Shining light on immunotherapy in metastatic urothelial carcinoma: trends and prospects

1. Introduction

Urothelial carcinoma (UC) arises from the urothelial epithelium, a specialized lining that extends throughout the urinary tract, beginning in the renal calyces and renal pelvis, coursing down the ureters, and continuing through the urinary bladder, urethra, and prostatic urethra.^[1] Although UC covers a spectrum of tumors originating from these various anatomical sites, the bladder is far the most commonly affected organ, accounting for over 90% of all urothelial malignancies. As such, UC represents the predominant histopathological subtype of bladder cancer, which is currently ranked as the tenth most frequently diagnosed malignancy globally.^[2] The increasing incidence of UC over time highlights its growing impact on public health concerns, with a significant socioeconomic burden.^[1–2–3] Nevertheless, despite progress in systematic medical oncology, outcomes in advanced or metastatic UC (mUC) remain discouraging, with median overall survival (OS) still hovering around 15 months from diagnosis. Past decades witnessed cisplatin-based chemotherapy, particularly gemcitabine plus cisplatin (GC) and methotrexate, vinblastine, doxorubicin, and cisplatin (M-VAC), as the first-line palliative treatment for advanced or mUC.^[3] While GC and M-VAC both offer comparable OS and time to treatment failure, GC is generally favored due to its lower mucosal and hematological toxicity. Despite achieving an overall response rate (ORR) of approximately 50%, a progression-free survival (PFS) of only 7 months, and an OS of about 13 to 15 months, these chemotherapy regimens generally yield modest benefits.^[1,4] The therapeutic window is further constrained by cisplatin ineligibility, affecting nearly half of the mUC population due to factors such as impaired renal function, hearing loss/poor Eastern cooperative oncology group (ECOG) performance status (PS), peripheral neuropathy, old age, or other comorbidities, leading to carboplatin being used as a substitute in these cases. Unfortunately, subsequent treatments after the first-line therapy failure have shown limited success, with conventional cytotoxic agents (monotherapy or in combination) yielding unsatisfactory outcomes. Historically, UC patients have had a median OS with a 5-year survival rate of less than 7%, highlighting the urgent need for more effective therapeutic strategies in advanced or mUC.^[5]

Recent phase I–III trials have accelerated the development of novel systemic therapies for UC, with several key results emerging over the past few years.^[6–7–8] At the front-line of this therapeutic evaluation are immune checkpoint inhibitors (ICIs), which target regulatory pathways, such as programmed death-1 (PD-1) and its ligand PD-L1 and CLTA-4, to restore antitumor immunity.^[9] These agents have demonstrated meaningful clinical activity and are now integrated across multiple lines of treatment in mUC patients after platinum-based chemotherapy. Similarly, precision-targeted therapies, including fibroblast growth factor receptor (FGFR), tyrosine kinase inhibitors, and antibody–drug conjugates (ADCs) directed against antigens such as Nectin-4, have further expanded the armamentarium.^[10] Nevertheless, ICIs remain the most transformative class to date and are strongly recommended as forefront treatment options for individuals who are ineligible for platinum-based chemotherapy, especially those demonstrating PD-L1 positivity.^[9,11] Notably, avelumab, a PD-L1 inhibitor, has received approval as maintenance therapy for patients who achieve disease control after initial chemotherapy.^[12] Although ICIs have demonstrated clinical benefits across various stages of UC, therapeutic challenges remain in terms of primary and acquired resistance, limited efficacy in biomarker-unselected populations, and the lack of reliable predictive biomarkers capable of guiding treatment selection.^[13] Tumor-intrinsic mechanisms, such as impaired antigen presentation and activation of oncogenic pathways (e.g., TGF-β, PI3K/AKT), combined with immunosuppressive components of the tumor microenvironment (TME), such as regulatory T cells (Treg), myeloid-derived suppressor cells (MDSCs), and tumor-associated macrophages (TAMs), contribute to immune evasion.^[14] A comprehensive genomic and molecular profiling of mUC (Figure 1) emphasizes the biological complexity and heterogeneity of the disease. Meanwhile, biomarkers including PD-L1, tumor mutational burden (TMB), and circulating tumor DNA (ctDNA) show promise but lack standardization and predictive consistency.^{[15–16–17]} Emerging biomarkers like T-effector gene signatures, APOBEC mutagenesis, TGF-β signaling, and tumor-infiltrating lymphocyte (TIL) profiles further highlight the need for biomarker-driven and combination-based immunotherapeutic strategies to optimize clinical outcomes and improve treatment efficacy.^[17,18]

In this mini-review, we summarize the evolution of ICIs in UC, critically assess emerging resistance mechanisms and biomarker-guided treatment strategies, and highlight novel combination and drug-delivery approaches designed to achieve more durable clinical responses in advanced or mUC.

