From mechanisms to therapy: the role of tertiary lymphoid structures in bladder cancer

Abstract

Tertiary lymphoid structures (TLS) are ectopic lymphoid tissues that form within the tumor microenvironment (TME) and play a crucial role in anti-tumor immunity. In recent years, their presence, formation mechanisms, and functional significance in bladder cancer have attracted considerable attention. This review comprehensively examines the mechanisms underlying TLS induction in bladder cancer, their role in mediating anti-tumor immunity, their correlation with favorable clinical prognosis, and their emerging potential as therapeutic targets. Current evidence suggests that high TLS density, particularly in mature forms, is associated with prolonged patient survival and improved response to immunotherapy. TLS formation is driven by a complex network of chemokines, cytokines, and specific immune cells. By providing a structured niche for the activation, clonal expansion, and effector functions of resident T/B cells, TLS exert potent anti-tumor effects. Therefore, strategies aimed at inducing or enhancing functional TLS represent a promising frontier in bladder cancer immunotherapy, although several challenges remain for successful clinical translation.

Introduction

Bladder cancer is a highly prevalent malignant tumor of the urinary system globally [1]. According to recent epidemiological statistics, bladder cancer ranks as the tenth most common cancer worldwide, with approximately 573,000 new cases and 212,000 deaths reported in 2020 [2]. Its incidence shows marked sex differences, being about four times higher in men than in women, and is strongly associated with aging, with most cases occurring in individuals over 65 years of age [2, 3]. Cigarette smoking remains the most significant risk factor, accounting for 50–65% of cases in men and 20–30% in women, followed by occupational exposure to aromatic amines and chronic bladder irritation [4]. These epidemiological characteristics underscore the global health burden posed by bladder cancer and highlight the urgent need for more effective therapeutic strategies. Although immune checkpoint inhibitors (ICIs) have undeniably transformed the treatment landscape for advanced bladder cancer, offering new therapeutic options and improving survival outcomes, the overall response rates remain suboptimal. However, the field continues to evolve, with ongoing research aimed at refining patient selection, developing predictive biomarkers, and exploring combination strategies. As the understanding of bladder cancer biology deepens, the role of ICIs is expected to expand, potentially offering greater benefits to patients in the future [5–7]. TLS are heterogeneous aggregates of lymphoid tissue formed at sites of chronic inflammation or tumors [8]. Resembling secondary lymphoid organs, TLS contain distinct T cell zones, B cell follicles (often with germinal centers), follicular dendritic cells (FDCs), and high endothelial venules (HEVs) [9, 10]. Importantly, the presence of TLS within tumors has been shown to correlate with improved prognosis and enhanced response to immunotherapy, particularly ICIs, distinguishing them from the generally immunosuppressive tumor microenvironment (TME) [11]. These molecules play a pivotal role in orchestrating the recruitment and organization of immune cells within the TME, and the presence of TLS is generally associated with improved prognosis and enhanced response to immunotherapy, even in immunosuppressive or “cold” tumor microenvironments [8]. This review explores the role of TLS in bladder cancer, focusing on their formation, function, clinical relevance, and therapeutic potential.

Mechanism of TLS formation in bladder cancer microenvironment

The induction of TLS is a multi-step process orchestrated by specific molecular signals within the TME.

Initiation phase: persistent inflammatory stimuli and APC activation

TLS initiation in bladder cancer is triggered by sustained inflammatory cues within the TME. Inflammatory signals and danger signals activate APCs and stromal cells, creating a pro-inflammatory milieu conducive to TLS initiation and maintenance. These signals can be damage-associated molecular patterns (DAMPs) released during immunogenic cell death [12], which include calreticulin (CRT), high-mobility group box 1 (HMGB1), ATP, and heat shock proteins (HSPs), etc [13]. When tumor cells undergo ICD, DAMPs are exposed or released, which can activate DCs and other immune cells, leading to the generation of anti-tumor T cell responses. For example, CRT exposure on the cell surface and the release of HMGB1 and ATP are hallmark features of ICD, which enhance the immunogenicity of tumor cell [14, 15]. The danger signals include MAMPs, such as UTI-related bacterial products, and pattern recognition receptor (PRR) signaling pathways (such as TLRs). They can activate APCs and stromal cells, initiating a pro-inflammatory milieu conducive to TLS initiation and maintenance [12].

