Targeting urological cancers with CAR-T cell therapy: current landscape and future directions.

Introduction

Cancer is a disease resulting from uncontrolled cell growth and has become a major public health problem worldwide [ 1 ]. When cancers originate in the urinary system of men and women, as well as the reproductive system of men, they are categorized as urological cancers, which mainly include renal, bladder, and prostate cancers [ 2 ]. According to global statistics, there were approximately 2,600,000 new cases of urological cancers, with mortality of 795,000 in 2022 [ 3 ]. Among them, renal cancer ranked as the 14th most commonly diagnosed cancer, 10th among men, and 16th in cancer-related mortality worldwide [ 3 , 4 ]. Renal cell carcinoma (RCC) is the most common type of renal cancer and is associated with a substantial number of cancer-related deaths [ 5 ]. Bladder cancer is the second most common urological cancer, ranked the ninth for incidence and the 13th for deaths [ 3 , 6 ]. In terms of prostate cancer, it is the most frequent urological cancer, accounting for the second incidence and the fifth mortality in men [ 3 , 7 ]. Due to population expansion and aging, the global burden of urological cancers remained a growing trend [ 8 , 9 ]. Although standard treatment methods such as surgery, radiotherapy and chemotherapy, have been applied for decades, the prognosis of patients with advanced urological cancers are far from optimistic [ 10 , 11 ]. Therefore, there is an urgent need to develop more strategies for urological cancer therapy.

The clinical application of immunotherapy for cancer dates to the 1890s, when William Coley unintentionally observed tumor regression in sarcoma patients infected with Streptococcus pyogenes [ 12 ]. In 1929, Raymond Pearl’s autopsy research also revealed a reduced cancer incidence in tuberculosis patients, suggesting the potential antitumor properties of the Bacillus Calmette-Guérin (BCG) vaccine [ 13 ]. Subsequently, more researchers evaluated BCG as an immunological agent for bladder cancer treatment and confirmed its efficacy [ 14 , 15 ]. Finally, the Food and Drug Administration (FDA) authorized BCG as a therapeutic therapy for bladder cancer in 1990 [ 16 ]. At present, BCG immunotherapy is still the standard of treatment for high-risk non-muscle invasive bladder cancer (NMIBC) [ 17 ]. In the past five years, the success of immune checkpoint inhibitors (ICIs) has reignited enthusiasm for developing immunotherapy strategies in urological cancers [ 18 , 20 ]. Chimeric antigen receptor (CAR)-T cell therapy involves inserting CAR molecules into T cells to provide them target functions, as well as enhanced antigen recognition and immune activities [ 21 ]. Binding to tumor targets rather than through major histocompatibility complex (MHC)-restricted recognition, CAR-T cells are activated to eliminate tumor cells with improved therapy efficacy [ 22 ]. In the treatment of hematologic malignancies, CAR-T cell therapy has achieved promising success [ 23 , 24 ], and it has been approved by the FDA for treating patients with B-cell malignancies or relapsed and/or refractory multiple myeloma [ 25 ]. Unlike the rapid progress in the hematological tumors, the efficacies of CAR-T therapy in most solid tumors remain uncertain [ 26 ]. Currently, CAR-T therapy for solid tumors faces serious challenges, such as inadequate specificity of the targeted antigen, poor trafficking, limited duration and tumor antigen heterogeneities [ 27 , 28 ]. Recently, one clinical trial ( NCT03874897 ) employing Claudin18.2 CAR-T cells demonstrated encouraging effectiveness and safety in treating 37 patients with digestive system cancers, with a 48.6% overall response rate and a 73.0% disease control rate [ 29 ]. In addition, Del et al. [ 30 ] reported that among 27 patients for high-risk neuroblastoma treatment via anglioside gd2 (GD2)-CAR-T cells, 9 patients achieved a complete response (CR) and 8 achieved a partial response (PR) ( NCT03373097 ). These two clinical trials delivered positive results, confirming the optimistic feasibility of CAR-T cells in solid tumor therapy.

