TPS8133 Background: LS-SCLC is a highly aggressive malignancy with poor prognosis. Positioning effective consolidation strategies is a key focus to improve long-term patient outcomes. Prominently, immune checkpoint inhibitors (ICIs) have emerged as consolidation therapy after cCRT or sCRT for LS-SCLC. QL1706 is a bifunctional antibody against both programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte antigen 4, and iparomlimab (QL1604) is an anti-PD-1 agent. In previous studies, both QL1706 and QL1604 demonstrated manageable safety profiles. Notably, QL1706 also showed encouraging preliminary anti-tumor signals in SCLC, which indicated the potential as consolidation therapy (Zhao et al. 2023; Huang et al. 2023). This trial aims to compare the efficacy and safety of QL1706 and QL1604 as consolidation therapy in pts with LS-SCLC without progression after cCRT or sCRT. Methods: In this multicenter double-blind double-dummy randomized controlled phase 3 trial (NCT06789796), pts with pathologically-confirmed LS-SCLC per AJCC 8 th edition are recruited. Pts are eligible if aged ≥18 years, with adequate organ function, ECOG PS scored 0 or 1, and do not have disease progression after completion of the requested cCRT or sCRT. Prophylactic cranial irradiation (PCI) is permitted before randomization. Approximately 636 pts are planned to be randomized 1:1 to receive either QL1706 (at 5 mg/kg) plus QL1604 placebo or QL1604 (at a fixed dose of 200 mg or at 3 mg/kg for pts weighing <40 kg) plus QL1706 placebo via intravenous infusion on day 1 in a 21-day cycle. Treatment will be continued until disease progression, intolerable toxicity, initiation of new anti-tumor treatment, withdrawal of informed consent, loss to follow-up, trial termination, or up to 24 months, whichever occurs first. Randomization is stratified by disease stage (I/II vs. III), receipt of PCI (yes vs. no), and the type of CRT (cCRT vs. sCRT). The co-primary endpoints are progression-free survival (PFS) per RECIST v1.1 assessed by blinded independent central review (BICR), and overall survival (OS). Secondary endpoints are investigator-assessed PFS, 1-year and 2-year PFS rates assessed by BICR and investigator, objective response rate, disease control rate, duration of response, 1-year and 2-year OS rates, safety, pharmacokinetics, and immunogenicity. Exploratory endpoints are biomarker assessments and their relationship to efficacy and prognosis, as well as patient-reported outcomes. Overall two-sided Type I error (α=0.05) controlled by fixed-sequence testing: BICR assessed PFS will be tested first, followed by OS if significant. An interim analysis is planned. The study will be conducted across around 79 sites in China, and enrollment is ongoing. Clinical trial information: NCT06789796 .

BACKGROUND:Central venous catheters for drug delivery introduce catheter-related thrombosis (CRT) and influence the survival of cancer patients. The key unmet needs to personalise CRT prevention include identifying high-risk patients and optimising extubation time. In this study, we aimed to develop a survival model to facilitate personalised CRT prevention strategies. METHODS:We prospectively collected tumour patient catheterization data across 4 centres. The SM-CRT survival model, which provides both continuous risk ranking (crank) predictions and the survival distribution (distr) predictions was constructed. RESULTS:Here we include a total of 30,947 patients. The SM-CRT model exhibits robust performance in identifying high-risk patients, with c-indexes of 0.714 in the prospective test dataset and 0.678 and 0.779 in 2 external test datasets based on crank predictions. Femorally inserted central catheter (FICC), peripherally inserted central catheter (PICC), tumours in the thoracic cavity, and alkylating agents are identified as high-risk factors. Patients are subsequently divided into high-risk, low-risk, and long-term period groups on the basis of their distr predictions. The predicted low-risk and long-term groups present significantly fewer CRT events per day than the high-risk group in both the training dataset (odds ratio [OR] = 0.54, 95% CI [0.38-0.91], adjusted p-value [padj] <0.001; OR = 0.39, 95% CI [0.34-0.44], padj <0.001) and the test dataset (OR = 0.47, 95% CI [0.28-0.87, padj = 0.024; OR = 0.41, 95% CI [0.28-0.61], padj <0.001). CONCLUSIONS:The high c-indexes based on crank predictions demonstrated the ability of the SM-CRT model to identify high-risk patients for thromboprophylaxis. Additionally, the SM-CRT model can guide extubation time by identifying high-risk periods through distr predictions.

