Le Meng
Xiangyu Zhu†
Bowen Wang
Haoxun Zhang
Guoling Zhang
Chunyang Wang- Department of Urology, the First Affiliated Hospital of Harbin Medical University, HeiLongJiang Harbin, China
Bladder cancer remains a significant global health challenge, particularly affecting male populations. While radical cystectomy and chemotherapy have been mainstays of treatment, their substantial morbidity and impact on quality of life have driven the development of bladder-preserving immunotherapeutic strategies. Clinical trial data support the use of ICIs as first-line therapy for cisplatin-ineligible patients, second-line treatment for platinum-refractory disease, and maintenance therapy. This review comprehensively summarizes the advances in bladder cancer immunotherapy, focusing on the tumor immune microenvironment and emerging treatment modalities, as well as the roles of immune checkpoint inhibitors (ICIs) targeting PD-1/PD-L1 and CTLA-4 pathways, which have demonstrated remarkable efficacy in both muscle-invasive (MIBC) and non-muscle invasive bladder cancer (NMIBC). This review also provides novel approaches including combination immunotherapies, tumor vaccines, adoptive cellular therapies, and oncolytic viruses. Overall, these immunotherapeutic advances are transforming bladder cancer management, offering improved outcomes while reducing treatment morbidity.
1 Introduction
Bladder cancer remains one of the most common malignancies among male populations (1, 2). Conventional treatment modalities, such as radical cystectomy and neoadjuvant chemotherapy, are associated with considerable morbidity and a profound impact on patients’ quality of life, prompting increasing interest in bladder-preserving therapeutic approaches (3, 4). While radical cystectomy demonstrates favorable oncological control, high recurrence rates and suboptimal five-year survival rates persist—even in cases with negative surgical margins and lymph node involvement—highlighting the urgent demand for novel anti-tumor strategies (5).
Recent advancements in immunotherapy have revolutionized the therapeutic paradigm for bladder cancer. Immune checkpoint inhibitors, particularly those targeting CTLA-4 and PD-1/PD-L1 pathways, play a crucial role in counteracting tumor immune evasion mechanisms (6, 7). These developments not only enhance treatment efficacy but also provide valuable insights into the mechanisms underlying tumor immune escape. Key approaches include immune checkpoint inhibitors, tumor vaccines, adoptive cellular immunotherapy, oncolytic immunotherapy, and biological response modifiers. Among these, CAR-T cell therapy and immune checkpoint inhibitors have demonstrated particularly promising clinical outcomes (8, 9). This review synthesizes current research on the immunological microenvironment and immunotherapy in bladder cancer, with a focus on strategies designed to reactivate the immune system against tumor cells. Besides, this review further provides evidence-based insights and potential directions for future bladder cancer treatment.
2 Immune microenvironment of bladder cancer
The tumor microenvironment (TME) consists of malignant cells, immunomodulatory components, and stromal elements, with the immune compartment exerting a profound influence on disease progression (10–12). In urothelial carcinoma, major immune effectors include CD4+ T helper cells, cytotoxic CD8+ T lymphocytes (CTLs), dendritic cells (DCs), tumor-associated macrophages (TAMs), and myeloid-derived suppressor cells (MDSCs) (13). CD4+ T cells differentiate into Th1 and Th2 subsets, with Th1 cells mediating antitumor immunity via IFN-γ and TNF-α, whereas Th2 cells promote oncogenesis through IL-4 and IL-5 (14). A Th2-skewed immune milieu, characterized by increased IL-4, IL-5, and IL-10, is frequently observed in affected patients (15). IL-10, in particular, exerts immunosuppressive effects primarily through activation of the JAK1/STAT3 pathway, which impairs dendritic cell and macrophage maturation, suppresses co-stimulatory molecule expression (CD80/CD86 and MHC-II), and diminishes proinflammatory cytokine secretion (16–18). These changes result in defective priming and expansion of cytotoxic CD8+ T lymphocytes, thereby fostering an immune-privileged tumor niche (19, 20). Concurrently, IL-10–driven STAT3 activation facilitates regulatory T cell differentiation, reinforcing immune tolerance and enabling tumor immune evasion (21, 22). Notably, neutralization of Th2-associated IL-10 has been shown to enhance the therapeutic efficacy of BCG immunotherapy (14, 23, 24). CTLs eliminate malignant cells through perforin–granzyme cytotoxicity and Fas–FasL signaling, with tumor-specific neoantigens augmenting their activity (25). In addition, CD8+ T cells induce ferroptosis via IFN-γ, thereby promoting antigen cross-presentation (26). Importantly, immune cell density and spatial organization within bladder tumors are heterogeneous (27, 28). Formation of tertiary lymphoid structures (TLS) at the tumor-stroma interface is associated with augmented antigen presentation, a favorable CD8+/Treg ratio, and improved patient survival, whereas an immune-excluded phenotype characterized by CD8+ T cells restricted to the tumor periphery without core infiltration is often linked to poor responses to immune checkpoint inhibitors (29, 30).
