Background: Patients with SMARCA4-deficient non-small cell lung cancer (SMARCA4-dNSCLC) typically exhibit resistance to conventional therapeutic strategies and have an extremely poor prognosis. However, the clinicopathological landscape and tumor immune microenvironment (TIME) signatures of SMARCA4-dNSCLC after neoadjuvant therapy remain unclear.Methods: A cohort of 41 patients was retrospectively enrolled with SMARCA4-dNSCLC who received neoadjuvant therapy followed by surgery. Dual CD20/CD3 immunohistochemistry was performed in 32 post-immunotherapy specimens to assess tertiary lymphoid structures (TLS), and multiplex immunofluorescence was applied in 11 cases to profile tumor-infiltrating lymphocyte (TIL) subsets.Results: Lung adenocarcinoma (LUAD) was the predominant subtype (n = 25, 61.0%). Pathological response assessment revealed non-major pathological response (non-MPR) in 35 patients (85.4%), MPR in 4 (9.8%), and complete pathological response (CPR) in 2 (4.9%). KRAS mutation was significantly associated with worse disease-free survival (DFS, χ² = 11.921, P = 0.001) and overall survival (OS, χ² = 7.535, P = 0.006). Post-neoadjuvant pathologic nodal stage (ypN) emerged as the strongest prognostic indicator for both DFS (χ² = 17.006, P < 0.001) and OS (χ² = 13.659, P = 0.001). In the LUAD subgroup (n = 25), TTF-1 negativity (48%, n=12) showed borderline association with poor OS (P = 0.050). Mucus-secreting histology showed no survival correlation in patients receiving neoadjuvant immunochemotherapy. For TLS, total TLS abundance was the only parameter significantly associated with favorable DFS (χ² = 3.976, P = 0.046). Notably, high intratumoral (IT)-CD8+ T cell infiltration predicted shorter OS (P = 0.047) and DFS (P = 0.010).Conclusions: SMARCA4-dNSCLC is characterized by aggressive biology, limited therapeutic options, and poor overall survival. Factors contributing to resistance to neoadjuvant therapy include KRAS mutation, ypN stage, TTF-1 negativity, high level of CD8⁺ T-cell infiltration, and TLS. These findings highlight the need for biomarker-driven stratification and immune-modulating strategies to improve outcomes in this aggressive subtype.​

BackgroundDistinguishing non-small lung cancer (NSCLC) with tuberculosis from pulmonary tuberculosis (PTB) is still a major clinical problem. Misdiagnosis or missed diagnosis can lead to missed opportunities for optimal treatment, making highly sensitive diagnostic criteria crucial.MethodsDatabase analysis and histological analysis were used at the same time. A total of 55 patients were included in the histological analysis, including 20 patients with both NSCLC and PTB (NSCLC-PTB group), 20 patients with NSCLC alone (NSCLC group), and 15 patients with PTB alone (PTB group). The levels of NLRC4 and NLRP3 in each sample were analysed using the optical density method. Statistical analyses were performed, including the LIMMA algorithm, regression, and ROC analysis, to assess biomarker levels and their correlation with clinical outcomes.ResultsThe expression of NLRC4 and NLRP3 was significantly down-regulated in NSCLC tissues (both P < 0.001), and low expression of NLRC4 was associated with shorter overall survival (HR = 0.76, P < 0.001), while low expression of NLRP3 was associated with longer survival (HR = 1.21, P < 0.001). The level of NLRC4 in cancer nodules in the NSCLC-PTB group was significantly lower than that in the PTB group (0.0177 ± 0.0218 vs. 0.0299 ± 0.0117, P = 0.021). The level of NLRP3 in adjacent nodules in the NSCLC-PTB group was significantly higher than that in the PTB group (0.0398 ± 0.0282 vs. 0.0097 ± 0.0078, P < 0.001). At the same time, the results show that NLRC4 has the best diagnostic effect in squamous cell carcinoma, patients aged 60 and above, as well as NLRP3 in patients below 60, and the combination of NLRC4 and NLRP3 in adenocarcinoma.ConclusionThe use of NLRC4 and NLRP3 as biomarkers can improve the certainty of NSCLC prediction and has great prospects.