8013 Background: Small-cell lung cancer (SCLC) grows rapidly, is aggressive, has a poor prognosis, and tends to recur after treatment. Autologous cellular immunotherapy (CIT) has demonstrated good safety and efficacy across various tumors; however, there are no prospective studies utilizing autologous natural killer (NK) cells for consolidation therapy following first-line chemoradiotherapy for SCLC. Methods: This study aimed to evaluate the safety and efficacy of autologous NK cell infusion (administered every 2 weeks for a total of six courses) as consolidation therapy after first-line standard treatment for limited-stage SCLC, compared to routine follow-up in a randomized, controlled, open-label, single-center phase II clinical trial. The primary endpoint was progression-free survival (PFS, assessed according to Response Evaluation Criteria in Solid Tumors version 1.1), while secondary endpoints included overall survival (OS), the 12- and 24-month PFS rate, the 24- and 36-month OS rate and safety. Results: Forty-three patients with limited-stage SCLC were included in the final analysis, comprising 21 patients in the treatment group who received autologous NK cell infusion after chemoradiotherapy and 22 patients in the control group who underwent routine follow-up. At 6 months, the response to initial chemoradiotherapy was maintained in 27.3% (6/22) of the control patients and 57.1% (12/21) of the treatment patients. The objective response rate (ORR) and PFS rates at 12 months for controls compared to treatment patients were 0% versus 19.0% (4/21) (P < 0.05) and 4.5% (1/22) versus 42.9% (9/21) (P < 0.01), respectively. Compared to the control group, the autologous NK cell consolidation group achieved significantly longer PFS (median 6.5 vs. 11.92 months; hazard ratio [HR] 0.38, 95% confidence intervals [CI] 0.18 to 0.79; P = 0.01) and OS (median 15.6 vs. 27.13 months; HR 0.41, 95% CI: 0.19 to 0.87, P = 0.02), with a particularly pronounced PFS benefit when calculated from the end of chemoradiotherapy (median 8.1 vs.16.3 months; HR 0.35, 95% CI 0.17 to 0.72, P = 0.01). Regarding safety, the incidence of all adverse events (AEs) due to any cause was 50.0% (11/22) in the observation group and 47.6% (10/21) in the treatment group, with most being grade 1–2 and considered unrelated to NK cell infusion. NK cell treatment exhibited good overall safety and tolerability. Additionally, we characterized changes in peripheral blood cell subsets and metabolites before and after treatment, as well as the tumor immune microenvironment characteristics in patients from the treatment group. Conclusions: Autologous NK cell infusion as consolidation therapy after first-line chemoradiotherapy for SCLC yielded promising preliminary PFS and OS results, with a well-tolerated safety profile. Clinical trial information: NCT03410368 .

Circulating tumor DNA (ctDNA) is emerging as a minimally invasive biomarker for risk stratification and treatment-response assessment in lung cancer immunotherapy, but its routine use for treatment selection has not been established. This review critically evaluates evidence across neoadjuvant, adjuvant, consolidation after definitive chemoradiotherapy, and advanced/metastatic settings, with emphasis on serial sampling and on the distinction among prognostic, response-associated, and predictive roles. Across disease stages, baseline or post-definitive-treatment ctDNA detectability consistently identifies patients at increased risk of recurrence or death and is therefore principally prognostic. Early on-treatment decline or clearance frequently precedes radiographic change and is associated with pathological response, progression-free survival, and overall survival, supporting ctDNA as a response-associated biomarker. By contrast, evidence that ctDNA identifies differential benefit from a specific immunotherapy remains limited, because most analyses are single-arm and/or retrospective, formal treatment-by-biomarker interaction tests are uncommon, and prospective ctDNA-guided trials have not yet demonstrated clinical utility. Nevertheless, ctDNA dynamics provide a biologically and clinically coherent framework for future risk-adapted strategies, including enrichment of molecular residual disease-positive patients, early identification of resistance, and prospective testing of treatment escalation, de-escalation, or duration. Translation into routine care will require harmonized assays and sampling time points, improved sensitivity at low disease burden, control of clonal hematopoiesis, and randomized interventional validation. Thus, ctDNA currently functions mainly as a prognostic and response-associated biomarker in lung cancer immunotherapy, while its predictive, decision-defining role remains an important but investigational objective.