Pro-inflammatory cytokines, particularly TNF-α, further amplify this early inflammatory phase. TNF-α produced by macrophages, DCs, and activated T cells enhances NF-κB signaling in stromal cells, promotes their activation, and cooperates with LT and IL-17 pathways to induce the expression of TLS-associated chemokines such as CXCL13, CCL19, and CCL21 [16, 17]. Through these mechanisms, TNF-α functions as a key inflammatory amplifier that supports the transition from nonspecific inflammation to structured TLS initiation.

These inflammatory and danger signals enhance antigen presentation and promote the recruitment of innate and adaptive immune cells, thereby laying the foundation for TLS formation.

Induction phase: cellular interactions and chemokine production

The LT axis, particularly the interaction between lymphotoxin-α (LTα) and the lymphotoxin-β receptor (LTβR), is essential for TLS formation across multiple cancer types. LTα, commonly expressed by immune cells such as group 2 innate lymphoid cells (ILC2s) and Th17 cells, binds to LTβR on stromal cells and induces the production of key chemokines—including CXCL13, CCL19, and CCL21—that drive TLS development in a wide range of tumors, including bladder cancer. These chemokines recruit lymphocytes to the site of inflammation, facilitating the initial aggregation of immune cells necessary for TLS formation [18–20]. The lymphotoxin axis is fundamental for the organization, maturation, and functionality of TLS. By driving chemokine production, stromal cell activation, and immune cell recruitment, LT signaling creates a microenvironment that supports adaptive immune responses at sites of chronic inflammation. Understanding and harnessing this pathway holds significant potential for developing novel immunotherapies in cancer and autoimmune diseases. LTα1β2 (mainly expressed by lymphocytes) interacts with its receptor LTβR on stromal cells. This triggers a signaling cascade essential for the differentiation of FDCs and the formation of specialized HEVs, which are critical for sustained lymphocyte recruitment into the TLS. LTα1β2, a heterotrimeric cytokine, binds to the LTβR expressed on stromal cells, initiating a signaling cascade that is essential for maintaining lymphoid microenvironmental homeostasis. This interaction is pivotal for the development and organization of lymphoid tissues, including the differentiation of FDCs and the formation of HEVs [21]. In summary, the LTα1β2-LTβR interaction on stromal cells is a cornerstone of immune system regulation, driving the differentiation of FDCs and the formation of HEVs. In addition to LTα1β2, IL-17 signaling plays an important complementary role in TLS induction. IL-17 A and IL-17 F, primarily produced by Th17 cells and γδ T cells, stimulate stromal cells, fibroblasts, and endothelial cells to produce CXCL13, CCL20, and additional TLS-associated chemokines. IL-17 also promotes the expression of adhesion molecules (VCAM-1, ICAM-1), enhancing lymphocyte retention and organization into early lymphoid aggregates [22–24].

These signaling pathways ensure the proper organization and function of lymphoid tissues, highlighting its importance in both physiological and pathological contexts. Understanding this mechanism provides insights into potential therapeutic strategies for immune-related disorders.