2. Immunobiology and resistance mechanism in mUC

mUC exhibits a highly immunogenic profile due to its high TMB and frequent neoantigen formation, which theoretically enhances susceptibility to ICIs. Despite these features, durable responses to ICIs remain limited to a subset of patients, largely due to both tumor-intrinsic and microenvironment-mediated immune evasion mechanisms. The TME in mUC plays a main role in modulating immune responses and promoting immune resistance.^[18] It is frequently populated by immunosuppressive cell populations, such as Tregs, MDSCs, and TAMs, which attenuate cytotoxic T-cell activity and hinder the efficacy of immunotherapies. Moreover, antigen presentation is often compromised in mUC through downregulation of major histocompatibility complex (MHC) class-I molecules and mutations in β2-microglobulin, impairing immune recognition and tumor surveillance.^[19] Another key feature of the mUC TME is the dysregulation of the TGF-β signaling pathway in stromal fibroblasts, which contributes to promoting immune exclusion by physically preventing T-cell infiltration into the tumor parenchyma, further complicating effective immune surveillance. This immune barrier, combined with chronic exposure to tumor antigens, induces T-cell exhaustion, marked by the upregulation of multiple inhibitory receptors (e.g., LAG-3, TIM-3, TIGIT) that may render PD-1/PD-L1 blockade insufficient.^[19,20] These resistance mechanisms highlight the need for biomarker-guided combinatorial approaches to overcome immunotherapy limitations.

To address the aforementioned challenges, integrating ICIs with agents targeting the TME is a promising strategy. Modulating pathways like TGF-β or myeloid suppression or utilizing alternative checkpoints (e.g., LAG-3, TIGIT) may enhance treatment efficacy, as summarized in Table 1. Investigational strategies under exploration include dual checkpoint inhibition (e.g., PD-1 plus CLTA-4, TIGIT, or LAG-3 blockade), TME modulation through TGF-β or adenosine pathway inhibition, and combinations with targeted therapies, ADCs, vaccines, and oncolytic viruses designed to enhance antigen presentation and T-cell recruitment.^[10,14,20] These combination therapies hold the potential to overcome the existing barriers in mUC immunotherapy and broaden the scope of patient responses. In this rapidly evolving landscape, a deeper understanding of the biological mechanisms behind the immune resistance is crucial for the rational design of new immunotherapeutic combinations (Table 1). Such strategies may ultimately help broaden and sustain responses in mUC patients, offering more durable and effective treatment outcomes.

3. Comparative evaluation of ICI trials in mUC and real-world data

Over the past decade, multiple phase I–III trials have evaluated ICIs across various treatment lines in mUC; however, meaningful cross-trial comparison remains challenging due to substantial methodological heterogeneity. Variations in trial designs, such as first-line, postplatinum, and maintenance settings, and differences in PD-L1 immunohistochemical assay platforms (e.g., SP142, 22C3, and SP263), cutoff thresholds, eligibility criteria (cisplatin-eligible versus cisplatin-ineligible), and endpoint definitions (RECIST v1.1 versus immune-modified response evoluation critera in solid tumors (RECIST)) contribute to variability in reported outcomes.^[22,23] For instance, the IMvigor210 and CheckMate275 trials showed response rates of 15% to 21% using single-arm designs in platinum-refractory disease, whereas the KEYNOTE-045 trial demonstrated an OS benefit for pembrolizumab over chemotherapy in a randomized setting, independent of PD-L1 status.^[10,18] In contrast, the IMvigor211 trial failed to meet its primary endpoint, illustrating how differences in PD-L1 scoring methodology and patient selection can influence results.^[10] Importantly, the JAVELIN Bladder 100 trial established avelumab as the first-line immunotherapy to improve survival in a switch-maintenance strategy after platinum-based chemotherapy, marking a pivotal shift in the treatment landscape.^[24]