Urologic cancers represent one of the most prevalent categories of solid tumors. Traditional treatment methods have demonstrated limited improvement in patient survival and prognosis, necessitating the exploration of new treatment strategies [ 31 , 33 ]. Given the remarkable antitumor effect of CAR-T therapy in hematological malignancies, it is imperative to validate its application value in urologic cancers. This article aims to review the latest research on CAR-T therapy in renal, bladder, and prostate cancers.

Developments of CAR-T cells

First-generation CAR-T

In 1987, Kuwana et al. transfected EL4 cells with a combined receptor gene constructed from antibody-derived variable regions and T-cell receptor (TCR)-derived constant regions via a vector, which facilitated EL4 cells to respond to specific bacterial antigens [ 34 ]. This study initially demonstrated the principle of integrating antibody-type antigen specificity with T-cell signaling. Similarly, in 1989, Gross and Eshhar successfully introduced an anti-2,4,6-trinitrophenyl (TNP) chimeric receptor gene into cytotoxic T cells, granting them a non-MHC-restricted response to TNP and cytotoxicity against TNP-bearing target cells [ 35 ]. Both methods depended on coupling the constant region of each of the two chains (α and β) with immunoglobulin (Ig) variable regions (VH or VL chains), resulting in limited transfection efficiency and receptor expression. Consequently, Eshhar developed the “T-body” method to improve chimeric TCR design by incorporating a single-chain variable fragment (scFv), in which VL and VH chains were connected via a linker [ 36 , 37 ]. Subsequently, the scFv was attached to a CD3ζ or Fc receptor γ (FcRγ) activating domain via a hinge and transmembrane sequence. This breakthrough marked the invention of the first-generation (1 G) CAR. In 1993, Eshhar et al. [ 38 ] first demonstrated the antitumor effects of 1 G CAR-transduced tumor-infiltrating lymphocytes using an ovarian carcinoma cell line (IGROV-1) and mouse tumor models. Based on prior research, Hege et al. [ 39 ] conducted two CAR-T clinical trials in patients with metastatic colorectal cancer, investigating the application of CC49-ζ-expressing CAR-T cells targeting TAG-72. A total of 14 patients were included across both studies, and the results demonstrated the safety of CAR-T therapy; however, the persistence of CAR-T cells was less than 14 weeks in most patients, and no positive tumor responses were observed. Other studies have also explored 1 G CAR-T cell therapy for ovarian cancer [ 40 ], renal cancer [ 41 ], lymphoma [ 42 ], and neuroblastoma [ 43 ]. Likewise, most of these early clinical trials primarily confirmed the safety of CAR-T cell therapy, with limited evidence of significant antitumor efficacy.