Regulatory T cells (Tregs) suppress effector T-cell activity through the secretion of immunosuppressive cytokines, including transforming growth factor−β (TGF−β) and IL−10, and by expressing inhibitory receptors such as CTLA−4 and LAG3, both of which are associated with BCG resistance and early disease recurrence (31, 32). Additional checkpoint receptors, notably TIM−3 and TIGIT, are frequently upregulated on Tregs and exhausted CD8+ T cells within the bladder TME, where they foster an immunosuppressive milieu and contribute to therapeutic resistance (33, 34). A high CD8+/Treg ratio has been linked to improved prognosis (35, 36). MDSCs further impair antitumor immunity by suppressing T- and natural killer (NK)-cell function through arginase−1 (ARG1) and inducible nitric oxide synthase (iNOS), while also exerting profound metabolic constraints on cytotoxic lymphocytes (37–39). ARG1 depletes extracellular L−arginine, diminishing CD3ζ chain expression and TCR signaling in T cells, whereas iNOS generates nitric oxide that forms peroxynitrite, leading to nitration of TCR components and subsequent T−cell apoptosis (40–42). These mechanisms collectively suppress CD8+ T−cell proliferation and cytotoxicity, creating an immunosuppressive niche that favors tumor progression and correlates strongly with advanced disease and poor clinical outcomes (23, 43, 44). TAMs, particularly the M2-polarized subset, are key orchestrators of this suppressive TME (45, 46). IL−4 and IL−13 secreted by Th2 cells activate STAT6 in macrophages, driving M2 polarization (47). M2−TAMs secrete VEGF, which promotes angiogenesis and tumor vascularization, and TGF−β, which facilitates extracellular matrix remodeling, invasion, and cytotoxic immune suppression (48). In addition, they produce IL−10 and ARG1, reinforcing immune tolerance by dampening effector T−cell function and promoting Treg expansion (23, 43). These mechanisms collectively contribute to tumor progression, immune evasion, and resistance to immunotherapy. Furthermore, PD-1/PD-L1 interactions between immune and tumor or stromal cells are central to local immune tolerance (49). Other checkpoint molecules including CTLA-4, LAG3 and TIGIT represent additional therapeutic targets currently under active investigation (50). Together, these immune components constitute a dynamic ecosystem where the balance between antitumor immunity mediated by factors such as CD8+ T cells and tertiary lymphoid structure formation, and immunosuppressive mechanisms involving regulatory T cells, myeloid-derived suppressor cells, tumor-associated macrophages and checkpoint engagement dictates disease evolution and therapeutic outcomes (51, 52). Elucidating these complex immune interactions provides a strong rationale for developing immune checkpoint blockade, adoptive cell therapy and combinatorial immunotherapeutic strategies in bladder cancer (Figure 1).
Figure 1. Immune Microenvironment and Immunotherapy of Bladder Cancer.