While these trial results are essential for advancing mUC therapy, real-world data increasingly provide valuable insights into how therapies perform in broader, more diverse patient populations outside the controlled clinical trial setting. Real-world studies such as READY and AVENANCE, which evaluated avelumab maintenance postchemotherapy, reveal different efficacy and toxicity profiles compared with clinical cohorts, highlighting the importance of assessing the real-world applicability of treatment regimens.^[25,26] These data often demonstrate variations in response rates, side-effect profiles, and treatment landscape across heterogeneous mUC patients. To better understand the strengths and limitations of current ICI therapies in mUC, a standardized, biomarker-guided evaluation framework is required. A more nuanced analysis combining data from clinical trials and real-world studies helps to optimize ICI utilization and patient outcomes. Table 2 summarizes key clinical trial features and outcomes, highlighting major limitations, such as selection bias, assay heterogeneity, and small sample sizes, while also indicating that real-world data increasingly reveal divergent toxicity and response patterns compared with those observed in highly selected clinical trial cohorts.^[18,26] Moreover, it compares the effectiveness of ICI regimens in controlled trial settings versus broader real-world populations to provide a more balanced perspective of their clinical utility.

4. Therapeutic landscape in mUC: trends and directions

The therapeutic landscape of mUC has advanced considerably, as illustrated in Figure 2. Platinum-based chemotherapy remains the cornerstone of first-line management for cisplatin-eligible patients, while carboplatin-based regimens or front-line ICIs are used in those who are cisplatin-ineligible, depending on PD-L1 expression status.^[20] The introduction of avelumab as switch-maintenance therapy following response or stable disease after platinum-based chemotherapy has established immunotherapy in the postinduction setting as standard practice. In the second-line setting, ICIs such as pembrolizumab remain a key option for platinum-refractory diseases, whereas targeted therapies such as erdafitinib are recommended for patients harboring susceptible FGFR alterations.^[10,17,19] In the third-line and beyond, ADCs such as enfortumab vedotin (EV) and sacituzumab govitecan have further expanded the treatment armamentarium. Overall, these advancements represent a shift toward biomarker-guided decision-making and molecular integration of chemotherapy, immunotherapy, and targeted agents across mUC treatment lines. To provide better clarity, the current therapeutic landscape is discussed in the following sections according to treatment setting and strategy, beginning with historical cytotoxic chemotherapy and progressing through modern immunotherapeutic and biomarker-guided approaches.

5. Front-line use of immunotherapy in mUC

The phase-III DANUBE trial (NCT02516241) assessed the efficacy of durvalumab alone and in combination with tremelimumab (a CTLA-4 inhibitor) versus platinum-based chemotherapy in treatment-naive patients with advanced or mUC. Neither approach demonstrated a significant enhancement in OS in contrast to chemotherapy, even among PD-L1-positive patients. Specifically, durvalumab monotherapy achieved a median OS of 14.4 months compared with 12.1 months with chemotherapy (hazard ratio [HR] = 0.89; P = 0.30), while the combination therapy showed a median OS of 15.1 months (HR = 0.85; P = 0.075). A major limitation of front-line immunotherapy has been its lower ORR and shorter PFS relative to chemotherapy. Although ICIs can elicit durable responses in selected patients, their slower onset of action and limited efficacy across broader populations have restricted their use. Thus, single-agent ICIs have not yet replaced chemotherapy as the standard care for first-line mUC. Nevertheless, recent advances in combination strategies are reshaping the mUC therapeutic landscape. Notably, the FDA approval of pembrolizumab in combination with EV marks a significant shift toward effective first-line immunotherapy-based regimens irrespective of cisplatin eligibility. Current clinical trials are actively investigating novel combinations of ICIs with chemotherapeutic agents or other targeted therapies in an effort to enhance response rates and improve long-term survival outcomes for mUC patients.^[45,46]

6. Front-line use of immune-chemotherapy combinations in mUC

The integration of ICIs with chemotherapy in the front-line treatment of mUC has yielded inconsistent outcomes. In the phase-III KEYNOTE-361 trial, combining pembrolizumab with platinum-based chemotherapy did not significantly improve OS compared with chemotherapy alone (median OS: 10.0 versus 14.3 months; HR = 0.86, P = 0.0407, which was not statistically significant at the prespecified alpha level).^[40] Similarly, pembrolizumab monotherapy also failed to demonstrate clear superiority. In the IMvigor130 trial, which evaluated atezolizumab combined with platinum-based chemotherapy, there was a modest improvement in PFS (8.2 versus 6.3 months; HR = 0.82; P = 0.007), but no statistically significant OS benefit was observed. Consequently, neither of these ICI-chemotherapy combinations has been widely adopted as a standard first-line treatment for mUC. This lack of strong additive benefit suggests that concurrent administration of chemotherapy and immunotherapy may not generate synergistic effects in mUC, possibly due to unique bladder tumor-specific immunogenic characteristics or differential tumor-immune interactions compared with other cancer types where such combinations have shown greater efficacy.^[5,9,12]