Second-generation CAR-T

Later, subsequent studies began to recognize the role of costimulatory ligand receptor interactions in the dual-signal activation of T cells, leading to the development of second-generation (2 G) CARs [ 44 ]. In 1994, Roberts et al. [ 45 ] (Cell Genesys) first described the concept of integrating costimulatory domains into CARs. Subsequently, Finney et al. [ 46 ] (Celltech Therapeutics) reported a similar approach, successfully transducing Jurkat cells with a scFv-based chimeric receptor incorporating the CD28 costimulatory domain. Concurrently, a series of studies demonstrated that adding costimulatory molecules (CMs) such as CD28 [ 47 , 48 ], 4-1BB (CD137) [ 49 ], and CD19 [ 50 , 51 ], enhanced the proliferation, persistence, cytokine production, and cytotoxicity of CAR-T cells. Moreover, improved persistence and resistance to apoptosis enabled 2 G CAR-T cells to exert more durable therapeutic effects in humans. Notably, when Carl June and colleagues applied CD19-targeted 2G CAR-T cells to treat patients with advanced chronic lymphocytic leukemia, complete remission was observed in two of three patients, representing a significant milestone in CAR-T cell therapy for cancer [ 52 ]. To date, the FDA has approved six 2G CAR-T cell therapies for hematological malignancies (Table 1 ). Table 1 CAR-T cells for hematological cancers therapy approved by the FDA Name Target Disease MFU (m) N ORR (%) CRR (%) Estimated Survival/ Survival Rate CRS (%) Neurotoxicity (%) Any Grade≥3 Any Grade≥3 Axicabtagene ciloleucel (YESCARTA) CD19 R/R LBCL [ 53 ] 63.1 101 83 58 25.8 m/42.6% (at 5y) 93 11 64 30 R/R LBCL [ 54 ] 47.0 37 92 86 81.1% (at 36 m) 100 8 73 23 R/R iNHL-FL [ 55 ] 41.7 127 94 / 40.2 m (PFS) 0 0 0 0 R/R iNHL-MZL [ 55 ] 31.8 31 77 / / 11 0 4 4 Brexucabtagene autoleucel (TECARTUS) CD19 R/R MM [ 56 ] 35.6 68 91 68 46.6 m 91 15 63 31 R/R MCL [ 57 ] 14.3 168 90 82 59% (PFS, at 12 m) 90 8 61 32 R/R B-ALL [ 58 ] 41.6 78 73 60 25.6 m 89 24 60 26 R/R B-ALL [ 59 ] 11.4 189 90 79 9.5 m (PFS) 84 11 56 31 Ciltacabtagene autoleucel (CARVYKTI) BCMA R/R MM [ 60 ] 27.7 97 97.9 82.5 70.4% (at 27 m) 94.8 5.1 21.6 12.3 R/R MM [ 61 ] 13 236 89 70 68% (PFS, at 12 m) 75 5 14 4 Idecabtagene vicleucel (ABECMA) BCMA R/R MM [ 62 ] 18.1 62 75.8 38.7 34.2 m 75.8 6.5 37.1 1.6 R/R MM [ 63 ] 18.6 255 71 39 13.3 m (PFS) 88 5 15 3 R/R MM [ 64 ] 6.1 159 84 42 12.5 m 82 3 16 8 Lisocabtagene maraleucel (BREYANZI) CD19 R/R LBCL [ 65 ] 19.9 257 73 53 27.3 m 42 2 30 10 CLL and SLL [ 66 ] 21.1 49 43 18 30.3 m 85 9 45 19 R/R FL [ 67 ] 18.9 101 97 94 92% (at 27 m) 58 1 15 2 RR MCL [ 68 ] 16.1 m 83 83.1 72.3 15.3 m (PFS) 61 1 31 9 Tisagenlecleucel (KYMRIAH) CD19 R/R B-ALL [ 69 ] 38.8 79 82 62 63% (at 36 m) 77 46 40 13 R/R BCL [ 70 ] 40.3 115 53 39 11.1 m 57 23 20 11 R/R FL [ 71 ] 29 97 86.2 68.1 87.7% (at 24 m) 48.5 0 37.1 3 MFU, median follow-up; ORR, overall response rate; CRR, complete response rate; CRS, cytokine release syndrome; PFS, progression free survival; R/R, relapsed/refractory; ALL, acute lymphoblastic leukemia; B-ALL, b-cell acute lymphoblastic leukemia; CLL, chronic lymphocytic leukemia; FL, follicular lymphoma; iNHL, indolent non-Hodgkin lymphoma; LBCL, large B-cell lymphoma; MCL, mantle cell lymphoma; MM, multiple myeloma; MZL, marginal zone lymphoma; SLL, small lymphocytic lymphoma