1049 Background: T-Bren is a HER2-directed antibody-drug conjugate (ADC) consisting of an anti-HER2 monoclonal antibody linked to a potent topoisomerase I inhibitor (Ed-04). In phase I study, T-Bren demonstrated encouraging antitumor activity with a manageable safety profile in patients (pts) with HER2-positive unresectable LA/M breast cancer (BC) who had failed standard treatments. Results of safety and efficacy from a phase II study assessing T-Bren monotherapy or in combination with pertuzumab in treatment-naïve HER2-positive unresectable LA/M BC are presented. Methods: Treatment-naïve pts with HER2-positive (IHC3+, or IHC2+/ISH+) unresectable LA/M BC were treated with T-Bren monotherapy at 4.4mg/kg Q3W (cohort A) or T-Bren 4.4mg/kg Q3W in combination with pertuzumab (cohort B). Primary endpoints were ORR and RP2D for combination treatment. Results: As of Nov 30, 2025, a total of 83 pts were enrolled and treated in cohort A (n = 43) and cohort B (n = 40). All pts were included in the analysis (see table below). The median follow-up was 10.6 months. In cohort A, ORR was 93.0%, confirmed ORR (cORR) was 86.0%. In cohort B, ORR and cORR were 87.5%. Median PFS have not reached in either cohort. The landmark PFS rate at 12-months was 79.1% in cohort A and 90.8% in cohort B. The most common grade 3 and above hematologic TRAEs in both cohorts were neutropenia (51.8%), anemia (37.3%), leukopenia (36.1%), and thrombocytopenia (26.5%); the most frequent grade 3 and above non-hematologic TRAEs were weight decreased (7.2%), hypokalemia (6.0%), and nausea (6.0%). Grade 3 and above TRAEs were able to be effectively managed with standard supportive measure including dose reductions, as demonstrated by the TRAE leading to discontinuation rate of 4.8%. No treatment related death or ILD was reported. Conclusions: T-Bren as monotherapy or in combination with pertuzumab has demonstrated a promising antitumor activity and a manageable safety profile in pts with treatment-naïve HER2-positive unresectable LA/M BC. Phase III study assessing T-Bren in treatment-naïve HER2-positive unresectable LA/M BC is in preparation. Clinical trial information: NCT06445400 . Cohort A: T-Bren 4.4 mg/kg D1Q3W (N=43) Cohort B: T-Bren 4.4 mg/kg D1Q3W+ pertuzumab D1Q3W (N=40) Total (N=83) ORR, % (95% CI) 93.0 (80.9, 98.5) 87.5 (73.2, 95.8) 90.4 (81.9, 95.7) cORR, % (95% CI) 86.0 (72.1, 94.7) 87.5 (73.2, 95.8) 86.7 (77.5, 93.2) DCR, % (95% CI) 100 (91.8, 100) 97.5 (86.8, 99.9) 98.8 (93.5, 100) 12-mo PFS rate, % (95% CI) 79.1 (32.9, 95.2) 90.8 (74.1, 97.0) 89.9 (77.8, 95.6) 12-mo OS rate, % (95% CI) 100 (100, 100) 95.0 (81.5, 98.7) 97.4 (89.9, 99.3)

Background Cardiovascular disease and osteoarthritis (OA) share risk factors, but the link between comprehensive cardiovascular health and OA incidence is unclear. We investigated the association of Life’s Essential 8 (LE8), a multidimensional health metric, with OA risk and explored proteomic mechanisms.Methods In 102 794 UK Biobank participants without OA at baseline, LE8 scores (0–100) were derived from eight components. Incident OA was ascertained from medical records. Cox models estimated HRs. Plasma proteomics in a subset identified proteins linked to LE8 and OA, used to construct a protein risk score.Results Over 13.1 median years, 15 984 OA cases occurred. The highest versus lowest LE8 quartile had a 32% lower OA risk (HR 0.68, 95% CI 0.64 to 0.71), consistent across knee (HR 0.56), hip (HR 0.72) and hand OA (HR 0.57). Each SD increase in LE8 reduced risk by 14% (HR 0.86, 95% CI 0.84 to 0.87). Protective associations were stronger in individuals with younger phenotypic age (HR 0.86, 95% CI 0.84 to 0.88). Proteomics identified nine associated proteins (eg, fibroblast growth factor 21, insulin-like growth factor-binding protein 1); a protein risk score showed graded positive associations with OA.Conclusions Higher cardiovascular health is associated with substantially lower OA risk, modified by biological ageing. Proteomic pathways involving metabolism, inflammation and tissue remodelling may underlie this relationship, supporting cardiovascular health optimisation for OA prevention.

