconstructed using artificial intelligence voice cloning for potential future use as a personalized assistive communication voice during postoperative recovery.

In this prospective single-centre feasibility study, adult patients with treatment-naïve carcinoma of the tongue planned for major glossectomy underwent a single approximately 30-60 second preoperative voice recording in a sound-treated room. Voices were cloned offline using the IndicF5 flow-matching text-to-speech model, generating a standardized reading-passage output and a patient-transcript output for each participant. Speaker fidelity was assessed using cosine similarity across three independent speaker-verification encoders, calibrated against each patient's intra-speaker and cohort impostor distributions, alongside mel-cepstral distortion and prosodic feature analysis. Subjective acceptance was assessed using the Personalised Synthetic Voice Acceptance Questionnaire across six domains, completed by patients and family members.

Of 34 enrolled patients, 26 formed the final cohort across four languages. Mean cosine similarity was 0.933 (Resemblyzer), 0.969 (WavLM), and 0.806 (ECAPA-TDNN), with clone scores generally falling within patient-specific intra-speaker distributions and above cohort impostor distributions. Mean mel-cepstral distortion was 7.87 dB. Fundamental frequency and other prosodic measures showed broad cohort-level correspondence with variable individual deviations. Identity-and-Ownership and Authenticity-and-Trust domains scored highest among both patients and family or attenders, while naturalness and emotional acceptance were rated more conservatively.

These findings demonstrate the feasibility of generating personalised synthetic voices from brief preoperative clinic-grade recordings, with objective speaker similarity and preliminary patient- and family-reported acceptance. The findings support further evaluation of these voices as potential assistive communication tools during postoperative recovery; however, postoperative communication performance and clinical benefit were not evaluated in the present study.

Magnetic resonance imaging (MRI)-based pelvimetry has been investigated for predicting surgical difficulty in total mesorectal excision (TME) for rectal cancer. However, heterogeneity in pelvimetric parameters, surrogate outcomes, and study design has resulted in inconsistent evidence. This systematic review aimed to synthesise the evidence on commonly used MRI parameters and difficulty surrogates and assess their methodological robustness and clinical relevance.

PubMed, Embase, and the Cochrane Library were systematically searched through December 2025 for studies evaluating preoperative MRI pelvimetry in patients undergoing TME for rectal cancer. Outcome parameters were surrogate measures of surgical difficulty, including operating time, intraoperative blood loss, conversion to open surgery, pathological quality metrics, and postoperative complications. Risk of bias was assessed using the Risk of Bias in Non-randomised Studies of Exposures (ROBINS-E) tool. This systematic review and meta-analysis was reported in accordance with the PRISMA 2020 statement and prospectively registered (PROSPERO: CRD420261287153).

Thirty-six studies comprising 8,364 patients were included. Common parameters included sagittal measurements and axial interspinous distance (ISD) and intertuberous distance (ITD). Definitions of surgical difficulty varied substantially. ROBINS-E identified some concerns in 30 studies, a high risk of bias in five, and insufficient information in one. Meta-analysis of six studies (n = 769) showed that shorter ISD (mean difference [MD] -5.13 mm, 95% CI -6.61 to -3.65; p < 0.001; I² = 0%) and ITD (MD -7.32 mm, 95% CI -10.24 to -4.39; p = 0.004; I² = 0%) were significantly associated with surrogate measures of surgical difficulty.

MRI-based pelvimetry, particularly ISD and ITD, may help predict surgical difficulty in TME. However, methodological heterogeneity limits broader quantitative synthesis and highlights the need for standardised pelvimetric protocols.

Combination therapy comprising immune checkpoint inhibitors (ICIs) and chemotherapy is standard treatment for many cancer types. However, the management of adverse events (AEs) induced by combination therapy is more complicated than that of AEs induced by ICI monotherapy. Although immune-related AEs (irAEs) induced by ICIs and AEs induced by chemotherapy require distinct therapeutic approaches, distinguishing between them can be challenging. Therefore, in this exploratory study, we aimed to investigate whether lymphocyte proportion could serve as a candidate biomarker associated with the occurrence of irAEs in patients receiving ICI plus chemotherapy combination therapy.

We categorized 122 patients into the irAE group (those who experienced irAEs), chemo-AE group (those with chemotherapy-induced AEs), and non-AE group (those without AEs) and analyzed their lymphocyte proportions before one course (baseline sample) and two courses (two-course sample) of treatment.

Lymphocyte proportions of the baseline samples did not differ between the non-AE, chemo-AE, and irAE groups. The lymphocyte proportion of the two-course sample of the irAE group was significantly higher than that of the non-AE group (25.8% vs. 21.9%; p < 0.05). The lymphocyte proportion of the two-course sample of the irAE group was significantly higher than that of the chemo-AE group (25.8% vs. 19.6%; p < 0.05). The multivariate logistic regression analysis showed that a lymphocyte proportion ≥ 23.9% in the two-course sample significantly increased the risk of irAEs (odds ratio = 3.04; p < 0.05).

An increased lymphocyte proportion before the two courses of treatment was associated with the occurrence of irAEs and may serve as a candidate biomarker.

FURIN, a proprotein convertase, has been implicated in tumor progression. Nevertheless, how it contributes to lung adenocarcinoma (LUAD) and ferroptosis is still not well understood.