Third-generation CAR-T

Building upon the design of 2G CAR-T cells, third-generation (3 G) CAR-T cells incorporate an additional costimulatory signaling domain [ 72 ]. Additional costimulation is generally considered advantageous, particularly when tumor cells express low antigen levels and provide insufficient signaling stimulation. Currently, the design of costimulatory domains in 3 G CAR-T cells primarily involves combining immunoglobulin (Ig) superfamily members (e.g., CD28 or ICOS) with tumor necrosis factor receptor superfamily (TNFRSF) members (e.g., 4-1BB or OX40) [ 73 ]. For example, the combination of CD28 and 4-1BB not only enhances the cytotoxicity and expansion of CAR-T cells but also significantly prolongs effector cell persistence in the host [ 74 , 75 ]. In addition, comparing the anti-Hodgkin lymphoma effects of 2G and 3 G CAR-T cells, Zhang et al. [ 76 ] demonstrated that 3 G (CD28/4-1BB) CAR-T cells exhibited enhanced tumor-homing abilities in xenograft models. Similarly, ICOS and 4-1BB costimulation improved CAR-T cell persistence in vivo [ 77 ], while the combination of O×40 and CD28 increased the proliferation, persistence, CAR molecule production, and pro-inflammatory cytokine secretion (e.g., interferon [IFN]-γ, tumor necrosis factor [TNF]-α and interleukin [IL]-2) by CAR-T cells [ 78 ]. The ICOS costimulatory domain combined with O×40 also positively influenced CAR-T cell proliferation, persistence, and antitumor activity. However, imbalanced costimulatory signaling may lead to pathway crosstalk and accelerated CAR-T cell exhaustion, ultimately diminishing antitumor efficacy [ 79 , 80 ]. Furthermore, the clinical effects of 3 G CAR-T cells remain controversial, particularly concerning differing outcomes between hematologic and solid tumors [ 30 , 81 ]. Therefore, further clinical data are needed to systematically and comprehensively evaluate the therapeutic efficacy of 3 G CAR-T cells.

Fourth- and next-generation CAR-T

The fourth-generation (4 G) CAR-T cells, also known as T cells redirected for antigen-unrestricted cytokine-activated killing (TRUCK), integrate advanced functional elements to enhance therapeutic efficacy [ 82 ]. By modifying intracellular signaling domains with transcriptional elements containing nuclear factor of activated T cells (NFAT), 4 G CAR-T cells combine direct antitumor attacks with immune modulation [ 83 ]. Upon CAR signal activation by the antigen, NFAT induces expression of transgenic immune modifiers, such as cytokines IL-7, IL-12, and IL-15 [ 84 , 85 ]. Combinations of several signaling factors have also been explored and under clinically evaluation, such as IL-7 [ 86 , 87 ], IL-12 [ 88 , 89 ], IL-15 [ 87 , 90 ], IL-17 [ 91 ] and IL-18 [ 92 ]. In addition, the TRUCK strategy can be utilized to generate specific antibodies triggered by CAR signaling, targeting common immune checkpoints (e.g., programmed cell death-1 [PD-1] [ 93 ] and programmed cell death ligand-1 [PD-L1] [ 94 ]) or typical biomarkers (e.g., carcinoembryonic antigen [CEA] [ 95 ], GD2 [ 96 ], and prostate-specific membrane antigen [PSMA] [ 97 ]). The next-generation CAR-T cells have been actively developed to address limitations in manufacturing, administration, safety, and response durability [ 98 ]. Key examples include multi-targeting CARs [ 99 ], on/off switch designs [ 100 ], logic-gated elements [ 101 ], integration of cytokine receptor intracellular domains (ICD) [ 85 ], allogeneic CAR-T cells and in situ approaches [ 102 ] (Fig. 1 ). Fig. 1 Generations of chimeric antigen receptors (CARs). First-generation (1 G) CARs comprise a single-chain variable fragment (scFv) formed by the VL and VH chains, and are linked to an intracellular CD3ζ or Fc receptor γ (FcRγ) signaling domain via a hinge region. Second-generation (2G) and third-generation (3 G) CARs incorporate one or two costimulatory domains, respectively, such as CD28, 4-1BB, or ICOS. Fourth-generation (4 G) CARs include intracellular signaling domains with a transcriptional regulatory element containing nuclear factor of activated T cells (NFAT), enabling inducible expression of immune modifiers (e.g., IL-7, IL-12, and IL-15). Next-generation CARs are currently under further development, such as multi-targeting CARs, on/off switch designs, and addition of cytokine receptors intracellular domains

