Tissue-resident memory T (T_RM) cells represent a unique subset of memory T cells that reside permanently within non-lymphoid tissues without recirculating through the blood or lymphatic systems (1). Unlike central or effector memory T cells, T_RM cells are characterized by the expression of markers such as CD69, which prevents egress from tissues, and CD103, which promotes adhesion to epithelial cells (2–4). These cells serve as sentinels of localized immunity, poised to rapidly respond to reinfection by previously encountered pathogens (5, 6). This unique population comprises two main subsets: CD4⁺ and CD8⁺ T_RM cells, each with distinct characteristics, developmental pathways, and functional roles (7). CD8⁺ T_RM cells act as the first line of defense against viral re-infections, rapidly eliminating infected cells upon pathogen re-encounter (8). In contrast, CD4⁺ T_RM cells play a critical role in coordinating broader immune responses, including the support of B cell activity and the maintenance of local immunity at various tissue sites, such as skin and mucosal surfaces (9). Recent studies have shown that T_RM cells comprise approximately 10-30% of the total T cell population in non-lymphoid tissues, with variations depending on tissue type and disease state (10). For example, in inflamed tissues, T_RM cells can account for up to 60% of the T cell population, while in cancer tissues, their proportion typically ranges from 5% to 20%, depending on the tumor microenvironment (11–13). This variability in T_RM cells frequency underscores their dynamic roles in immune responses across different conditions. Furthermore, T_RM cells have been shown to persist in non-lymphoid tissues for extended periods, with some studies reporting survival times ranging from several months to years. This long-term presence highlights their critical role in maintaining tissue immunity (14, 15). These distinct functions underscore the importance of understanding the heterogeneity of T_RM cells in the context of urinary tract diseases, setting the stage for a more detailed exploration of their roles in infections, tumors, and chronic inflammation that follows.

The urinary tract is a critical site for immune responses, balancing pathogen defense with tolerance of non-harmful antigens. It comprises the urinary and reproductive systems, including the kidneys, bladder, and genital organs. T_RM cells, identified in bladder, ovarian, vaginal, kidney, uterine, prostate, and penile tissues, are vital for local immunity against infections and tumors and may modulate autoimmune responses (16–21). Beyond the urinary tract, T_RM cells have also been implicated in other cancer types, such as melanoma, lung cancer, and breast cancer, where they contribute to tumor surveillance and immune control (22–24). For instance, in melanoma, high densities of CD8⁺ T_RM cells are associated with improved patient survival and response to immunotherapy (25). Similarly, in lung cancer, T_RM cells have been shown to enhance anti-tumor immunity and predict favorable clinical outcomes (26). These findings highlight the broader relevance of T_RM cells in cancer immunity and underscore the need for further research into their roles across different tissue types and disease contexts. Their strategic localization within the epithelial barriers and ability to interact with other immune and stromal cells underline their importance as both defenders and regulators of tissue health. Understanding the unique biology of T_RM cells in this context is vital for developing targeted therapeutic strategies.

T_RM cells in the urinary tract share features with those in other parts of the body, such as the expression of CD69 and CD103, as well as the characteristic of tissue residency. They also display unique adaptations to their local microenvironments, including their positioning in specific tissues-like the lamina propria and basal epithelial lining in vaginal and penile tissues-and the expression of molecular markers such as CXCR3, P2RX7, CXCR6, and CD49a (27–31). Immediately upon entry, these adaptations indicate their strategic positioning in barrier tissues to intercept pathogens, including bacteria, viruses, and fungi.