Maturation phase: immune cell recruitment, activation, and germinal center formation

The chemokines CCL19, CCL21 and CXCL13 have been identified as critical drivers of TLS formation in muscle-invasive bladder cancer (MIBC). These molecules play a pivotal role in orchestrating the recruitment and organization of immune cells within the TME. CXCL13, primarily produced by tumor-associated fibroblasts (CAFs), myeloid cells, and some T cells, is the core chemokine that recruits CXCR5⁺ B cells and follicular helper T cells (Tfh) to the TLS formation sites. The expression level of CXCL13 in bladder cancer is often positively correlated with the density of TLS. CCL19 and CCL21 [25], mainly produced by stromal cells (such as lymphatic endothelial cells and fibroblasts) and specific dendritic cell (DC) subsets, recruit naïve T cells, central memory T cells, and mature DCs to the T cell area of TLS by binding to the CCR7 receptor [26]. Experimental studies have shown that recombinant CCL19/CCL21 protein injections can promote intratumoral TLS formation and enhance the efficacy of immunotherapy in MIBC [27].

Mature TLS are organized lymphoid aggregates characterized by the presence of distinct B cell follicles with germinal centers, T cell zones, and specialized stromal networks. These mature TLS support effective antigen presentation, B cell maturation, and the generation of high-affinity antibodies, thereby promoting anti-tumor immunity [9]. In contrast, immature TLS lack well-formed germinal centers and structured T/B cell zones. They may recruit immune cells but are less effective in coordinating adaptive immune responses [28]. Thus, the presence of mature TLS is often associated with improved clinical outcomes, while immature TLS may represent an early or less functional stage of TLS development [29].

In tumor immunity, IL-7 improves the efficacy of chimeric antigen receptor (CAR) T cells by enhancing their expansion, persistence, and infiltration into solid tumors. For example, CAR-T cells engineered to express IL-7 exhibit superior anti-tumor activity and prolonged survival in preclinical models [30, 31]. Additionally, BAFF(B-cell activating factor)/APRIL(A proliferation-inducing ligand) promotes B cell survival, proliferation, and differentiation within TLS [32]. Interferon-gamma [33] (IFN-γ), produced by activated T cells and natural killer (NK) cells, induces the expression of various chemokines, including CXCL9, CXCL10, and CXCL11 [34]. These chemokines are critical for recruiting immune cells to sites of inflammation or infection, thereby amplifying the immune response and enhance antigen presentation [35]. Continuous stimulation by tumor-associated antigens (TAAs) and neoantigens, presented by intratumoral antigen-presenting cells (APCs, such as DCs), is a necessary condition for maintaining TLS activity and germinal center reactions.

Impact of TLS maturity on prognosis and therapeutic response

The maturation stage of TLS—defined by the presence of germinal centers (GCs), follicular dendritic cell (FDC) networks, and high endothelial venules (HEVs)—has a profound influence on anti-tumor immunity in bladder cancer. Mature TLS provide a structured microenvironment that supports efficient antigen presentation, B-cell affinity maturation, and sustained recruitment of naïve and memory lymphocytes through HEVs, thereby enhancing both humoral and cellular immune responses [36, 37]. These functional features lead to enhanced activation of both B cells and cytotoxic T cells, thereby strengthening intratumoral immune responses.

Clinically, tumors containing mature, GC-forming TLS are consistently associated with improved prognosis and stronger responses to immune checkpoint blockade. Studies across multiple malignancies, including bladder cancer, have demonstrated that mature TLS correlate with higher effector T-cell infiltration, increased interferon signaling, and superior patient survival, whereas immature TLS lacking GCs or HEVs exhibit limited immunological activity and reduced predictive value [38–40]. These observations highlight TLS maturity as a key determinant of their functional relevance and a promising biomarker for therapeutic responsiveness.

The mechanism of TLS-mediated anti-tumor immunity in bladder cancer

In bladder cancer, TLS are associated with mature immune responses and improved prognosis. For instance, mature TLS patterns (Fig. 1) are linked to higher immune cell infiltration and better survival outcomes [41].

Fig. 1.