Renal cancer

Immunotherapy for renal cancer

RCC constitutes over 90% of renal malignancies [ 103 ]. In 2022, there were approximately 430,000 new RCC diagnoses and 150,000 deaths worldwide [ 3 ]. For localized disease, partial or radical nephrectomy remains the standard therapeutic strategy, yet postoperative tumor recurrence and progress rates approach around 20–40% [ 5 , 104 ]. Notably, 30% of patients had locally advanced or metastatic RCC (mRCC) at the time of initial diagnosis, and the 5-year survival rate for these patients was less than 12% [ 105 ]. RCC exhibits intrinsic resistance to conventional cytotoxic and hormonal therapies [ 106 , 107 ]. Historically, the management of advanced RCC relied on high-dose cytokine regimens (IFN-α/IL-2) [ 108 , 109 ]. Although the treatment efficacy was constrained by severe adverse events, the observed response of advanced RCC to cytokine therapy represented an early success in immunotherapy. Over the past decades, therapeutic paradigms for advanced RCC shifted with the development and application of molecular-targeted agents, including vascular endothelial growth factor (VEGF) inhibitors (e.g., sunitinib [ 110 ], sorafenib [ 111 ], pazopanib [ 112 ] and axitinib [ 113 ]), mammalian target of rapamycin (mTOR) inhibitors (e.g., everolimus [ 114 ] and temsirolimus [ 115 ]), and the hypoxia-inducible factor 2α (HIF-2α) inhibitor belzutifan [ 116 ]. Subsequently, ICIs profoundly transformed the therapeutic landscape of RCC [ 117 ]. For example, nivolumab, a PD-1 inhibitor, has been approved by the FDA for advanced RCC following prior anti-angiogenic therapy, based on its improvement in overall survival (OS) [ 118 ]. Recently, more ICIs have been investigated in clinical trials and shown promising antitumor efficacy to RCC, such as pembrolizumab (anti-PD-1) [ 119 ], atezolizumab (anti-PD-L1) [ 120 ], ipilimumab (anti-cytotoxic T lymphocyte-associated antigen-4 [CTLA-4]) [ 121 ] and durvalumab (anti-PD-L1) [ 122 ]. These studies further demonstrated the importance of combining molecular-targeted agents and ICIs in advanced RCC therapy. Currently, guidelines have endorsed dual ICIs or ICIs-tyrosine kinase inhibitors (TKIs) combinations as preferred first-line regimens for advanced RCC [ 123 , 124 ].