Urinary tract infections (UTIs) are among the most common infections globally, characterized by frequent recurrence despite antibiotic treatment (32, 33). T_RM cells play a pivotal role in the immune defense against these infections by establishing localized, long-term immunity in the urinary tract. In response to primary infection, pathogen-specific T_RM cells are generated and retained in the bladder mucosa, where they can rapidly detect and respond to reinfection. However, T_RM cells, including CD4⁺ and CD8⁺ subsets, do not directly recognize pathogens but instead rely on interactions with antigen-presenting cells (APCs) to initiate their immune responses. Upon reinfection, dendritic cells (DCs) and macrophages in the urinary tract rapidly process and present pathogen-derived antigens via MHC class II and class I molecules, respectively. CD4⁺ T_RM cells recognize antigens presented on MHC class II by APCs, leading to their activation and subsequent secretion of cytokines, such as interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α), which recruit and activate additional immune cells like neutrophils and macrophages (34). Similarly, CD8⁺ T_RM cells are activated through the recognition of antigens presented on MHC class I by APCs, enabling them to exert cytotoxic effects via the release of granzymes and perforin (35). This interaction between T_RM cells and APCs ensures a rapid and localized immune response that is essential for the effective clearance of pathogens during secondary infections. These cells express markers such as CD69, which anchors them within tissues, and secrete cytokines like IFN-γ upon activation, initiating a cascade of immune responses that recruit neutrophils and other effector cells to the site of infection (18). T_RM cells are particularly effective in combating uropathogenic Escherichia coli (UPEC), the most common causative agent of UTIs. CD4⁺ and CD8⁺ T_RM cells play complementary roles in the immune defense against UTIs. CD4⁺ T_RM cells primarily facilitate immune responses by secreting cytokines that help activate other immune cells, such as macrophages and B cells, promoting antibody production and maintaining immune homeostasis (36). These cells also contribute to tissue repair and inflammation regulation in the urinary tract. In contrast, CD8⁺ T_RM cells exert direct cytotoxic effects by killing infected epithelial cells through the release of granzymes and perforin, limiting pathogen replication (37). Both CD4⁺ and CD8⁺ T_RM cells provide long-term immunity by persisting in the bladder mucosa, enabling rapid and effective responses to reinfection. However, the activation and persistence of T_RM cells, especially during recurrent UTIs, can also lead to chronic inflammation and tissue damage, emphasizing the need for therapeutic strategies that balance immune protection with the prevention of excessive tissue injury.

In the context of secondary infections, T_RM cells are poised to rapidly exert their effector functions. They produce granzyme B and pro-inflammatory cytokines that serve to recruit and activate additional immune cells. This swift response is essential for controlling viral reactivation and combating bacterial infections. Studies have shown that UPEC-specific T_RM cells remain in the bladder mucosa long after the initial infection has resolved, providing a robust immunological memory that reduces the severity of subsequent infections (18). However, the persistence and activation of T_RM cells can also contribute to tissue damage and inflammation in the bladder, especially in recurrent infections, potentially exacerbating symptoms. Moreover, their interactions with other immune cells, including macrophages and DCs, further shape the local immune microenvironment (38, 39).

When T_RM cells function is impaired-due to factors such as immunosuppressive environments, chronic inflammation, or aging-the immune response becomes less effective (40–42). In such scenarios, pathogen clearance is delayed, leading to prolonged infection, increased pathogen load, and heightened risk of tissue damage. The absence of immediate effector responses also results in a heavier reliance on systemic adaptive immunity, which takes more time to activate and may not effectively localize to the infection site.

T_RM cells are emerging as critical players in the immune response to urinary tract tumors, including bladder, prostate, and kidney cancers ( Figure 1 ). These cells reside within tumor tissues, where they exert localized anti-tumor effects by recognizing and responding to tumor-specific antigens. T_RM cells contribute to immune surveillance, influence the tumor microenvironment (TME), and enhance responses to immune checkpoint inhibitors (ICIs). In urinary tract tumors, T cell exhaustion is a well-known feature of the tumor immune microenvironment, characterized by the upregulation of inhibitory receptors such as PD-1, TIM-3, and LAG-3 (43). Interestingly, while T_RM cells are generally associated with robust immune responses, they are not immune to the effects of exhaustion in tumor settings. T_RM cells within the TME can become exhausted over time due to chronic antigen stimulation and the immunosuppressive signals present in the tumor. This exhaustion is associated with a reduced capacity for cytokine production, cytotoxic activity, and overall immune surveillance (44). However, unlike recirculating T cells, T_RM cells may maintain some degree of function due to their unique tissue-residency markers, such as CD69 and CD103. These markers help anchor T_RM cells in the tissue, potentially allowing them to persist in the TME even when other T cells become exhausted. Recent studies suggest that enhancing the functionality of exhausted T_RM cells in tumors could improve responses to immunotherapies, such as ICIs, by restoring their effector functions (45).

In urinary cancers, tumor-infiltrating T cells display a heterogeneous phenotype. The majority of these cells express CD69 in prostate and kidney cancers, while in bladder cancers, they also commonly express CD103. Understanding the role of T_RM cells in these cancers offers valuable insights into novel immunotherapeutic strategies and their potential to improve clinical outcomes.