3 Immunological diagnosis of bladder cancer
Histopathological evaluation remains the gold standard for diagnosing urothelial carcinoma, with cystoscopy serving as the principal modality for both preoperative assessment and postoperative surveillance (53). Recent advances have introduced non-invasive immunodiagnostic strategies for urothelial carcinoma, notably assays for nuclear matrix protein−22 (NMP−22), bladder tumor antigen (BTA), and urinary cytology–based markers (uCyt+) (54–56). NMP-22 is a urinary biomarker overexpressed in affected patients, exhibits 52–59% sensitivity and 87–89% specificity (55, 56). The BTAstat assay achieves 64–69% sensitivity and 73–77% specificity, whereas the ELISA-based BTA−TRAK test shows 66% and 69%, with improved detection of high−grade tumors (57). uCyt+ identifies tumor-associated proteins in exfoliated urinary cells (73% sensitivity, 66% specificity), thereby reducing the need for unnecessary cystoscopy (58). Importantly, immunomagnetic enrichment coupled with immunofluorescence detection of circulating tumor cells (CTCs) demonstrates 35% sensitivity and 97% specificity for diagnosing urothelial malignancies, with CTC presence independently predicting unfavorable prognosis (59). Beyond simple enumeration, the phenotypic profiling of CTCs has revealed that PD-L1 expression on CTCs may serve as a dynamic biomarker of adaptive immune resistance (60). PD-L1–positive CTCs can directly suppress cytotoxic T cell activity, mirroring the tumor microenvironment’s immunosuppressive mechanisms.
4 Emerging immunotherapeutic strategies for bladder cancer
4.1 Intravesical BCG immunotherapy
Intravesical BCG administration remains the gold standard therapy for non-muscle invasive urothelial carcinoma. Its immunomodulatory effects are mediated by multiple mechanisms. Bacterial cell wall components, including antigen 85, bind to urothelial fibronectin and promote phagocytosis by antigen-presenting cells and malignant cells (61). Microbial recognition relies critically on pattern recognition receptors such as TLR2, TLR4, and TLR9 (62, 63). In addition to exerting direct cytotoxic effects, BCG induces the release of inflammatory mediators (IL-6, IL-8, TNF-α, GM-CSF), which recruit immune effector cells including T lymphocytes, B cells, and dendritic cells. Secondary cytokines such as IL-1β, IL-2, IFN-γ, and TRAIL subsequently activate innate and adaptive immune pathways, ultimately resulting in tumor cell apoptosis (64, 65). Current investigative efforts focus on three key domains: mechanistic elucidation, predictive biomarker discovery, and therapeutic optimization. Clinical parameters such as tumor burden, histological grade, and prior recurrence patterns influence therapeutic response (66). Moreover, molecular biomarkers (p53, retinoblastoma protein, survivin expression) and immunological parameters (urinary immune cell profiles) are emerging as promising predictive potential (66, 67). Notably, increased urinary regulatory T cell counts following BCG instillation associate with diminished therapeutic efficacy (68). The CyPRIT trial established a nine-cytokine signature (incorporating IL-2, IL-6, IFN-γ) with 85.5% predictive accuracy for recurrence (66). Innovative strategies to improve BCG efficacy include the development of genetically modified BCG strains (69) and combinatorial approaches with immunomodulators, particularly immune checkpoint inhibitors, which hold the potential to redefine the therapeutic standard for non-muscle-invasive disease (70).
4.2 The application of ICIs in bladder cancer management
4.2.1 ICIs in advanced bladder cancer (platinum-refractory)
Therapeutic strategies for cisplatin-ineligible locally advanced or metastatic urothelial carcinoma now incorporate PD-L1 blockers (Atezolizumab, Durvalumab, Avelumab) and PD-1 antagonists (Nivolumab, Pembrolizumab) as secondary interventions (71–73). First-line approval has been granted to pembrolizumab and atezolizumab for PD-L1-positive cases or patients unsuitable for platinum-based regimens (74, 75). The advent of ICIs has revolutionized bladder cancer management, with PD-1/PD-L1 and CTLA-4 inhibitors representing the most clinically validated immunotherapies. Translational research concurrently focuses on identifying predictive biomarkers and managing immune-mediated adverse events (irAEs) (76). Preclinical evidence suggests selective targeting of CX-072 toward PD-L1-expressing malignancies, supported by early-phase data confirming its safety and efficacy in treatment-refractory solid tumors (77). Emerging agents targeting alternative immune checkpoints, including LAG3 and killer immunoglobulin-like receptors (KIR), are under investigation. LAG3 regulates T-cell function and exhibits antitumor activity, with compounds like BMS-986016 and LAG-525 showing promising early results (78).