1076 Background: Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors plus endocrine therapy are standard first-line treatment for HR-positive/HER2-negative (HR + /HER2 - ) metastatic breast cancer (MBC). However, patients with brain metastases have poor prognosis and limited treatment options due to inadequate blood-brain barrier penetration of most agents and limited evidence for intracranial efficacy. SPH4336, a novel oral CDK4/6 inhibitor, exhibits potent CDK4/6 inhibition in preclinical models with favorable blood-brain barrier penetration. It has shown acceptable safety profiles and preliminary antitumor activities in advanced solid tumors, including HR + /HER2 - MBC. This study assessed the efficacy and safety of SPH4336 plus endocrine therapy in HR + /HER2 - MBC with brain metastases. Methods: This open-label, single-arm, phase II study enrolled patients aged 18-75 years with histologically confirmed HR + /HER2 - and radiologically confirmed brain metastases at 25 centers in China. Prior CDK4/6 inhibitor exposure before brain metastases was limited to <2 agents. Patients received SPH4336 (400 mg orally once daily) plus physician's choice of endocrine therapy (letrozole, fulvestrant, or exemestane) in 28-day cycles until disease progression or unacceptable toxicity. Primary endpoint was intracranial objective response rate (ORR) per RANO-BM criteria. Results: Between September 19, 2023, and August 22, 2025, 30 patients were enrolled. Two patients (6.7%) had a history of palliative radiotherapy for brain metastases. As of December 10, 2025, the median follow-up was 11.7 months (range: 1.6-26.7). Per RANO-BM criteria in 29 evaluable subjects, the intracranial ORR, disease control rate (DCR), and clinical benefit rate were 37.9% (95% CI: 20.7-57.7), 72.4% (95% CI: 52.8-87.3), and 44.8% (95% CI: 26.4-64.3), respectively. Based on RECIST 1.1, the extracranial ORR and DCR were 33.3% (95% CI:17.3-52.8) and 66.7% (95% CI: 47.2-82.7), respectively. The overall ORR was 33.3% (95% CI: 17.3-52.8), and the overall DCR was 60.0% (95% CI: 40.6-77.3). The median intracranial, extracranial, and overall progression-free survival were 8.4 months (95% CI: 1.9-not reached [NR]), 11.0 months (95% CI: 1.9-NR), and 8.1 months (95% CI: 1.9-11.0), respectively. Grade ≥3 treatment-related adverse events occurred in 70.0% of patients, most commonly γ-glutamyltransferase elevation (43.3%), aspartate aminotransferase elevation (20.0%), and neutrophil count decrease (20.0%). No treatment-related death occurred. Conclusions: SPH4336 plus endocrine therapy demonstrated clinically meaningful intracranial antitumor activity with a manageable safety profile in HR + /HER2 - MBC with brain metastases. These findings warrant further investigation in randomized studies for this patient population with high unmet medical need. Clinical trial information: NCT05872347 .

Cancer cachexia (CCx) is a complex, multifactorial syndrome associated with poor outcomes, yet its clinical identification is often hindered by unreliable recall of historical body weight. We developed an interpretable machine learning (ML) framework to detect CCx by integrating routinely collected metabolic and inflammatory hematological features from the nationwide multicenter INSCOC cohort in China (N = 16,858). Using a systematic, data-driven strategies, we identified a stable and biologically coherent set of features that collectively characterize a cachexia-associated phenotype. The final model demonstrates consistent predictive discrimination for CCx in both test cohort (AUC: 0.758, 95% CI: 0.742-0.775) and validation cohort (AUC: 0.748, 95% CI: 0.730-0.766). Importantly, this phenotype-based model generalizes under strict temporal validation and enables objective identification of CCx in real-world clinical settings without reliance on recalled body weight. Together, our findings support a conceptual shift from a purely weight-based syndrome of CCx toward an integrative metabolic-inflammatory phenotype.