The roles of T_RM cells in various urinary tract diseases differ significantly. As summarized in Table 1 , their functions range from immune surveillance in bladder cancer to fibrosis promotion in chronic pyelonephritis. The heterogeneity of T_RM cells populations, evidenced by their varied phenotypic and functional profiles within the urinary tract, offers a range of benefits. This diversity is crucial for the immune response to infections and cancers, as well as for the complex dynamics of autoimmune and inflammatory diseases affecting the urinary system. T_RM cells infiltration in the kidney positively correlates with disease activity, as indicated by increased serum creatinine, proteinuria, hematuria, and histological scores in patients with lupus nephritis (LN) and antineutrophil cytoplasmic antibody (ANCA) associated glomerulonephritis (GN), as well as in murine systemic lupus erythematosus (SLE) models (61, 63–65). In murine GN models, the number of CD4⁺ T cells predominates over CD8⁺ T cells, whereas in humans, nearly equal numbers of CD4⁺ and CD8⁺ T cells are reported in many studies (66–68). Similarly, in the kidneys of patients and mice with LN, the abundance of CD8⁺ T_RM cells was significantly increased (69). Under inflammatory conditions, renal T cells exhibit a tissue-resident phenotype, with CD69 widely expressed on both CD4⁺ and CD8⁺ T cells, indicating their significant role in local immune responses. Additionally, CD103 expression is observed on renal T cells, particularly on CD8⁺ T cells in patients with SLE and in SLE-prone mice (63–65). Mice studies show that both commensal and pathogenic bacteria can trigger kidney inflammation. Infection with S. aureus, and C. albicans leads to kidney CD4⁺ T_RM cells adopting an inflammatory TH17 phenotype, exacerbating disease (64). Activation of kidney T_RM cells by cytokines like IL-1β, IL-6, and IL-23 through the JAK-STAT pathway amplifies the inflammatory response. Microbiota may activate T cells with kidney-homing potential in the intestine, and fate-mapping suggests T cells migrate from the intestine to the kidney post-nephritis induction. This migration is driven by S1PR1-dependent egress from the intestine and CCL20-dependent entry into the kidney. The role of these newly infiltrated T cells in disease progression is unclear, but their presence suggests a role for microbiota-driven inflammation in promoting autoimmunity in the kidney.

In cases of chronic infections, such as chronic pyelonephritis, the formation and role of T_RM cells may differ from acute infections. While T_RM cells are typically associated with rapid immune responses to reinfection, their role in chronic infections is more complex. In chronic pyelonephritis, the persistent presence of pathogens and ongoing inflammation may affect the dynamics of T_RM cells formation. It is possible that T_RM cells are generated and persist in the kidneys during chronic infection, but their function may be impaired or dysregulated due to the prolonged inflammatory environment (70). In such conditions, T_RM cells may contribute to the chronic inflammation by promoting tissue damage and fibrosis, potentially leading to a maladaptive immune response. Further research is needed to fully understand the mechanisms underlying T_RM cells persistence in chronic infections and their dual role in both protective immunity and tissue pathology.

The therapeutic potential of T_RM cells in urinary tract diseases, including infections, cancers, and chronic inflammatory conditions, is an area of growing interest ( Table 2 ). Harnessing the localized immune response of T_RM cells offers several promising strategies for improving treatment outcomes. In the context of infections like UTIs, vaccines designed to generate pathogen-specific T_RM cells in mucosal tissues could provide long-lasting protection and reduce recurrence (71, 82). Enhancing T_RM cells responses through adjuvants or immune modulators could also improve the efficacy of current vaccines and reduce the burden of recurrent infections (83). By deepening our understanding of T_RM cells biology in the context of UTIs, novel interventions can be designed to improve long-term immune protection while minimizing immune-mediated pathology.

In urinary tract cancers, T_RM cells have demonstrated a significant role in immune surveillance and anti-tumor immunity. Strategies that aim to boost the function of T_RM cells, such as ICIs targeting PD-1/PD-L1 or enhancing their local activation, hold promise for improving response rates to immunotherapy (84, 85). In addition to PD-1/PD-L1 inhibitors, recent studies have also highlighted the importance of other immune checkpoints, such as CXCR3 and IL-15, in regulating the immune response to urinary tract tumors (86). CXCR3, a chemokine receptor, plays a crucial role in the trafficking and retention of effector T cells, including T_RM cells, to tumor sites. Its expression on tumor-infiltrating lymphocytes is associated with improved immune surveillance and better responses to immunotherapy (87). Targeting CXCR3 may enhance T cell infiltration into tumors, especially in cancers such as bladder and prostate cancer, where T_RM cells are critical for anti-tumor immunity. IL-15 is another key molecule involved in the activation and maintenance of T_RM cells. It promotes the survival and function of memory T cells, including both CD4⁺ and CD8⁺ subsets. IL-15-based therapies are being explored as a way to boost T_RM cells responses in tumors by enhancing their persistence and effector function. Recent preclinical and clinical studies suggest that IL-15 can be used to improve the efficacy of immunotherapies, particularly in cancers where T_RM cells play a central role in local immunity (88). Together with PD-1 blockade, targeting these additional immune checkpoints could lead to more effective immune responses by not only reinvigorating exhausted T cells but also enhancing the recruitment and function of T_RM cells within tumors. Additionally, combining these approaches with conventional therapies like chemotherapy or radiation could optimize anti-tumor responses (89).