Schematic diagram of a tertiary lymphoid structure (TLS)

In situ T cell activation and expansion

TLS facilitate the activation of T cells by providing a microenvironment where antigen-presenting cells can interact with T cells, leading to their expansion and differentiation into effector cells [42]. Mature DCs within TLS efficiently present tumor antigens to T cells, directly activating naive or memory T cells (CD4⁺ and CD8⁺), leading to the local massive expansion of antigen-specific T cells without the need for migration to distant lymph nodes. These DCs can present antigens via both major histocompatibility complex (MHC) class I and II pathways, activating CD8⁺ cytotoxic T cells and CD4⁺ helper T cells, respectively. For instance, DCs loaded with full-length tumor antigens can prime both CD4⁺ and CD8⁺ T cells, leading to broad and robust immune responses [43]. Additionally, DCs can cross-present tumor antigens, a process essential for activating CD8⁺ T cells, which is critical for tumor eradication.

Generation and function of effector T cells

TLS are important sites for the generation and maintenance of tumor-specific effector CD8⁺ T cells and CD4⁺ Th1 cells, which form in non-lymphoid tissues under conditions of chronic inflammation or immune stimulation, serve as privileged sites for antigen presentation, T cell activation, and effector differentiation [44]. Effector T cells, especially CD8⁺ T cells, are capable of migrating into the TME and infiltrating the tumor parenchyma [45]. This infiltration is often facilitated by chemokines and other signaling molecules that guide T cells to the tumor site [46]. For example, CD8⁺CXCR5⁺ T cells are highly enriched in pancreatic tumors and exhibit potent migratory and cytotoxic capabilities. Similarly, T-bet⁺ CD8⁺ T cells in gastric cancers are known for their superior ability to infiltrate tumors and secrete cytotoxic molecules [47]. Moreover, high endothelial venules (HEVs) within TLS act as a crucial access point, enabling lymphocytes, especially effector T cells, to extravasate from the bloodstream into the tumor parenchyma. Unlike typical tumor vasculature, HEVs express specialized adhesion molecules that facilitate lymphocyte homing and migration, helping TLS to bypass the endothelial barrier of the tumor and enhance immune cell infiltration [48]. Functionally, the density and proportion of HEVs in TLS correlate with increased T cell infiltration and better patient outcomes in various cancers [49].

B cell activation and antibody production

Within the germinal centers of TLS, aided by Tfh cells, undergo clonal expansion, somatic hypermutation, class switching, and affinity maturation, generating high-affinity tumor antigen-specific antibodies (including IgG and IgA). These antibodies exert anti-tumor effects through mechanisms such as antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cell-mediated phagocytosis (ADCP), complement-dependent cytotoxicity, and formation of immune complexes, enhancing antigen presentation.

Overcoming immunosuppression and promoting memory

TLS play a pivotal role in modulating the tumor microenvironment (TME), particularly by counteracting its immunosuppressive nature. One key mechanism is the production of cytokines such as IFN-γ within TLS, which inhibit the polarization of tumor-associated macrophages toward the immunosuppressive M2 phenotype and limit the activity of regulatory T cells (Tregs). Through this coordinated action, TLS promote a pro-inflammatory TME that enhances antitumor immune responses and supports effective immune surveillance [50, 51]. Understanding the mechanisms underlying TLS function offers promising avenues for developing novel immunotherapies and improving patient outcomes. Furthermore, TLS may support the local formation and maintenance of memory T cells (particularly tissue-resident memory T cells) and memory B cells, providing long-lasting anti-tumor immune surveillance. TLS are ectopic lymphoid formations that arise in non-lymphoid tissues under conditions of chronic inflammation, such as cancer. These structures play a crucial role in supporting the local formation and maintenance of memory T cells, particularly tissue-resident memory T cells, and memory B cells, thereby providing long-lasting anti-tumor immune surveillance [52–54].

In summary, TLS are critical for the local formation and maintenance of memory T cells and memory B cells, providing sustained anti-tumor immune surveillance. Their ability to support tissue-resident memory cells and facilitate B cell maturation underscores their importance in shaping the immune landscape of the TME. Future therapeutic strategies aimed at inducing TLS formation or enhancing their function could significantly improve cancer immunotherapy outcomes.