IntroductionNatural killer cells (NK cells) play a critical role in the surveillance of tumor immunity. However, NK cell-based immunotherapy, including autologous and allogeneic NK cell reinfusion, has not brought significant clinical benefits to patients.MethodsTo identify factors that control the intrinsic cytotoxicity of NK cells, we utilized the histone deacetylase inhibitor valproic acid (VPA) to develop a NK cell cytotoxicity suppression model. With RNA-seq and functional assays, we identified a lncRNA, LINC02470, as a negative regulatory factor of NK cell-mediated cytotoxicity. LINC02470 was significantly upregulated in VPA-treated NK cells and was negatively associated with the cytotoxicity of NK cells. Knockdown of LINC02470 enhanced, and overexpression of LINC02470 suppressed antitumor activity in NK-92MI cells and human primary NK cells. Then reverse transcription-associated capture sequencing (RAT-seq) and mechanistic studies were explored to find the target and mechanisms of LINC02470.ResultsBy RAT-seq we found that LINC02470 functioned by targeting the Natural cytotoxicity triggering receptor 1 (NCR1) gene, which encodes the activating receptor NKp46 involved in the natural cytotoxicity. Mechanistic studies revealed that LINC02470 interacted with the regulatory elements of NCR1 and blocked the formation of an intrachromosomal interaction that is required for optimal expression of NCR1. In addition, LINC02470 inhibited the synthesis of NCR1 enhancer RNA. Through these dual mechanisms, LINC02470 induced a suppressive epigenotype in the NCR1 promoter and suppressed the expression of the NCR1 gene.DiscussionThe LINC02470-NCR1 axis identified in this study may serve as a novel target to improve therapeutic intervention of NK cells in tumor immunotherapy.

Background: Hypoxia-driven metabolic reprogramming is a hallmark of hepatocellular carcinoma (HCC) and depends critically on mitochondrial signaling. We sought to identify RNA-based molecular factors that orchestrate the hypoxia-mitochondria crosstalk and regulate metabolic adaptation in HCC cells. Methods: An integrated mtRNA-seq and mitochondria-specific LwaCas13a-BN-MLS RNA targeting approach was employed to profile RNA molecules aberrantly enriched in HCC mitochondria. Mitophagy was assessed via mt-Keima assay, immunofluorescence, transmission electron microscopy, and Western blotting of key autophagic markers. RNA-protein interactions were examined using RNA immunoprecipitation (RIP), electrophoretic mobility shift assays (EMSA), and computational structural modeling. In vitro and in vivo tumorigenicity was evaluated using colony formation, transwell invasion, wound healing, and subcutaneous xenograft models in nude mice. Results: Nuclear-encoded EGR1 mRNA was aberrantly translocated to mitochondria, where it functions as a non-translating mRNA (ntmRNA) essential for mitophagy. Mitochondria-specific EGR1 targeting disrupted mitochondrial homeostasis by accumulating damaged mitochondria, lowering ATP, increasing ROS, reducing membrane potential, diminishing spare respiratory capacity, and impairing hypoxia-induced mitophagy. Mechanistically, EGR1 ntmRNA promoted mitophagy through the HIF-1α/BNIP3/NIX axis by recruiting BNIP3 to mitochondria and coordinating its homodimerization via a 3'-UTR MRE. A synthetic MRE oligonucleotide rescued BNIP3 dimerization after EGR1 depletion. Finally, we demonstrated that EGR1 loss suppressed malignant phenotypes in vitro and reduced xenograft tumor growth in vivo. Conclusions: This study reveals a noncanonical role for EGR1 mRNA as an epigenetic regulator of mitophagy in HCC, thus expanding the functional repertoire of mRNA molecules beyond protein coding. Targeting this noncanonical EGR1 ntmRNA-BNIP3 homodimerization mechanism may suggest new therapeutic strategies for treating HCC.