For chronic inflammatory diseases, targeting T_RM cells presents a unique challenge, as their persistent activation can contribute to tissue damage and pain. Therapies that modulate T_RM cell activity, such as cytokine blockers or interventions that restore immune homeostasis (e.g. Sparsentan, the dual angiotensin II receptor and endothelin type A receptor antagonist), could reduce T_RM cell responses, alleviate symptoms and reduce inflammation without compromising immune protection (69).

Looking forward, research into the specific signaling pathways that regulate T_RM cell differentiation, retention, and activation will be crucial for developing targeted therapeutic approaches. While T_RM cells are well recognized for their role in defending against acute reinfections, their role in chronic infections, such as tuberculosis, HIV, and chronic pyelonephritis, remains less explored. Future studies should focus on understanding how T_RM cells are generated and maintained in chronic infection settings, and how their function may be altered over time in the face of persistent antigen exposure and inflammation. Targeting the modulation of T_RM cells in chronic infections could lead to novel therapeutic strategies to enhance long-term immunity without causing excessive tissue damage. Immunotherapies targeting T_RM cells in tumors: T_RM cells have emerged as critical players in anti-tumor immunity, yet their full potential in cancer immunotherapy is still not fully realized. Future research should explore how to enhance the recruitment, persistence, and functionality of T_RM cells in tumors, particularly through combination therapies that target immune checkpoints like PD-1, CXCR3, and IL-15. Investigating how T_RM cells interact with the TME and their potential exhaustion during long-term antigen exposure could provide valuable insights into how to prevent or reverse T_RM cells exhaustion in cancers. T_RM in vaccine development: There is growing interest in developing vaccines that aim to generate long-lasting T_RM cells populations at mucosal surfaces, such as the urinary tracts. These vaccines could be crucial for preventing infections like UTIs. Future research should focus on identifying the best strategies for inducing robust T_RM cells responses through mucosal vaccination, as well as understanding how T_RM cells contribute to vaccine-mediated immunity in both infectious and cancer settings.

In conclusion, T_RM cells play a crucial role in the immune defense of the urinary tract, offering protection against infections, modulating tumor immunity, and influencing chronic inflammatory diseases. While their ability to provide long-lasting, localized immunity is promising, their dysregulation can contribute to chronic inflammation and tissue damage, especially in conditions like interstitial cystitis or chronic prostatitis. The therapeutic potential of T_RM cells is immense, particularly in developing vaccines, enhancing cancer immunotherapy, and targeting chronic inflammation. Beyond urinary tract cancers, T_RM cells have also been implicated in other malignancies, including lung cancer, breast cancer, and colorectal cancer. In non-small cell lung cancer, T_RM cells enriched in tumor tissues have been associated with improved responses to ICIs, particularly PD-1/PD-L1 blockade. Similarly, in breast cancer, T_RM cells contribute to local immune surveillance, though their exact role varies across molecular subtypes. In colorectal cancer, T_RM cells have been linked to enhanced tumor control and better prognosis, especially in microsatellite instability-high tumors. Future research should explore how T_RM cells contribute to tumor immunity across different cancer types and how their functional states may vary depending on the tumor microenvironment. Understanding the mechanisms regulating T_RM cells exhaustion and activation in diverse cancers could provide insights into optimizing T_RM-targeted immunotherapies. Expanding research beyond urinary tract cancers will be crucial for fully harnessing the therapeutic potential of T_RM cells in oncology. Future research should focus on understanding the complex interactions of T_RM cells in different disease contexts and exploring strategies to harness their protective functions while mitigating their pathological effects. By doing so, we can develop more effective and personalized treatments for urinary tract diseases.