CAR-T targets in renal cancer

Carbonic anhydrase IX (CAIX), a transmembrane enzyme regulated by hypoxia-inducible factor 1α (HIF-1α), is implicated in the progression and prognosis of RCC [ 125 ]. As one of the earliest targets for CAR-T cell therapy in RCC, CAIX was initially investigated in a phase I/II clinical trial by Lamers et al. [ 41 , 126 , 127 ], in which 12 mRCC patients received up to 10 infusions of 2 × 10 7 to 2 × 10 9 CAR-T cells. The study observed antigen-specific activity in circulating CAR-T cells post-infusion, but these cells failed to proliferate or persist beyond four weeks. Additionally, Grade 2–4 liver toxicity occurred in four of eight patients in cohorts 1 and 2, and cholangitis was confirmed in three patients via liver biopsy, revealing T-cell infiltration in biliary tracts. Ultimately, no survival benefit was observed before trial termination. In evaluating different costimulatory domains (BBζ, 28ζ, and 28BBζ), Wang et al. [ 128 ] reported that 2G anti-CAIX BBζ CAR-T cells exhibited superior long-term antitumor efficacy in ccRCC, driven by increased cytotoxicity, enhanced memory phenotype, reduced exhaustion markers, and suppressed CD8 + Treg differentiation. To address on-target/off-tumor (OTOT) toxicity, Wang et al. [ 129 ] developed a low-affinity/high-avidity G9 CAR-T cell with fine-tuned specificity, demonstrating an expanded therapeutic window across varying CAIX densities and superior tumor control in orthotopic RCC murine models. Additionally, incorporation of the CD30 ICD was reported to autonomously activate the NF-κB pathway in CAIX CAR-T cells, significantly enhancing their proliferation, cytotoxicity, and antitumor activity against RCC both in vitro and in vivo [ 130 ]. PD-L1 is a critical immunosuppressive regulator. Upon binding to PD-1, the PD-1/PD-L1 complex induces T-cell apoptosis and exhaustion, leading to immune evasion by tumors [ 131 ]. Marasco et al. [ 94 ] first introduced anti-PD-L1 antibody secretion (IgG1 or IgG4) into anti-CAIX CAR-T cells using a bicistronic lentiviral vector. In orthotopic human ccRCC xenograft murine models, these modified CAR-T cells reversed T-cell exhaustion and suppressed tumor growth, achieving a five-fold reduction in tumor volume and a 50–80% reduction in tumor weight compared to monotherapy. Furthermore, Suarez et al. [ 132 ] demonstrated that moderate doses (~10 7 cells) of anti-CAIX CAR-T cells secreting anti-PD-L1 IgG4 effectively eliminated tumors in murine models without inducing CAR-T-related liver toxicity. Building upon these findings, Marasco et al. [ 133 ] subsequently constructed immune-restoring CAR-T cells, which mitigated immunosuppressive factors and promoted follicular helper T cell–B cell crosstalk, thus establishing active antitumor immunity against RCC.

CD70, a member of the tumor necrosis factor superfamily, has emerged as a significant biomarker and promising therapeutic target for RCC [ 134 ]. Signal transduction through CD70 and its receptor CD27 can restrict T-cell expansion, promote the proliferation of regulatory T cells (Tregs), and facilitate immune evasion [ 135 ]. In contrast to previous studies utilizing truncated CD27-based CARs targeting CD70, Panowski et al. [ 136 ] generated a panel of anti-CD70 scFv-based CAR-T cells with rituximab-derived mimotopes as a safety off-switch. These anti-CD70 CAR-T cells demonstrated potent antitumor efficacy with limited off-target toxicity in RCC models derived from established cell lines (786-O, ACHN) and patient-derived samples, with limited off-target toxicity. Moreover, an allogeneic CD70 CAR-T product (ALLO-316) was successfully scaled up using TALEN gene editing and has progressed to clinical trials. Recent investigations by Yang et al. [ 137 , 138 ] identified significant co-upregulation of CD70 and B7–H3 (CD276) at both RNA and protein levels across multiple malignancies, including RCC. Subsequently, the researchers engineered a bispecific tandem CAR (TanCAR) targeting CD70 and B7–H3, which showed robust antitumor efficacy against the 786-O cell line. In addition, through an integration of CAR- and NK receptor-mediated mechanisms, Li et al. [ 139 ] established allogeneic CAR-engineered invariant natural killer (NK) T cells targeting CD70 ( Allo CAR70-NKT), which exhibited remarkable cytotoxic activity against multiple RCC cell lines, as well as primary and metastatic RCC models. Furthermore, the Allo CAR70-NKT cells could not only effectively depleted immunosuppressive tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs) to remodel the immunosuppressive tumor microenvironment (TME), but also improve their persistence and cytotoxic activity by selectively targeting alloreactive CD70-expressing T cells. CTX130, an allogeneic CD70-targeted CAR-T cell product, utilized employed CRISPR/Cas9-mediated gene editing to disrupt TCR, β2-microglobulin, and CD70 expression in T cells [ 140 , 141 ]. Preclinical studies demonstrated that CTX130 possessed superior proliferative capacity and sustained cytotoxicity against CD70 + RCC cells compared to isogenic anti-CD70 CAR-T controls; notably, CTX130 induced complete tumor regression in A498 RCC xenograft models, whereas conventional anti-CD70 CAR-T cells showed no antitumor activity. Encouraged by these promising preclinical outcomes, Pal et al. [ 141 ] conducted a multicenter phase I clinical trial ( NCT04438083 ), in which a total of 16 patients with relapsed/refractory ccRCC received CTX130 infusions at doses ranging from 3 × 10 7 to 9 × 10 8 cells. During the trial, only eight patients experienced Grade 1 or 2 cytokine release syndrome (CRS), with no Grade ≥3 events reported. Additionally, efficacy analysis indicated that 12 patients (75%) achieved stable disease (SD), and one patient (6%) achieved a CR, with a median OS of 20.5 months (95% CI, 14.3–NA). This trial represents the first documented CR in RCC patients treated with CAR-T therapy, underscoring the potential of CTX130 as a breakthrough therapeutic strategy for advanced RCC.