Clinical prognostic significance and therapeutic implications in bladder cancer

TLS act as A favorable prognostic biomarker

A high density of mature TLS, particularly those with germinal centers, is strongly associated with improved clinical outcomes in bladder cancer. In non–muscle-invasive bladder cancer (NMIBC), the presence of mature TLS within or around the tumor correlates with significantly prolonged overall survival (OS) and recurrence-free survival (RFS). Moreover, emerging evidence suggests that TLS may enhance the efficacy of intravesical Bacillus Calmette–Guérin (BCG) therapy, as the local immune microenvironment shaped by TLS can promote antitumor immune responses and improve treatment outcomes in NMIBC patients [55, 56]. These organized lymphoid aggregates support local immune responses, including T and B cell activation, which likely contribute to their prognostic value. The strong correlation between TLS density/maturity and patient survival highlights their potential as a reliable prognostic biomarker and suggests that incorporating TLS assessment into clinical practice could inform personalized treatment strategies. Future studies should focus on standardizing TLS evaluation and integrating it into multimodal prognostic models to further refine risk stratification.

Prediction of immunotherapy response

In patients with advanced bladder cancer receiving anti-PD-1/PD-L1 therapy, the presence of TLS (especially B-cell-rich TLS) in baseline tumor samples is an important biomarker for predicting treatment response and longer survival. Studies have demonstrated a strong correlation between high TLS density and improved response rates to ICIs. A meta-analysis of 19 clinical trials involving 1,752 patients revealed that high TLS density was associated with a significantly increased RR (OR = 2.99, 95% CI: 2.14–4.18, P < 0.001) and prolonged PFS (HR = 0.75, 95% CI: 0.63–0.88, P < 0.001). In bladder cancer specifically, TLS-rich tumors exhibited a more favorable immune microenvironment, characterized by increased infiltration of immune effector cells, which further supports their predictive value [57–59] .

The presence of TLS in baseline tumor samples is a robust predictor of response to anti-PD-1/PD-L1 therapy and longer survival in patients with advanced bladder cancer. By fostering a favorable immune microenvironment and enhancing antitumor immune responses, TLS represent a promising biomarker for guiding treatment decisions and improving patient outcomes. Further research is needed to validate these findings and translate them into clinical practice. TLS are often found in the invasive margins of tumors and are associated with a more robust immune response, characterized by the presence of immune effector cells such as CD8⁺ T cells and macrophages [59]. TLS are thought to indicate a pre-existing, organized anti-tumor immune response that can be effectively unleashed by ICIs.

TLS as therapeutic targets in bladder cancer

Given the positive role of TLS, inducing or enhancing the formation of functional TLS in bladder cancer has become an emerging therapeutic strategy.

ICI monotherapy, while revolutionary, often fails to induce TLS that are critical for sustained anti-tumor immune responses. The inability of ICIs alone to induce TLS is partly due to the immunosuppressive TME, which inhibits immune cell infiltration and activation [60]. Combining with other drugs that promote lymphoid tissue formation is a hot topic; Combination with radiotherapy/chemotherapy: Radiotherapy or some chemotherapy drugs (such as gemcitabine, oxaliplatin) can induce immunogenic cell death, releasing TAAs and DAMPs that promote APCs maturation and chemokine secretion, synergizing with ICI to induce TLS formation [61].

Combination with cytokine/chemokine therapy: Direct injection or delivery through carriers (viruses, mRNA) of key molecules (such as recombinant CXCL13, CCL21, LTα) or activation of their signaling pathways (such as LTβR agonists) directly promotes lymphoid neogenesis. PRR agonists activate DCs by engaging specific receptors, leading to the production of cytokines such as IL-12p70 and IFNβ, which are critical for Th1 polarization and antitumor immunity [62]. For example, TLR3 agonists like poly(I: C) and TLR7/8 agonists like R848 have been shown to synergize, significantly enhancing IL-12p70 production in human DCs. Similarly, combining STING agonists with TLR7/8 agonists in acetalated dextran microparticles (Ace-DEX MPs) elicits a broad cytokine response, including IL-12 and IFNβ, which are essential for antitumor immunity [63].