To evaluate the efficacy and safety of the anti-lymphocyte activation gene-3 (LAG-3) antibody IBI110 in combination with sintilimab and chemotherapy in patients with advanced squamous non-small cell lung cancer (sqNSCLC). In this multicenter, randomized, open-label, phase II study, 153 patients with previously untreated advanced sqNSCLC were randomly assigned at a 1:1:1 ratio to one of three groups: IBI110 200 mg plus sintilimab (200 mg) and chemotherapy (n = 51), IBI110 600 mg plus sintilimab and chemotherapy (n = 51), or sintilimab plus chemotherapy (standard-of-care, SOC, n = 51). The primary endpoints included the objective response rate (ORR), progression-free survival (PFS) and safety. LAG-3 expression in tumor tissue was detected by immunohistochemistry (IHC) to explore its correlation with treatment efficacy. While no statistically significant differences in ORR, PFS, or overall survival (OS) were observed across the three arms in the overall population, promising efficacy signals emerged in the LAG-3 expression ≥ 2

e13545 Background: We initiated the first patient-centric, multicenter, phase II trial (CTONG2203, NCT 06092086) to investigate the efficacy and safety of first-line lorlatinib and other TKIs in advanced ALK-positive non-small cell lung cancer. The follow-up schedule of treatment intervention cohorts aligns with that of the CROWN study, requiring patients to undergo frequent on-site visits over a prolonged observation period. Approximately 30% of subjects expressed a preference for reduced visit frequency, with two withdrawals due to this demanding schedule. Methods: We have made appropriate adjustments to the follow-up procedures while preserving the reliability and validity of the study results. For subjects who have received 24 months of study treatment with efficacy benefit, investigators may extend the interval of response evaluation from 8 weeks to 12 weeks. Pre-adjustment data analysis validated that the extended interval does not compromise efficacy assessment. During visit cycles in which efficacy evaluation is not required, patients may have laboratory tests performed at local hospitals (qualified through prior verification of test standardization and result consistency with study sites) and sent the results to the investigators for assessment and archiving (imaging examinations must be conducted at the study site to ensure unified evaluation standards). In a multicenter setting, the follow-up site may be relocated—upon confirming consistency across sites in medical resources, detection capacity, and follow-up procedures. as well as and documented informed consent—to accommodate changes in subjects' work or domicile. All adapted measures were approved by the medical ethics committee to ensure they adhered to the trial’s scientific objectives and did not introduce bias into the results. Results: Participants reported that these modifications significantly reduced their travel and time costs associated with follow-up visits. No more patients dropped out due to visit-related burden. About 25% of the subjects have undergone laboratory tests at local hospitals, and comparative analysis with site-based tests showed no statistically significant differences (P > 0.05), confirming that local testing did not compromise data accuracy or safety assessments. In accordance with the aforementioned adjusted protocol, one subject will relocate from the Nanchang center to the Guangzhou center due to a job change, while another will transfer from the Guangzhou center to the Fuzhou center for closer proximity to her resident. Conclusions: By incorporating patient feedback to create adaptable visit schedules, patient-centric trials can optimize long-term monitoring without compromising data integrity and accuracy, offering valuable insights for future trial design. Clinical trial information: NCT06092086 .

Drug-induced liver injury (DILI) remains a major clinical challenge because effective treatments are limited. Natural polysaccharides may alleviate DILI in preclinical models by reducing oxidative stress, inflammation, immune dysregulation, apoptosis, and gut-liver axis dysfunction. This review summarizes the mechanisms of DILI caused by representative hepatotoxic drugs and evaluates polysaccharides from medicinal plants, edible fungi, algae, marine organisms, and food sources. It focuses on structure-activity relationships involving molecular weight, monosaccharide composition, glycosidic linkages, branching, uronic acid content, chain conformation, and chemical modification. Key pathways include nuclear factor erythroid 2-related factor 2/antioxidant response element (Nrf2/ARE), nuclear factor kappa B (NF-κB), phosphoinositide 3-kinase/protein kinase B (PI3K/Akt), apoptosis-related signaling, bile acid transport, and gut-liver axis regulation. Major barriers include low bioavailability, limited pharmacokinetic and safety data, unclear active forms in vivo, and insufficiently validated delivery systems. This review presents a DILI-centered structure-mechanism-activity framework for the rational development of natural polysaccharides as hepatoprotective agents.