For platinum-resistant metastatic urothelial carcinoma, ICIs constitute the therapeutic mainstay. KEYNOTE-045 demonstrated superior efficacy of pembrolizumab versus chemotherapy, achieving a 21.1% response rate and 10.3-month median survival. Enhanced outcomes (8.0-month survival) were noted in the PD-L1-high (≥10%) cohort, coupled with fewer severe toxicities (40). Long-term analysis confirmed enduring survival benefits (79). Similarly, IMvigor211 reported improved median OS (8.6 months) and lower severe toxicity rates with atezolizumab (10), with sustained survival advantages at 30 months (80–82). In CheckMate 275, nivolumab achieved an ORR of 19.6%, with differential responses across PD-L1 subgroups (28.4%, 23.8%, and 16.1%), alongside 8.6-month median survival and 40% 1-year survival, with 18% experiencing grade 3~4 toxicities (83, 84). Other PD-L1 inhibitors, including durvalumab and avelumab, exhibited comparable efficacy (85, 86). The PD-1 inhibitor tislelizumab yielded a 24% ORR, median OS of 9.8 months, and median progression-free survival (PFS) of 2.1 months, with one-year OS and PFS rates of 43% and 20% (87). CheckMate 032 evaluated nivolumab-ipilimumab combinations, revealing ORRs of 25.6% (nivolumab monotherapy), 26.9% (low-dose combination), and 38.0% (high-dose combination), with corresponding survival durations of 9.9, 7.4, and 15.3 months (88). Recent findings indicate a 37% response rate in rare urogenital malignancies with dual checkpoint blockade, though heightened irAEs necessitate careful patient selection (89) (Supplementary Table S1). These findings establish PD-1/PD-L1 inhibitors as standard second-line therapy for advanced platinum-refractory bladder cancer.
4.2.2 ICIs for chemotherapy-naïve advanced bladder cancer
For cisplatin-ineligible patients with untreated advanced/metastatic bladder cancer, ICIs provide a non-chemotherapy option. KEYNOTE-052 assessed pembrolizumab in cisplatin-ineligible patients, reporting a 24% ORR and 67% six-month OS rate (90). Five-year data indicated median OS of 11.3 months, with PD-L1-high (CPS ≥10) patients exhibiting superior outcomes (OS: 18.5 months; ORR: 47.3%) (91). IMvigor210 documented a 23% ORR, median PFS of 2.7 months, and median OS of 15.9 months with atezolizumab (92, 93). KEYNOTE-361 detected no PFS improvement with pembrolizumab-chemotherapy versus chemotherapy alone (8.3 months), though pembrolizumab monotherapy correlated with higher durable response rates (52.0% at 18 months) (94, 95). IMvigor-130 demonstrated enhanced PFS (8.2 months) and OS (16.0 months) with atezolizumab-chemotherapy (94). Both trials highlighted reduced survival in low PD-L1 patients, prompting EMA and FDA to restrict ICIs to cisplatin-ineligible, high PD-L1 patients (96). Suboptimal outcomes in PD-L1-low subgroups prompted regulatory restrictions to cisplatin-ineligible, PD-L1-high populations (97), but DANUBE showed no significant efficacy difference between durvalumab ± tremelimumab and chemotherapy (98). Preclinical models support dual checkpoint inhibition (99), yet DANUBE revealed no OS benefit with durvalumab ± tremelimumab versus chemotherapy (100, 101). Maintenance immunotherapy seeks to prolong clinical responses while mitigating chemotherapy-induced toxicity. In the maintenance setting after initial chemotherapy, the phase III JAVELIN Bladder 100 trial established avelumab’s superiority, with median OS of 21.4 months. Avelumab exhibited a median PFS of 5.7 months in PD-L1-positive subgroup (102, 103). In contrast, pembrolizumab maintenance (phase II) improved PFS (5.4 months) and ORR (23%) without better OS benefit (22 months) (104).