We investigated FURIN expression and its prognostic value using the TCGA-LUAD cohort, CPTAC, and GEO datasets. In vitro functional assays, including CCK-8, colony formation, EdU, wound healing, invasion, and tube formation, were conducted in HCC827, PC9 and H460 cells following FURIN knockdown, with or without the ferroptosis inhibitor Ferrostatin-1 (Fer-1). RNA-seq, ferroptosis signature scoring, and GSEA were used to explore mechanisms. Ferroptosis was assessed by ROS and Fe accumulation, MDA and GSH/GSSG ratio, T-AOC, and ferroptosis-related protein expression. Preliminary exploration of the mechanism by which FURIN regulates NRF2 was performed using confocal microscopy. A multiple cell death-related gene signature was developed for prognostic prediction and immune/mutational landscape analysis.

In LUAD, FURIN was highly expressed and linked to poor prognosis. Knockdown of FURIN suppressed proliferation, migration, invasion, and angiogenesis, accompanied by increased ROS, Fe²⁺, elevated MDA, and decreased GSH/GSSG ratio and T-AOC. RNA sequencing showed downregulation of SLC7A11, GPX4, FTH1, and GSS, accompanied by upregulation of ACSL4, PTGS2, NCOA4, and DPP4. Furthermore, Fer-1 treatment reversed these changes, supporting a ferroptosis-dependent mechanism. Western blot confirmed FURIN knockdown may inhibit the NRF2-xCT-GPX4 axis, which lead to ferroptosis. Mechanistically, we preliminarily demonstrated that FURIN promotes NRF2 nuclear translocation and upregulates xCT and GPX4. The FURIN inhibitor Decanoyl-RVKR-CMK effectively inhibits the growth of LUAD in vitro. The cell death-related gene signature showed robust predictive performance (AUC 0.73-0.78) and served as an independent prognostic factor. Risk stratification revealed distinct immune infiltration, with high-risk patients enriched in immunosuppressive macrophages and low-risk patients in CD8⁺ T and NK cells. High-risk patients also exhibited increased tumor mutational burden and driver mutations.

FURIN promotes LUAD progression by suppressing ferroptosis through the NRF2-xCT-GPX4 axis. Targeting the FURIN-ferroptosis axis and using ferroptosis-based risk stratification may offer novel strategies for prognosis and individualized therapy.

Patients with nasopharyngeal carcinoma (NPC) undergoing definitive treatment commonly experience muscle loss, nutritional deterioration, symptom burden, and functional decline, increasing sarcopenia risk. This study aimed to develop a context-sensitive supportive care pathway integrating multidisciplinary care strategies for sarcopenia prevention across the NPC treatment trajectory.

A multidisciplinary team (MDT) developed the pathway iteratively, guided by the updated Medical Research Council framework for complex interventions. Development integrated evidence synthesis, semi-structured interviews with healthcare professionals, programme theory, economic and resource considerations, contextual analysis, and informal consultations with patients and family caregivers. These inputs informed implementation requirements, professional roles, longitudinal care procedures, and core supportive care domains.

Evidence was most extensive for nutritional interventions; evidence for exercise and probiotic approaches was more limited and heterogeneous. Interviews with 21 healthcare professionals generated three themes comprising 11 subthemes, synthesised into four implementation requirements: recognition and professional competency; care organisation and MDT coordination; longitudinal monitoring and continuity of care; and patient self-management and family-supported care. Patient and caregiver consultations informed refinements to education, home-based self-management, and family involvement. The final pathway specified MDT roles, six longitudinal care procedures, and five integrated domains: nutritional and immune management, exercise management, head and neck symptom cluster management, gastrointestinal symptom cluster management, and psycho-behavioural support.

The resulting pathway provides a context-sensitive, implementation-informed structure for coordinating multidisciplinary sarcopenia prevention across the NPC treatment trajectory. It incorporates clinical workflow, resource considerations, and continuity of care, but its feasibility, implementation, and effectiveness require prospective evaluation.

Claudin 18.2 (CLDN18.2)-targeted CAR-T cell and antibody therapies show promise against gastrointestinal cancers, but biomarkers predictive of long-term benefit and therapeutic sensitization strategies are needed. Here we show that proteins carried by circulating extracellular vesicles (EVs) can reflect and influence the efficacy of CLDN18.2-targeted therapies. By profiling serial plasma samples of patients from the CT041-CG4006 trial (CLDN18.2- CAR-T-therapy) or the GLOW trial (Zolbetuximab), we identified EV-associated CLDN18.2, PD1 and PD-L2 as therapeutic markers and integrated them into a signature (CPP-score) for better predictive robustness. Mechanistically, specific EV-proteins exhaust CAR-T cells, neutralize CLDN18.2-targeted-antibodies, activate immunosuppressive IL-6-expressing cancer-associated fibroblasts, and alter the TH1/TH2 balance, thereby reshaping the tumor microenvironment and interfere with CLDN18.2-targeted therapies. Strategies including combining anti-PD1 antibody or CAF inhibitor, CLDN18.2-CAR-T plus CLDN18.2-antibody, and depleting plasma EVs, can sensitize CLDN18.2-CAR-T/antibody by countermeasuring EV-proteins' therapeutic interferences. Collectively, our work provides potential options to monitor and improve CLDN18.2-targeted therapies in clinical practice.