7. Maintenance immunotherapy

Maintenance immune therapy has significantly advanced the treatment landscape for mUC-suffering patients. The phase-III JAVELIN bladder 100 trial established avelumab as the standard maintenance therapy for patients achieving disease control after first-line platinum-based chemotherapy. The trial demonstrated a median OS of 21.4 months with avelumab, compared with 14.3 months with best supportive care (BSC) alone (HR = 0.69; P = 0.001). This benefit was consistent across all subgroups, including PD-L1 positive patients, who showed a 1-year survival rate of 79.1% with avelumab versus 60.4% with BSC (HR = 0.56; P < 0.001). Avelumab also significantly improved PFS, with a manageable safety profile, despite a higher incidence of grade ≥3 adverse events.^[47] Extended follow-up data further confirmed the durability of these benefits, showing a median OS of 23.80 months compared with 15.0 months with BSC, and a median PFS of 5.5 versus 2.1 months. These results led to avelumab national comprehensive cancer network (NCCN) category 1 recommendation as maintenance therapy for mUC.

Real-world evidence from the READY and AVENANCE studies further validated these findings. Additionally, the CheckMate-901 trial demonstrated the potential of combining nivolumab with cisplatin-based chemotherapy, expanding clinicians’ personalized treatment options based on patient-specific factors. As both avelumab and nivolumab continue to shape maintenance strategies, ongoing studies are evaluating combination approaches and subsequent therapies for patients who progress following maintenance.^[47] Future research efforts are focused on novel combinations, including ADCs paired with immunotherapy, dual checkpoint inhibition targeting CTLA-4 and PD-L1, and other emerging treatment modalities designed to further improve outcomes in mUC patients.^[7,9,11,45]

8. Emerging immune combinations in mUC

Novel immunotherapeutic strategies in mUC increasingly rely on rational combinations to enhance antitumor efficacy beyond monotherapy. A key example is the combination of pembrolizumab with sEphB4-HSA, which targets tumor growth factors EphB4 (on tumor cells) and EphrinB2 (on tumor vasculature), inhibiting tumor angiogenesis and promoting tumor cell apoptosis.^[48] Phase-II data showed a 37% ORR overall, with markedly higher benefit in EphrinB2-positive patients (ORR: 52%, complete response (CR): 24%, PFS: 5.7 months, OS: 21.5 months). This type of combination therapy received FDA breakthrough approval in 2021; however, randomized phase-III validation is required. Similarly, the NORSE study (NCT03473743) evaluated erdafitinib plus the anti-PD-1 antibody cetrelimab in cisplatin-ineligible FGFR-mutant patients, reporting an ORR of 68% compared with 33% with erdafitinib alone, emphasizing the value of genomic stratification.^[48,49] Conversely, the BISCAY trial (NCT02546661) assessed durvalumab with various targeted inhibitors, such as FGFR, PARP, and mechanistic target of rapamycin (mTOR) inhibitors in biomarker-selected mUC populations, but showed no significant improvement over targeted therapy alone, suggesting that only select combinations yield synergistic immunomodulation. ADCs represent another promising class, whereas EV targets nectin-4 as monotherapy improves OS postchemotherapy and immunotherapy (EV-301). In combination with pembrolizumab (EV-103), EV has shown an ORR of 73.3% in cisplatin-ineligible first-line patients, with phase-III results eagerly awaited (EV-302). Another ADC, sacituzumab govitecan, has demonstrated ORRs of 27% as monotherapy and 35% in combination with pembrolizumab in heavily pretreated mUC patients, with ongoing trials evaluating the potential of immune-ADC combinations in future lines of therapy.^[49,50]