In addition, several other potential targets have been investigated for CAR-T therapy in RCC. For instance, it has been reported that anti-c-Met CAR-T cells significant tumor cell apoptosis and IFN-γ secretion when co-cultured with c-Met-high RCC (A498) cells, achieving complete tumor regression in approximately 60% of murine models [ 142 ]. DNAJB8, a protein crucial for cancer stem-like cell tumorigenicity, has been proposed as a safe CAR-T target due to its testis-specific expression [ 143 ]. Watanabe et al. [ 144 ] further confirmed that B10 CAR-T cells targeting DNAJB8 manifested strong antitumor activity against CAKI-1 cells in vitro and mediated tumor regression in vivo. Similarly, given the critical role of receptor tyrosine kinase-like orphan receptor 2 (ROR2) in ccRCC invasion and metastasis, preclinical studies by Weber et al. [ 145 ] demonstrated that ROR2-targeting CAR-T cells efficiently eradicated multiple ROR2-positive ccRCC cell lines and significantly prolonged survival in murine models of advanced ccRCC. These findings support further clinical investigation of CAR-T cell therapy in RCC.

Combination strategies in renal cancer

A complex immune microenvironment represents one of the primary obstacles to the efficacy of CAR-T cell therapy in solid tumors [ 146 ]. In renal cancer, TKIs have been reported not only to inhibit angiogenesis but also to modulate the TME in favor of antitumor immunity [ 147 ]. Therefore, the addition of TKIs was considered a promising strategy to enhance the antitumor activity of CAR-T cells. For instance, the combination of sunitinib and CAIX-targeted CAR-T cells significantly increased the proliferation and tumor infiltration of CAR-T cells, contributing to a robust synergistic antitumor effect in a mouse cancer model derived from human RCC cell lines [ 148 ]. Similarly, axitinib reduced the treatment dose of anti-c-Met CAR-T cells to 1 × 10 6 per administration, which more effectively controlled the tumor growth of RCC in vivo [ 142 ]. Li et al. [ 149 ] showed that cabozantinib suppressed the M2 polarization of TAMs by inhibiting the PD-1/PD-L1 axis, while simultaneously strengthened the infiltration and antitumor activity of CAIX-CAR-T cells. Recently, Lu et al. [ 150 ] reported that lenvatinib improved T cell-mediated antitumor immunity by upregulating chemokines CXCL10 and CCL8, which increased T cell proliferation, tumor infiltration, and reduced MDSCs. In subsequent animal experiments, the combination of lenvatinib and CAIX-CAR-T cells also exhibited significantly greater antitumor efficacy than either agent monotherapy. Oncolytic viruses (OVs) have emerged as a powerful approach in tumor immunotherapy, which induced direct tumor cell lysis and enhanced the efficacy of other immunotherapies [ 151 ]. Fang et al. [ 152 ] reported that an oncolytic adenovirus (OAV) engineered to express CCL5 and IL-12 (Ad5-ZD55–CCL5–IL12) significantly promoted the proliferation and activity of anti-CA9 CAR-T cells in vitro, as well as their persistence and infiltration in vivo, resulting in a synergistic antitumor effect in RCC. When combined with CAIX-CAR-T cells, an OAV expressing decorin could reduce collagen fiber deposition in the extracellular matrix (ECM), downregulate transforming growth factor (TGF)-β expression, and increase IFN-γ secretion, collectively reducing tumor burden and prolonging the survival of RCC mice [ 153 ]. Additionally, poly (ADP-ribose) polymerase inhibitors (PARPis) targeting DNA damage repair pathways, have been reported to improve the recruitment of CD8 + CD70-CAR-T cells in renal cancer via activation of the cGAS/STING pathway [ 154 ]. Recently, Shi et al. [ 155 ] indicated that the overexpression of glucose transporter 1 (GLUT1) contributed to CD19-CAR-T cell expansion and metabolic adaptability under glucose-restricted conditions, significantly reducing tumor burden in RCC mice.