Cancer cachexia is a multifactorial syndrome of progressive skeletal muscle wasting and functional decline that affects 50-80% of patients with advanced malignancies, frequently overlaps with sarcopenia, and contributes to 22-30% of cancer-related deaths. Effective therapies remain lacking, in part because the driving mechanisms are incompletely understood. Systemic inflammation-particularly interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α)-has long been considered central to muscle wasting, yet cytokine-targeted trials have shown limited efficacy, prompting investigation of additional pathways. Among these, endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) have emerged as candidates, and this review focuses specifically on the IRE1α/XBP1 branch. The rationale rests on three observations from recent preclinical studies: XBP1s activity is increased in cachectic muscle; XBP1s occupies regulatory regions of autophagy-lysosome and ubiquitin-proteasome genes, a direct transcriptional link to protein degradation that distinguishes it from the translation-attenuating PERK and folding-oriented ATF6 branches; and genetic or pharmacological suppression of IRE1α/XBP1 attenuates wasting in these models. We examine how tumor-derived signals activate IRE1α/XBP1 to upregulate both the autophagy-lysosome pathway (ALP) and ubiquitin-proteasome system (UPS); its crosstalk with inflammatory (JAK-STAT3, NF-κB) and metabolic (mitochondrial dysfunction, fatty acid metabolism) networks; the evidence across cancer models and clinical contexts; and the therapeutic potential of IRE1α inhibitors, XBP1-directed strategies, and nutritional approaches including arginine. We frame the ER stress-autophagy axis as a mechanistically plausible, potentially tractable therapeutic target that requires further cross-model and clinical validation.

Skeletal muscle mass assessment using computed tomography (CT) is crucial for evaluating nutritional status and prognosis in cancer patients. While the third lumbar vertebra (L3) level is widely accepted for this purpose, not all patients undergo abdominal CT scans. This study aimed to explore the potential of the third thoracic vertebra (T3) level as an alternative measurement site. This retrospective study included 257 patients with digestive system malignancies. Skeletal muscle area (SMA) and skeletal muscle index (SMI) were measured at both T3 and L3 levels using CT scans. Correlation analyses, linear regression models, and cox regression analyses were performed to evaluate the relationship between T3 and L3 measurements and their prognostic value. Strong correlations were observed between T3 and L3 measurements (r = 0.833 for SMA, r = 0.747 for SMI). A multivariate linear regression model effectively predicted L3 SMA from T3 SMA (adjusted R² = 0.829). Cox regression analyses revealed that lower T3 SMA and SMI were independently associated with increased mortality risk. Patients in the lowest quartile of T3 SMA had significantly higher mortality risk compared to those in the highest quartile (HR = 5.82, 95% CI: 1.86–18.16, P = 0.002), after adjusting for confounders. Similar results were observed for T3 SMI and L3 measurements. T3 skeletal muscle measurements strongly correlate with L3 measurements and serve as independent prognostic factors in patients with digestive system malignancies. T3 measurements offer a viable alternative for assessing skeletal muscle mass and predicting prognosis when L3 measurements are unavailable.

Circle RNA (circRNA) is a closed-loop nucleic acid resistant to exonuclease degradation. Their enhanced stability and potential for efficient protein expression through circRNA modification render them promising novel therapeutic agents for cancer treatment. In this study, we systematically investigated the antitumor and anti-inflammatory activities of circRNA vaccines in mice, as well as their effects on activating antigen-specific immune responses, through a meta-analysis. Subsequently, we further validated the immune-activating effects of circRNA using monocytes and T cells isolated from human peripheral blood mononuclear cells. We found that circRNA induces the activation and maturation of dendritic cells, as well as the responses of CD4 + and CD8 + T cells. These findings demonstrate the potential of circRNA to exert significant effects in therapeutic cancer vaccines.