9. Biomarkers for precision immunotherapy in mUC

Emerging immune combinations have significantly advanced the therapeutic options for mUC, with biomarker integration playing a crucial role in personalizing treatment. The effective use of biomarkers, such as PD-L1, TMB, and ctDNA, holds great promise in improving patients’ selection and treatment outcomes. Nonetheless, their clinical utility is limited by variable predictive value and practical challenges.^[17] PD-L1 expression, while extensively studied, suffers from methodological inconsistencies, including differences in antibody clones, scoring systems, and tumor versus immune cell expression, which affect its reliability as an individual biomarker.^[22] TMB, a surrogate for neoantigen load, has shown promise in predicting responses to immunotherapy but is influenced by intertumoral heterogeneity and lacks standardized cutoff values, limiting its widespread adoption. ctDNA has emerged as a dynamic tool for detecting minimal residual disease (MRD) and guiding adjuvant therapy decisions,^[50] with the IMvigor010 trial demonstrating that ctDNA-positive patients have a higher risk of relapse and benefit from adjuvant atezolizumab (HR = 0.58; P = 0.0024).^[40] Despite its potential, ctDNA’s clinical implementation is constrained by logistical barriers, including assay availability, turnaround time, and cost. Additionally, emerging biomarkers, such as T-effector gene signatures, APOBEC mutagenesis, TGF-β signaling, and natural killer (NK) and macrophage signatures, are being investigated for their predictive value but remain in the exploratory phase, requiring further validation.^[34] The role of tertiary lymphoid structure (TLS), associated with robust immune responses, is also under investigation but requires more evidence before clinical integration. The development of multimodal biomarker strategies, combining mutational profiles with immune-related signatures, aims to enhance patient selection and treatment prediction. As illustrated in Figure 3, biomarker research in mUC is evolving from traditional markers like PD-L1 toward more comprehensive, combinational-induced approaches, particularly after the introduction of EV and EVP.^[51] However, real-world integration of these biomarkers remains challenging due to inconsistent predictive value, a lack of harmonization, and the absence of robust composite models. As summarized in Table 3, overcoming these limitations through multiplatform biomarker strategies is critical for advancing precision immunotherapy in mUC, guiding therapeutic combinations, and optimizing patient selection for personalized therapy.^{[10,16,20,28,52]}

10. Toxicity comparisons and management of ICIs in comorbid populations in mUC

11. Future perspectives

Immunotherapy has profoundly transformed the therapeutic landscape for mUC patients, offering the potential for durable responses and prolonged remission. However, significant challenges persist in optimizing patient selection, refining treatment timing, and enhancing overall efficacy. Current immune strategies are often implemented at later disease stages, and the absence of robust predictive biomarkers continues to impede precision medicine. Therefore, future directions must prioritize 3 key areas, including enhancing therapeutic combinations, advancing biomarker development, and optimizing treatment settings.

The first priority is the development of more effective therapies and rational combinations. ADCs, ICIs, and targeted agents represent the forefront of this evolution. EV, an ADC targeting Nectin-4, has demonstrated high ORR, particularly when combined with pembrolizumab, with phase-II trials showing an ORR of >70%. The ongoing EV-302 trial is anticipated to confirm these results and potentially establish a new standard of care in the front-line setting. Similarly, the combination of pembrolizumab with sEphB4-HSA in EphrinB2-positive tumors showed an ORR of 52% and a CR of 24%, with extended OS. In FGFR-mutant populations, the NORSE trial found that erdafitinib plus cetrelimab achieved a 68% ORR in cisplatin-ineligible patients, suggesting this targeted-immunotherapy combination may be synergistic and worthy of phase-III validation. Moreover, dual checkpoint blockade remains under investigation, with trials like CheckMate-901 and NILE exploring CTLA-4 and PD-1/PD-L1 inhibition with or without chemotherapy. Emerging ADCs, such as sacituzumab govitecan and RC48, are also advancing both as monotherapies and in combination with ICIs, showing promising preliminary activity.^[68] These advancements in therapeutic combinations emphasize the potential for increasing the depth and duration of responses in mUC.