PPP2R3A is a key regulatory subunit of the PP2A B’’ family that encodes PR130 and PR72, two isoforms highly expressed in the heart. It has been implicated in heart failure and represents a potential molecular hub connecting pathological remodeling to disease progression. However, its functional dynamics in pressure overload-induced heart failure remain unclear. This study aims to investigate the expression changes and regulatory mechanisms of PPP2R3A in pressure overload-induced decompensated heart failure. A chronic pressure overload model was established in C57BL/6J mice using transverse aortic constriction (TAC), and cardiac function and remodeling were assessed by echocardiography and histological analyses. In vitro, PPP2R3A was silenced or overexpressed in H9c2 cardiomyocytes to evaluate its effects on transcription, viability, and apoptosis. Protein interactions and downstream signaling were examined using co-immunoprecipitation, GST pull-down, and Western blotting. PPP2R3A expression was markedly downregulated in the TAC model, accompanied by impaired systolic function, pathological hypertrophy, and fibrosis. In cardiomyocytes, PPP2R3A knockdown exacerbated apoptosis and reduced viability, whereas overexpression promoted robust survival. Mechanistically, PPP2R3A stabilized the β-catenin destruction complex, thereby suppressing canonical Wnt/β-catenin signaling and preventing maladaptive β-catenin-driven transcription. Proteomic assays identified a direct interaction between PPP2R3A and RGS19, with PPP2R3A negatively regulating RGS19 protein abundance and Ser/Thr phosphorylation. PPP2R3A protects the heart against pressure overload-induced heart failure by stabilizing the β-catenin degradation complex and limiting maladaptive Wnt/β-catenin signaling. Its regulation of RGS19 reveals a novel axis in the transition from compensated to decompensated heart failure, highlighting PPP2R3A as a potential therapeutic target.

Bronchiolar adenoma (BA) is a generally benign peripheral lung neoplasm with a bilayered structure of basal and luminal cells. Recently, an increasing number of bronchiolar adenoma-like tumor with squamous epithelial metaplasia (BATSM) have been reported, raising the question of whether they represent variant subtypes of BA or potentially novel tumor entities. Pulmonary metastasis of ameloblastoma (MA) shares morphological similarities with BATSM, exhibiting TTF-1/Napsin A-positive luminal cells and P40/P63-positive basal cells; this overlap can lead to misdiagnosis of MA as BATSM. We collected 5 MA and 10 BATSM cases, analyzing their morphology, immunohistochemistry, elastic fiber staining and molecular pathology. MA presents as well-circumscribed bronchiole-unrelated nodules with alveolar destruction, intraluminal serous secretions, and Calretinin-positive stellate reticulum-like cells. BATSM is bronchiole-associated, preserves alveolar architecture, and is Calretinin-negative with weak basal TTF-1 positivity. 80% of MA cases harbored BRAF V600E mutations; 30% of BATSM cases exhibited EGFR exon 20 insertions. This study highlights the need for integrating clinical history, morphology, immunohistochemistry and molecular testing to avoid misdiagnosing MA as BATSM.

Human epidermal growth factor receptor 2 (HER2) is a key biomarker and therapeutic target in several malignancies, including breast, gastric, and other solid tumors. Recent advancements in cancer molecular profiling and the Food and Drug Administration's approval of trastuzumab deruxtecan for HER2u2010positive panu2010tumor indications have highlighted the broader relevance of HER2 alterations across diverse cancers. However, the lack of standardized guidelines for HER2 testing in a panu2010tumor context creates variability in clinical practice, hindering the optimal implementation of HER2u2010targeted therapies beyond traditional indications. To address this gap, a multidisciplinary panel of Chinese experts has developed a consensus providing comprehensive recommendations on diagnostic strategies, testing methodologies, and clinical applications of HER2 overexpression detection. By establishing a unified framework for HER2 overexpression assessment, this consensus aims to enhance the precision of HER2 testing, optimize patient selection for targeted therapies, and improve clinical outcomes across a wide spectrum of HER2 overexpression malignancies.

[This retracts the article DOI: 10.1016/j.isci.2025.113945.].