Combination with other therapies: Activating CD40 on APCs (DCs, B cells, macrophages) promote their maturation and migration ability, potently inducing TLS formation. Infusion of T cells modified to express specific chemokine receptors or with homing ability may promote their aggregation at tumor sites and participate in TLS formation. Oncolytic viruses (OVs)—viruses engineered to selectively infect and replicate within tumor cells—can not only directly lyse tumor cells to release TAAs and DAMPs^[36] but also express immune-stimulating factors (such as GM-CSF) or chemokines, reshape the TME, and promote TLS formation. For example, the herpesvirus-based OV T-VEC has been modified to express granulocyte-macrophage colony-stimulating factor (GM-CSF), which enhances the recruitment and activation of dendritic cells, thereby promoting antigen presentation and immune activation [64].

Challenges and future directions

Despite their promise, several challenges must be addressed. Efficient and stable induction: How to efficiently induce structurally complete and functionally mature TLS in the immunosuppressive TME of bladder cancer remains a challenge. The ability and mechanism of different subtypes of bladder cancer (such as basal, luminal) to induce TLS may vary [65]. Basal-like tumors are generally more immunogenic, exhibiting higher infiltration of T cells, B cells, and myeloid cells, and are therefore more likely to form mature TLS [66]. These tumors often express higher levels of chemokines, including CXCL13, CCL19, and CCL21, which facilitate recruitment and organization of immune cells into functional TLS [38]. In contrast, luminal-like tumors typically have lower immune cell infiltration and reduced expression of TLS-inducing signals, resulting in fewer or immature TLS (Molecular classification of urothelial carcinoma: global transcriptomic analysis). Clinically, the presence of TLS in basal tumors is associated with improved patient survival and enhanced responsiveness to immunotherapy, whereas TLS in luminal tumors may have a weaker or less consistent prognostic impact [39, 67]. These subtype-specific differences underscore the importance of considering molecular context when evaluating TLS as prognostic biomarkers or potential targets for therapeutic modulation. Standardized assessment system: There is a critical need for unified and repeatable criteria for TLS detection, quantification, and maturity grading using techniques such as HE staining, multiplex immunohistochemistry immunofluorescence combined with AI-base analysis.

TLS heterogeneity and immune composition

TLS exhibit substantial heterogeneity in cellular composition, maturation status, and spatial organization within the tumor microenvironment. Based on immune cell dominance, TLS can be categorized as B cell–rich, T cell–rich, or myeloid-rich. B cell–rich TLS support robust humoral responses and Tfh–B cell interactions, enhancing antigen presentation and antibody production. T cell–rich TLS primarily amplify cytotoxic T cell responses and promote local tumor cell killing. Myeloid-rich TLS may exert either stimulatory or immunosuppressive effects depending on the activation state of myeloid subsets. These differences in composition and maturity likely determine the antitumor efficacy of TLS and their impact on therapy response. However, the precise functional roles of these distinct TLS types in bladder cancer remain incompletely understood and warrant further investigation.

Spatial analysis of TLS

Recent advances in spatial technologies, including spatial transcriptomics and spatial proteomics, provide powerful tools to dissect the molecular and spatial architecture of TLS and their interactions with tumor cells and stromal compartments. These approaches enable high-resolution mapping of immune cell localization, cellular crosstalk, and functional states within TLS, offering insights into how heterogeneity in composition and maturation affects antitumor immunity. Despite these advances, challenges remain, including the computational demands of analyzing large spatial datasets, the lack of standardized analytical pipelines, and the complexity of integrating multi-omics data from transcriptomics, proteomics, and other modalities.