The second crucial pillar involves advancing biomarker science to enable better patient stratification and personalized treatment. While PD-L1 expression has been extensively studied as a predictive biomarker, its clinical utility in mUC remains inconsistent, preliminary due to methodological variability in testing, such as differences in antibody clones and scoring systems. Consequently, PD-L1’s impartial role in patient selection for immunotherapy is increasingly questionable, and multidimensional biomarker strategies are gaining importance. The utility of TMB as a marker for neoantigen load has shown promise in predicting responses to immunotherapy, but its predictive value remains influenced by intertumoral heterogeneity and the lack of standardized cutoff values, limiting its consistency across studies. ctDNA, a dynamic marker for MRD, has demonstrated potential in guiding adjuvant immunotherapy decisions, particularly in patients with high ctDNA levels, as highlighted by the IMvigor010 trials. However, despite its promise, ctDNA’s clinical implementation remains hampered by logistical barriers, such as assay availability, cost, and turnaround time. Emerging biomarkers, including T-effector gene signatures, APOBEC mutagenesis patterns, and TGF-β pathway activity, provide insights into the immune response and TME but require further validation.^[16,17] Additionally, biomarkers related to NK cells, macrophage signatures, and TLS are being explored; however, their clinical application remains limited without more robust evidence. Based on these challenges, future biomarker research will likely focus on multiplatform strategies, integrating tumor genomics, immune signatures, and TME features to create more comprehensive patient profiles. Techniques such as single-cell RNA sequencing, spatial transcriptomics, and epigenetic profiling, including circulating methylation signatures, are expected to provide deeper insights into tumor-immune dynamics, offering a more personalized approach to immunotherapy.^[34]

The third strategic imperative is the optimization of treatment timing and sequencing based on disease progression and therapeutic response. Administering immunotherapy earlier, particularly in the neoadjuvant or perioperative setting, may maximize benefits by targeting tumor evolution at a less resistant stage. Combining therapies preoperatively, potentially guided by molecular monitoring like ctDNA, could enhance curative potential. Additionally, ICIs are expanding beyond the metastatic setting. For example, ICIs have demonstrated promising results in both non–muscle-invasive bladder cancer (NMIBC) and muscle-invasive bladder cancer (MIBC).^[69] Pembrolizumab is already approved for BCG-unresponsive NMIBC in cystectomy-ineligible patients, and adjuvant nivolumab postcystectomy in MIBC has shown significant promise. Optimizing the sequencing of ICIs with other modalities could yield greater clinical benefits and potentially redefine treatment paradigms for earlier-stage disease.

In summary, the future of precision immunotherapy in mUC will be shaped by the synergistic integration of more effective drugs, advanced DDS, refined biomarker-guided patient stratification, biological understanding, and optimization of treatment timing. The ultimate success will depend on the development of multimodal therapies, informed by comprehensive biomarker profiles that guide personalized therapeutic decisions. Advanced DDS, such as nanocarriers for targeted ICIs delivery and biomaterial scaffolds for localized immune activation, hold significant promise in addressing the limitations of current treatments by enhancing the efficacy, specificity, and durability of immune responses. DDS technologies can ensure that immunotherapy agents are delivered directly to tumor sites, minimizing systematic toxicity and maximizing therapeutic effects. As we move into this next era, important advances in both therapeutic agents, drug-delivery technologies, and biomarker science will be critical to improving clinical results. By optimizing DDS alongside precision biomarkers-guided patient selection, treatments can be better tailored to the unique tumor and immune profiles of individual patients, thus ultimately enhancing both the effectiveness and safety of immunotherapy for mUC patients.

12. Conclusions

Platinum-based chemotherapy remains the standard front-line option in mUC, offering superior initial tumor control, but its effectiveness is often limited by its chemoresistance. The integration of ICIs, particularly avelumab as maintenance therapy following chemotherapy, provides a durable survival benefit by combining early cytoreduction with sustained immune activity. While first-line ICI monotherapy and chemotherapy-ICI combinations have demonstrated consistent improvement in OS, combinations like EVP are redefining treatment algorithms, resulting in significantly higher response rates. The future of mUC therapy demands precision medicine, guided by biomarkers like ctDNA, TMB, PD-L1, FGFR alterations, and T-effector signatures, as well as innovations in advanced DDS to enhance therapeutic targeting and minimize toxicity. The current ongoing trials aim to optimize therapeutic combinations and sequencing, advancing toward a more personalized, biomarker-driven standard of care that integrates multimodal therapies for improved outcomes in mUC patients.

Funding

This work was financially supported by Guangdong Basic and Applied Research Foundation (No. 2024A1515220095), the Scientific Research Project of Guangdong Provincial Administration of Traditional Chinese Medicine (No. 20252006), and the postdoctoral startup fund (No. Q0301-182).

Conflicts of interests

The authors declare that they have no conflicts of interest.

Author Contributions

Basit Ali Shah: Writing – original draft, Conceptualization and Funding acquisition. Asma Sardar: Investigation and Validation, Yunyi Li: Writing – Review & editing, Bin Yang: Supervision, Validation, Resources and Funding acquisition.