Primary pulmonary lymphoepithelial carcinoma (PPLEC) is a rare Epstein–Barr virus (EBV)-associated subtype of lung cancer classified under pulmonary squamous cell carcinoma (PSCC) in the fifth WHO classification of thoracic tumors. However, its clinicopathological features remain poorly defined. This study compared the histomorphological characteristics and prognostic outcomes of PPLEC and conventional non-keratinizing PSCC, a morphologically mimicking tumor entity. We retrospectively analyzed 103 Epstein-Barr virus-encoded small RNA (EBER)-positive PPLEC cases and 86 PSCC cases diagnosed at Shanghai Pulmonary Hospital from October 2014 to August 2023. Based on tumor morphology and tumor-infiltrating lymphocyte (TIL) density, lesions were categorized as stromal lymphocyte-rich or lymphocyte-poor subtypes. Clinicopathological features, immunohistochemistry, molecular profiles, and survival outcomes were evaluated. Compared with patients with PSCC, PPLEC cases presented a higher female proportion (37.9

The diffuse co-expression of thyroid transcription factor-1 (TTF-1) and p40 defines a rare and diagnostically challenging subtype of non-small cell lung carcinoma (NSCLC). Due to its extreme rarity, the clinicopathologic and molecular characteristics of this entity remain poorly characterized. We conducted a comprehensive analysis of the largest single-institution cohort to date (n = 19) of NSCLCs with diffuse TTF-1/p40 co-expression. All cases underwent detailed histopathologic review. Immunohistochemistry (IHC) utilized specific antibody clones (TTF-1: 8G7G3/1; p40). Molecular profiling was performed via next-generation sequencing in a subset of cases, including multi-region analysis for select tumors. The cohort mainly consisted of elderly male smokers (median age 65; 84.2

BackgroundNeoadjuvant chemo-immunotherapy (NCI) has significantly improved outcomes in advanced lung squamous cell carcinoma (LUSC). However, some patients remain resistant to NCI, resulting in poor outcomes. The mechanisms behind this resistance remain unclear.MethodsForty LUSC patients receiving NCI were selected and categorized into major pathological response (MPR) and non-MPR groups based on their pathological response. Pre- and post-treatment samples underwent bulk RNA sequencing (RNA-seq) to assess the composition of immune cell subtypes, including T cells, B cells, NK cells, dendritic cells, and macrophages. A panel of 134 immune cell subtypes were further analyzed to differentiate between “cold” and “hot” tumor immune phenotypes.ResultsAfter surgery, 75% of patients achieved MPR, while 25% were classified as non-MPR. In MPR patients, NCI transformed the tumor immune microenvironment (TME) from a “cold” to a “hot” phenotype, characterized by increased anti-tumor immune activity. We identified seven genes potentially linked to NCI response. Among these, HOXC13 was associated with reduced immune-cell infiltration and inferior NCI response. High HOXC13 expression was associated with worse progression-free survival (PFS) and overall survival (OS), as confirmed by the OAK database.ConclusionsNCI altered the TME and was linked to treatment response in LUSC. Identifying predictors of immunotherapy efficacy, such as HOXC13, provides potential strategies to overcome resistance in clinical practice.

AIM:The aim of this study was to evaluate whether the utility of cytokeratin (AE1/AE3) rapid immunohistochemistry (IHC) in combination with haematoxylin-eosin (H&E) staining improves the intraoperative diagnosis of spread through air spaces (STAS) on frozen sections (FS). METHODS AND RESULTS:This study included 153 patients. Three pathologists independently evaluated STAS on FS using either HE staining alone or in combination with rapid IHC, with postoperative paraffin sections serving as the gold standard. Sensitivity and specificity were compared, along with interobserver and intraobserver agreement (κ values), diagnostic time, and causes of misdiagnosis. Compared with HE alone, HE combined with rapid IHC staining increased mean diagnostic sensitivity from 73.7% to 87.8% and specificity from 85.5% to 89.9% across pathologists with varying levels of experience. Mean intraobserver agreement improved from κ = 0.644 (83.9%) to κ = 0.907 (95.9%), and mean interobserver agreement improved from κ = 0.485 (65.0%) to κ = 0.671 (77.2%). Average diagnostic time decreased from 2 min 53-23 s. Misdiagnoses were primarily attributable to a limited number of STAS clusters, confusion with macrophages, and artefacts. CONCLUSIONS:Intraoperative H&E combined with rapid IHC enhanced the sensitivity and specificity of STAS detection, improved interobserver/intraobserver agreement and reduced diagnostic time during FS evaluation without significantly extending the overall intraoperative FS processing time. Nevertheless, additional multicenter validation is required.