4.2.3 ICIs in muscle-invasive disease
In contrast to metastatic disease, MIBC is treated with a curative intent. Here, ICIs are evaluated as neoadjuvant, adjuvant, or part of bladder-preserving strategies. While cisplatin-based neoadjuvant chemotherapy remains standard for MIBC, ICIs offer a less toxic alternative. PURE-01 reported a 42% pathological complete response (pT0) rate with pembrolizumab, escalating to 54.3% in PD-L1-high patients (105). At 23-month follow-up, 24-month event-free survival was 71.7% (106). ABACUS (phase II) observed a 31% pT0 rate with atezolizumab (107, 108), while pembrolizumab plus gemcitabine-cisplatin achieved pT0N0 in 36% (109). Dual ICIs (nivolumab-ipilimumab) showed a 46% pT0 rate but frequent high-grade toxicity (110). Durvalumab plus Tremelimumab achieved 37.5% pT0 with 21% grade 3+ adverse events (111). Durvalumab-tremelimumab yielded 37.5% pT0 with manageable toxicity (82). Adjuvant nivolumab in CheckMate 274 doubled median disease-free survival (DFS: 20.8 vs. 10.8 months) without compromising health-related quality of life (HRQoL) (112, 113). Conversely, IMvigor010 reported no DFS/OS benefit with adjuvant atezolizumab, underscoring the need for further validation (114). Radical cystectomy remains the gold standard for MIBC, offering 5-year survival rates approaching 66%. However, the procedure carries substantial perioperative morbidity and adversely impacts patients’ quality of life (115, 116). Consequently, organ-sparing multimodal therapies have gained traction, particularly with the integration of ICIs. Radiotherapy has demonstrated immunomodulatory effects, including expansion of T-cell receptor repertoires, PD-L1 upregulation, and abscopal tumor regression (117, 118). The IMMUNOPRESERVE-SOGUG phase II trial investigated durvalumab and tremelimumab combined with radiotherapy following transurethral resection (TURBT) in MIBC patients. This chemotherapy-free regimen achieved 81% complete response (CR) rates, 73% 1-year bladder-intact disease-free survival (BIDFS), and 87% 1-year overall survival (OS), with grade ≥3 adverse events occurring in 31% of participants (119). Similarly, pembrolizumab with chemoradiation yielded 77% 1-year BIDFS and 80% CR at 12 weeks, albeit with 35% grade ≥3 toxicities (120). An alternative approach using nivolumab plus gemcitabine-cisplatin (GC) chemotherapy resulted in 48% CR, 92.4% 1-year OS, and 78% 1-year BIDFS among responders (121). These findings underscore the potential of immunotherapy-based bladder preservation strategies.
4.2.4 Immunotherapy in non-muscle invasive bladder cancer
For high-risk NMIBC, the standard of care involves TURBT followed by intravesical Bacillus Calmette-Guérin (BCG) immunotherapy. Nevertheless, up to 50% of patients develop recurrence or BCG resistance within five years (122). While RC is an option for BCG-refractory disease, its associated risks necessitate alternative non-surgical interventions (123). Emerging evidence indicates that repeated BCG instillations, while initially stimulating anti-tumor immunity, can eventually induce adaptive immune resistance (124, 125). Chronic BCG exposure promotes sustained PD-L1 expression on tumor cells and infiltrating myeloid populations, thereby inhibiting cytotoxic T cell activity and creating an immunosuppressive microenvironment that underlies BCG treatment failure (126). This biological shift provides a strong rationale for targeting the PD-1/PD-L1 axis in BCG-unresponsive NMIBC. Emerging evidence implicates PD-1/PD-L1 axis activation in BCG resistance, with elevated PD-L1 expression observed in refractory tumors (127). The KEYNOTE-057 trial evaluated pembrolizumab in BCG-unresponsive NMIBC, demonstrating a 41% pathological CR at 3 months, with a median response duration of 16.2 months. Notably, no progression to muscle-invasive or metastatic disease occurred, and 3-year OS rates reached 91%. Grade III-IV toxicities were reported in 12.7% of patients (128). Based on these outcomes, ESMO guidelines endorse pembrolizumab for BCG-refractory NMIBC patients ineligible for or declining RC (113). Similarly, the SWOG S1605 trial reported a 41% CR at 3 months with atezolizumab, alongside a median response duration of 16.5 months. The 18-month event-free survival rate was 29%, with 12.3% grade III-IV adverse events (129, 130). Both agents exhibit comparable efficacy, with ongoing studies expected to refine their roles in clinical practice.