BACKGROUND:Overcoming tyrosine kinase inhibitor (TKI) resistance improves survival in advanced epidermal growth factor receptor (EGFR)-mutated non-small-cell lung cancer (NSCLC). We therefore examined the safety and preliminary efficacy of pelcitoclax, a B-cell lymphoma-2 (BCL-2)/BCL-extra-large (BCL-xL) inhibitor, and osimertinib in patients with EGFR-mutated advanced NSCLC. METHODS:Enrolled patients included Cohort 1 (previously progressed after third-generation TKI treatment+chemotherapy), Cohort 2 (previously progressed after first-generation or second-generation TKI treatment+chemotherapy), and Cohort 3 (TKI treatment-naive±prior chemotherapy). Patients received intravenous pelcitoclax (160 mg in dose-expansion and either 160 or 240 mg in dose-escalation) weekly and oral osimertinib 80 mg daily. Primary endpoints were safety and recommended phase 2 dose (dose-escalation), objective response rate (ORR) and safety (dose-expansion). RESULTS:64 patients were enrolled (13, dose-escalation; 51, dose-expansion): 29 patients in Cohort 1, 8 in Cohort 2, and 27 in Cohort 3. One dose-limiting toxicity occurred at pelcitoclax 240 mg, and the recommended phase 2 dose was 160 mg plus osimertinib 80 mg. The ORR was 10.7% and median progression-free survival (mPFS) 2.7 months in patients previously progressed after third-generation TKI treatment+chemotherapy (Cohort 1) and 80.8% and 16.4 months in TKI treatment-naïve patients±prior chemotherapy (Cohort 3). mPFS was longer in Cohort 1 patients with high expression of BCL-xL (4.2 vs 2.7 months, p=0.058). CONCLUSIONS:Pelcitoclax combined with osimertinib showed promising safety and antitumor activity in EGFR-mutated NSCLC. TRIAL REGISTRATION NUMBER:NCT04001777.

Tropomyosin receptor kinases (TRK) tyrosine kinase inhibitors (TKIs) have demonstrated marked efficacy in neurotrophic receptor tyrosine kinase (NTRK) fusion positive tumors. However, resistance inevitably develops. Eratrectinib (VC004) is a next-generation selective TRK TKI which can overcome drug resistance. In this phase 1 study, patients with locally advanced or metastatic solid tumors were enrolled in the dose-escalation part. A standard 3 + 3 design was adopted to sequentially assign patients at 25 mg twice daily (BID), 50 mg BID, 100 mg BID, and 200 mg BID dose levels of oral eratrectinib. After each dose had been established, we expanded specific dose cohorts in patients with NTRK fusion positive locally advanced or metastatic solid tumors to obtain adequate data for safety, pharmacokinetics (PK), and efficacy. The primary endpoints of this study were safety, maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D). Between December 4, 2020 and November 4, 2021, 16 patients were enrolled in the dose-escalation part and a dose of 100 mg BID was identified as MTD. Between May 8, 2021 and March 19, 2025, 75 patients were enrolled in the dose-expansion part at doses of eratrectinib 25 mg BID, 50 mg BID, and 75 mg BID. Treatment-emergent adverse events (TEAEs) occurred in 94.7

BACKGROUND:Metabolic dysfunction is implicated in Alzheimer's disease (AD) pathogenesis. Branched-chain amino acids have been prospectively linked to dementia risk, yet prospective associations of composite metabolic vulnerability indices with incident AD remain untested. OBJECTIVES:This study aimed to examine associations of the metabolic vulnerability index (MVX), inflammatory vulnerability index (IVX), and metabolic malnutrition index (MMX) with incident AD in the United Kingdom Biobank (UKB). METHODS:Among 367,715 UKB participants without dementia (mean age 56.93 y, 54.3% female; 2006-2010 baseline), incident AD was ascertained through hospital and death registry linkage. Fully adjusted Cox models (model 3) constituted the prespecified primary analysis; 3 Bonferroni-corrected tests (α = 0.0167) addressed multiple comparisons. Restricted cubic splines characterized the association shape; interaction analyses examined potential effect modification by sex, age group, diabetes status, body mass index, inflammatory status, and polygenic risk. RESULTS:Over 13.7 y, 2615 participants developed AD. Per 1-SD increase, MMX [hazard ratio (HR) = 1.16, 95% confidence interval (CI): 1.12, 1.21; P = 4.93 × 10-13] and MVX (HR = 1.12, 95% CI: 1.07, 1.17; P = 3.72 × 10-6) were each associated with higher AD risk, both meeting the Bonferroni-corrected threshold; IVX showed no association (P = 0.108). Associations were approximately linear and monotonically increasing. Sex-specific associations were observed for MMX (stronger in males, P-interaction = 0.004) and MVX (stronger in females, P-interaction = 0.003). Sensitivity analyses confirmed robustness. CONCLUSIONS:MMX and MVX are independently associated with incident AD, supporting the clinical relevance of metabolic health monitoring in neurodegeneration risk stratification.