Purpose This study sought to elucidate the possible biological association between BA and lung adenocarcinoma through an analysis of cases in which both lesions coexist within the same specimen.Methods In our cohort, the BA and lung cancer components of nine mixed-type BAs were microdissected using the Millisect system for whole-exome sequencing (WES) and their histopathological, immunohistochemical, and genomic profiles were comparatively evaluated.Results Histopathologically, BA regions of mixed-type BAs exhibited a classic bilayered architecture, comprising continuous luminal and basal cells. The adjacent monolayered atypia cuboidal cells were diagnosed as adenocarcinoma in situ (AIS, N=4), minimally invasive adenocarcinoma (MIA, N=2), and invasive adenocarcinoma (ADC, N=3). Immunohistochemically, both luminal and basal cells in BA regions expressed thyroid transcription factor 1 (TTF1) with more heterogeneous staining intensity compared to that in tumor areas. Molecularly, the EGFR mutations were the most frequently detected in both components. In BA components, the EGFR mutations included exon 19 p.S752F, exon 19 deletions (p.L747_T751delins P and p.E746_T751delinsVP), and compound G719C/S768I. Tumor components exhibited exon 28 S1130C, exon 19 indel (p.E746_S752delins), and exon 18 p. G719C mutations. Only three cases demonstrated limited overlap of mutations and copy number variations (CNVs) between BA and tumor components. Phylogenetic analysis revealed that six cases shared truncal alterations in genes such as KMT2A, PIK3CA, SETD2, MITF, PBRM1, and SRSF3, one case exhibited a shared canonical lung cancer mutation (EGFR p. G719C), with the BA component additionally harboring p.S768I mutation.Conclusion There is insufficient evidence to support BA as a premalignant lesion for lung adenocarcinoma base on morphological and molecular variables, and they may represent distinct pathological entities.

Human epidermal growth factor receptor 2 (HER2) is a key biomarker and therapeutic target in several malignancies, including breast, gastric, and other solid tumors. Recent advancements in cancer molecular profiling and the Food and Drug Administration's approval of trastuzumab deruxtecan for HER2-positive pan-tumor indications have highlighted the broader relevance of HER2 alterations across diverse cancers. However, the lack of standardized guidelines for HER2 testing in a pan-tumor context creates variability in clinical practice, hindering the optimal implementation of HER2-targeted therapies beyond traditional indications. To address this gap, a multidisciplinary panel of Chinese experts has developed a consensus providing comprehensive recommendations on diagnostic strategies, testing methodologies, and clinical applications of HER2 overexpression detection. By establishing a unified framework for HER2 overexpression assessment, this consensus aims to enhance the precision of HER2 testing, optimize patient selection for targeted therapies, and improve clinical outcomes across a wide spectrum of HER2 overexpression malignancies.

Although immunotherapy for colorectal cancer (CRC) has recently gained widespread attention, many patients continue to exhibit inherent or acquired resistance due to a lack of tumor-infiltrating lymphocytes and the poor immunogenicity of cancer cells within an immunosuppressive tumor microenvironment. Advances in high-throughput sequencing and bioinformatics have increasingly highlighted the role of the gut microbiome (GM) in modulating the quantity and phenotypes of innate and/or adaptive immune cells, thereby influencing CRC pathogenesis and the clinical response to immunotherapy. The GM maintains a symbiotic relationship with the host, contributes to protection against opportunistic pathogens, and supports intestinal homeostasis. Dysbiosis in GM composition and metabolite profiles drive uncontrolled inflammatory cascades, induces oxidative DNA damage, and promotes neoplastic progression. Furthermore, targeting GM populations, such as next-generation probiotics or dietary interventions, can enhance the prevalence of effector T cells in a “hot” immunogenic microenvironment, thereby ameliorating the efficacy of CRC immunotherapy, improving survival and potentially reducing toxicities in patients. This review briefly summarizes current findings and molecular mechanisms underlying host-GM mutualism under physiological and cancerous conditions, which may inform the development of novel strategies for CRC diagnosis, treatment, and prevention.