Recent advances in adoptive cell transfer have highlighted CAR-T cell therapy as a novel therapeutic strategy for treating solid malignancies such as bladder cancer (131). Preclinical investigations have provided evidence supporting the utility of CAR-T cells in BC models. In one study, Grunewald and colleagues reported that CAR-T cells directed against EGFR and CD44V6 effectively induced BC cell lysis, with decitabine, an inhibitor of DNA methyltransferase, further augmenting their antitumor activity (132). Another preclinical evaluation revealed that CAR-T cells targeting MUC1 exhibited cytotoxic effects on BC-derived organoids (133). Additionally, multiple clinical trials are currently evaluating CAR-T cell therapies in BC, focusing on antigens including PSMA, FRα, HER2, and ROR2 (134). Notably, SIA-CIgG, a glycosylated form of cancer-derived IgG, is abundantly expressed in BC and correlates with aggressive tumor behavior. Compared to HER2-targeting CAR-T cells, which have been widely tested in clinical settings, SIA-CIgG-specific CAR-T cells exhibit prolonged persistence and a more moderate tumor-lytic profile (135).
5 Conclusion
The immunotherapy revolution has fundamentally transformed bladder cancer management, offering new hope for patients across disease stages. Our review highlights several key advances: First, immune checkpoint inhibitors have established durable clinical benefits in advanced disease, with pembrolizumab demonstrating superior survival over chemotherapy in platinum-refractory patients and avelumab showing significant survival advantages as maintenance therapy. Second, bladder-preserving strategies combining ICIs with radiotherapy achieve impressive complete response rates (up to 81%) while maintaining organ function, challenging the traditional dominance of radical cystectomy for MIBC. Third, in NMIBC, PD-1 inhibitors provide effective salvage therapy for BCG-unresponsive disease, with pembrolizumab achieving 41% complete responses and 91% 3-year survival.
Critical challenges remain, including the need for better predictive biomarkers to guide patient selection, as PD-L1 expression and tumor mutational burden show imperfect correlation with treatment response. The management of immune-related adverse events requires ongoing refinement, particularly for combination therapies showing increased toxicity. Emerging approaches such as bispecific antibodies, CAR-T cell therapy, and novel ICIs targeting LAG-3 and KIR show preclinical promise but require further clinical validation. Future directions should focus on optimizing combination strategies, including ICI-chemotherapy-radiotherapy regimens, and developing next-generation biomarkers through multi-omics approaches. The integration of artificial intelligence for treatment response prediction and the development of personalized neoantigen vaccines represent exciting frontiers. As these innovations mature, they promise to further improve outcomes while reducing treatment morbidity, ultimately.
Author contributions
LM: Writing – original draft. XZ: Writing – original draft. XJ: Writing – original draft. BW: Writing – original draft. HZ: Writing – original draft. GZ: Writing – original draft. YX: Writing – original draft. CW: Writing – review & editing, Writing – original draft.
Funding
The author(s) declare financial support was received for the research and/or publication of this article. This work was supported by the Research Fund of the National Natural Scientific Foundation of China (82473337).
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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Supplementary material
The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fimmu.2025.1609871/full#supplementary-material
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Keywords: bladder cancer, immunotherapy, immune checkpoint inhibitors, tumor microenvironment, PD-1/PD-L1, CAR-T cells
Citation: Meng L, Zhu X, Ji X, Wang B, Zhang H, Zhang G, Xue Y and Wang C (2025) Advances in the immunological microenvironment and immunotherapy of bladder cancer. Front. Immunol. 16:1609871. doi: 10.3389/fimmu.2025.1609871
Received: 11 April 2025; Accepted: 01 August 2025;
Published: 19 August 2025.
Edited by:
Jin Bin, Shandong University, ChinaReviewed by:
Lexin Wang, Ningxia Medical University, ChinaCopyright © 2025 Meng, Zhu, Ji, Wang, Zhang, Zhang, Xue and Wang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Chunyang Wang, d2FuZ2NodW55YW5nMDAxQGhvdG1haWwuY29t
†These authors have contributed equally to this work