Future studies should combine spatially resolved single-cell analyses with functional assays to define how TLS composition, maturation, and spatial positioning influence neoantigen reactivity, lymphocyte activation, and immunotherapy response. A deeper understanding of TLS heterogeneity and spatial organization could guide therapeutic strategies aimed at promoting the formation of mature, functionally optimal TLS to enhance antitumor immunity in bladder cancer.

Alternative approaches

Beyond immune checkpoint inhibitors, therapies such as ADCs, BCG, and vaccination or oncolytic virus strategies may modulate TLS in bladder cancer. ADCs can induce immunogenic cell death and release tumor antigens, potentially promoting TLS formation, but efficacy may vary between basal-like and luminal tumors, and optimizing delivery while avoiding toxicity remains challenging. BCG therapy stimulates local immune responses and may facilitate TLS formation, yet TLS maturation and patient-to-patient variability require further study. Vaccines and oncolytic viruses can prime T and B cell responses and support TLS development, but tumor antigen heterogeneity and immune variability limit consistent outcomes. Future research should focus on mapping TLS composition and function in therapy-treated bladder tumors using spatial and single-cell technologies, and identifying strategies to selectively promote mature, functional TLS to enhance antitumor immunity and improve patient outcomes.

Safety concerns

Excessive or inappropriate immune activation may trigger autoimmune diseases or severe inflammatory responses (such as cytokine release syndrome) [68]. Caution should be exercised when targeting pathways such as LTβR to assess safety.

Model development

The development of reliable preclinical models to simulate TLS formation and function remains a significant gap in bladder cancer research. More reliable models (such as humanized mouse models, organoid co-culture systems) are needed to simulate the formation and function of TLS in bladder cancer, accelerating mechanism research and drug screening [69].

Conclusion

TLS are key organizers and executors of anti-tumor immune responses in bladder cancer. Their formation is regulated by a complex network of chemokines and cytokines, and they significantly enhance anti-tumor immunity by promoting in situ T/B cell activation, clonal expansion, and effector functions. Although the efficient induction of functional TLS remains a challenge, targeting TLS through strategies such as combining ICI, cytokine/chemokine therapy, PRR agonists, and CD40 agonists has emerged as a highly promising new direction for bladder cancer immunotherapy. Future research should focus on in-depth analysis of the precise regulatory mechanism of TLS formation, understanding their heterogeneous functions and association with tumor molecular subtypes, as well as developmenting safe and effective translational strategies to ultimately improve survival benefits for bladder cancer patients.

Abbreviations

TLS

Tertiary lymphoid structures

TME

tumor microenvironment

ICIs

immune checkpoint inhibitors

FDCs

follicular dendritic cells

HEVs

high endothelial venules

MIBC

muscle-invasive bladder cancer

CAR

antigen receptor

TAAs

tumor-associated antigens

APCs

antigen-presenting cells

DAMPs

damage-associated molecular patterns

HMGB1

high-mobility group box 1

HSPs

heat shock proteins

PRR

pattern recognition receptor

MHC

major histocompatibility complex

ADCC

antibody-dependent cell-mediated cytotoxicity

ADCP

antibody-dependent cell-mediated phagocytosis

NMIBC

non-muscle-invasive bladder cancer

PFS

progression-free survival

OS

Overall Survival

Authors’ contributions

YJS: Conceptualization, investigation, original draft preparation and Preparation of manuscript. LXX: Resources, investigation. XH: literature review, Resources. GJH: Resources. WJH: Concept and design, and editing of manuscript. Lch: Funding acquisition, Project Administration, Supervision and Conceptualization. All authors read and approved the final manuscript.

Funding

This study was funded by the Taishan Scholar Program of Shandong Province (no. Tsqn202103198), Natural Science Foundation of Shandong Province (ZR2024MH305), Yantai Scientific and Technological Innovation Development Program (2024YT06000818).

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

Not applicable.

Competing interests

The authors declare no competing interests.