PURPOSE:This study aimed to provide a detailed clinicopathological, molecular genetics, and immune landscape analysis of a large cohort of primary thoracic NUT carcinomas to identify diagnostic challenges, uncover potential therapeutic targets, and define the spatial heterogeneity of the tumor immune microenvironment (TIME). MATERIALS AND METHODS:Fifty-three thoracic NUT carcinoma cases were analyzed using integrated immunohistochemistry, fluorescence in situ hybridization, targeted RNA sequencing, and multiplex immunofluorescence. RESULTS:Histologically, the majority of tumors exhibited pleomorphic presentations. Notably, we observed diverse, atypical morphological patterns, including squamous like, basaloid, neuroendocrine tumor like, and undifferentiated, pseudoglandular structure, and lymphoma-like presentations. Immunophenotypically, tumor cells consistently expressed keratins, p63 or p40 and NUT (100%), with focal expression of Syn and CgA in a subset. RNA sequencing identified NUTM1 fusion partners in 20 cases: BRD3::NUTM1, BRD4::NUTM1, NSD3::NUTM1, and notably, the first reported thoracic NUT carcinoma case with YAP1::NUTM1 fusion, which also exhibited SMARCA4 deficiency. Specifically, 2 cases exhibited pseudoglandular structure with myxoid stroma, 1 case displayed a predominantly lymphoma-like morphology, and 2 basaloid cases contained NSD3::NUTM1 fusions. Follow-up data were available for limited 33 patients (8 survivors and 25 deaths). Male sex was associated with improved survival in univariate analysis, whereas fusion type was not an independent prognostic factor. Furthermore, we characterized the TIME of thoracic NUT carcinoma (6 cases), demonstrating the presence of cytotoxic T cells, macrophages, and both mature and immature tertiary lymphoid structures. This heterogeneity in the TIME may contribute to the variable response to immunotherapy in NUT carcinoma. CONCLUSIONS:Primary thoracic NUT carcinoma exhibits significant pathological and immune microenvironmental heterogeneity, which was first described, as evidenced by the identification of a novel YAP1::NUTM1 fusion and diverse immune cell infiltrates. This heterogeneity warrants further investigation because it may inform prognostic stratification and the development of immune-targeted therapies.

Combined pulmonary fibrosis and emphysema-associated pulmonary hypertension (CPFE-PH) has emerged as a distinct third category of PH, yet its detailed clinical-hemodynamic profile, pathological features, and comparative outcomes remain poorly defined. This study aims to characterize the phenotype of CPFE-PH and compare it with chronic obstructive pulmonary disease-related PH (COPD-PH) and idiopathic interstitial pneumonia-related PH (IIP-PH). In this multicenter cohort study, we analyzed 113 patients with CPFE-PH, 277 with COPD-PH, and 78 with IIP-PH, all diagnosed by right heart catheterization. Clinical, physiological, imaging, pathological, treatment response, and survival data were statistically compared across groups. CPFE-PH patients were older, predominantly male smokers, and exhibited preserved ventilatory function but severely reduced diffusing capacity (DLCO 31.6

The peroxynitrite (ONOO-) generated by reactive oxygen species (ROS) and reactive nitrogen species (RNS) under ultrasonic treatment has been recognized as a powerful tool in tumor apoptosis induction in recent years. However, the short lifespan and difficult transportation of ONOO- make it difficult to exert good anti-tumor effect. Therefore, we constructed a multifunctional pH-sensitive bionanoparticle, M@DRSZ. The nanoparticle (NPs) is composed of Zeolitic Imidazolate Framework-8 (ZIF-8), loaded with doxorubicin (DOX), S-Nitrosomercaptosuccinic acid (S-MSA) and Rhein (Rh), and finally encapsulated with the A549 tumor cell membrane. After optimization, the M@DRSZ was characterized by good particle size of 203.1 nm and excellent stability. It can generate nitric oxide (NO), ROS and ONOO- in vitro and in vivo, disrupting the metabolic homeostasis in A549 cells. Also, M@DRSZ exhibited superior cellular apoptotic ability after being treated with ultrasound (US), which could induce mitochondrial damage and lysosomal destruction. Additionally, the NPs behaved good tumor targeting and effectively prolonged drug retention according to in vivo experiments. Their penetration into tumor tissues was enhanced with the help of MMP-2 protein synthesis. Along with the powerful tumor-suppression effect, the M@DRSZ could evoke potent antitumor immune response, including promoting the mature of DC cells, reducing the number of regulatory T cells, and restoring the infiltration of CD8+ and CD4+ T cells. In conclusion, a multifunctional bionanoparticle that integrated chemotherapy, sonodynamic therapy (SDT), homotargeting strategies, ONOO--mediated apoptosis and immunomodulation was developed. And the study is aspired to provide a new strategy for enhancing immunotherapy sensitivity of systemic curing of lung cancer.

The Vici syndrome protein EPG5 acts as a tethering factor determining the fusion specificity of autophagosomes with late endosomes/lysosomes. Here we demonstrated that during C. elegans development, EPG-5 modulates SMA and MAB TGFB/TGF-β signaling in controlling body size and also WNT signaling in regulating cell migration. EPG-5 is required for retrograde trafficking of the TGFB receptor SMA-6 and WLS/Wntless homolog MIG-14. In epg-5 mutants, SMA-6 and MIG-14 are trapped within hybrid endosomal structures, which colocalize with SNX-1- and SNX-3-labeled vesicles, respectively. Basolateral recycling processes of transmembrane cargos H.s.TFR/hTfR and H.s.IL2RA/hTAC are also defective in epg-5 mutants. Depletion of EPG-5 causes defective RAB-5 and RAB-7, and RAB-5 and RAB-10 conversion, leading to the formation of these hybrid vesicles. The defects in endocytic trafficking and autophagy in epg-5 mutants are ameliorated by knocking down components of the HOPS complex. Our study demonstrates the intersection between the autophagy pathway and the endocytic pathway, providing insights into the pathogenesis of amyotrophic lateral sclerosis (ALS) and Vici syndrome.Abbreviations: ALM: anterior lateral microtubule; ATG: autophagy related; AVM: anterior ventral microtubule; CORVET: class C core vacuole/endosome tethering; DAF-4: abnormal dauer formation 4; DIC: differential interference contrast; EPG: ectopic PGL granules; EPG-5: ectopic P granules 5; GAP: GTPase activating protein; GFP: green fluorescent protein; HOPS: homotypic fusion and vacuole protein sorting; H.s.IL2RA/hTAC: human interleukin 2 receptor subunit alpha; H.s.TFR/hTfR: human transferrin receptor; L1/L4: the first/fourth larval; mCh: mCherry; MIG-14: abnormal cell migration 14; PLM: posterior lateral microtubule; PVM: posterior ventral microtubule; RAB: ras-related protein; RFP: red fluorescent protein; RME-1: receptor mediated endocytosis 1; SMA-6: small 6; SNARE: soluble N-ethylmaleimide-sensitive factor attachment protein receptor; SNX: sorting nexin; TBC-2: TBC1 (Tre-2/Bub2/Cdc16) domain family 2; TGFB/TGF-β: transforming growth factor beta; TGN: trans-Golgi network; VPS: related to yeast vacuolar protein sorting factor; WT: wild type.

The intricate molecular landscape within tissues holds crucial information about cellular behavior and disease progression, yet capturing this complexity at a spatial level remains challenging. While Spatial transcriptomics (ST) offers valuable insights into gene expression patterns within their native tissue context, its widespread adoption is hindered by high costs and limited gene detection capabilities. Here we introduce CarHE (Contrastive Alignment of gene expRession for hematoxylin and eosin image), a method that overcomes these limitations by accurately predicting high-dimensional ST data (over 10,000 genes) solely from readily available H&E (Hematoxylin and Eosin) stained images. This novel pre-trained architecture employs contrastive learning through two mechanisms: cell-type-based transcriptomics information transfer and image-based histology information transfer. These mechanisms precisely align image features with spatial single-cell gene expressions, achieving prediction accuracies exceeding 0.7 (up to 1.7 folds compared to second best) across diverse tissue types and species. CarHE’s superior performance extends to identifying subtle pathological features such as tertiary lymphoid structures in various cancers, including breast cancer, lung cancer, melanoma and ccRCC (clear cell renal cell carcinoma), and reconstructing 3D spatial transcriptomics from images alone, offering a cost-effective and robust alternative for large-scale spatial transcriptomics. We further validated CarHE’s effectiveness by predicting DFS (Disease-Free Survival) from >1,600 lung cancer patients HE images, achieving a significantly higher AUC (Area Under the Receiver Operating Characteristic Curve) of 0.73 compared to state-of-the-art alternatives (0.58-0.64). ### Competing Interest Statement The authors have declared no competing interest. National Key R&D Program of China, 2022YFA1004800, 2025YFF1207900 Natural Science Foundation of China, T2341007, T2350003, 12131020, 42450084, 42450135, 12326614, and 12426310 Zhejiang Province Vanguard Goose-Leading Initiative, 23JS1401300 Zhejiang Province Vanguard Goose-Leading Initiative, 2025C01114 JST Moonshot R&D, JPMJMS2021 Hangzhou Institute for advanced study of UCAS, 2024HIAS-P004