Bladder cancer

Immunotherapy for bladder cancer

Bladder cancer is a major global urological malignancy, with approximately 613,000 new cases and 220,000 deaths worldwide in 2022 [ 156 ]. Approximately 75% of patients present with NMIBC at initial diagnosis, characterized by disease confined to the mucosa and submucosal stroma [ 17 , 157 ]. While standard therapies such as transurethral resection followed by intravesical BCG or chemotherapy, led to favorable survival outcomes, frequent recurrence possibility necessitates lifelong surveillance, causing persistent quality-of-life and economic burdens [ 17 , 158 ]. The remaining 25% of patients have muscle-invasive bladder cancer (MIBC), which exhibits more aggressive clinical behaviors, with 5-year OS rates of 60–70% [ 159 , 160 ]. Despite treatment with radical cystectomy and neoadjuvant chemotherapy (NAC), approximately 50% of these patients experienced postoperative tumor recurrence [ 159 , 161 ]. Moreover, up to 50% of patients are not eligible for NAC due to renal dysfunction or comorbidities, resulting in an even worse prognosis [ 31 , 162 ]. Early genomic profiling showed that bladder cancer has one of the highest tumor mutational burdens (TMB) among solid malignancies, coupled with diverse immune cell infiltration within the TME, revealing the intrinsic immunogenicity of bladder cancer [ 163 ]. The application of immunotherapy in bladder cancer can be traced back to 1976, when intravesical BCG was introduced as a treatment for NMIBC [ 164 ]. Since then, BCG has remained the gold-standard first-line therapy for intermediate/high-risk NMIBC [ 165 ]. With the rapid advancement of immunotherapy, several ICIs have been approved by the FDA for monotherapy in patients with metastatic bladder cancer, including atezolizumab [ 166 ], nivolumab [ 167 ], avelumab [ 168 ], and pembrolizumab [ 169 ]. In addition to treating patients who are ineligible for platinum-based chemotherapy, the ICIs are also employed as a second-line treatment option in patients who experienced cancer relapse following platinum chemotherapy [ 170 , 171 ].

CAR-T targets in bladder cancer

Recent advancements in CAR-T cell therapy for solid tumors have prompted a rapid growth of studies on bladder cancer. One major factor influencing the clinical translation of CAR-T cell therapy for bladder cancer is the selection of tumor-specific antigens [ 172 ]. Therefore, there is increasing interest in exploring the target value of more protein antigens and other types of molecules. Previous studies have shown that bladder cancer can produce sialylated cancer-derived IgG (SIA-CIgG), which facilitated cancer cell proliferation, migration, and invasion. Results from functional experiments demonstrated that SIA-CIgG CAR-T cells exhibited lower off-target cytotoxicity and superior persistence in vitro; moreover, administration of SIA-CIgG CAR-T cells achieved complete tumor clearance in all eight treated mice within 28 days [ 173 ]. In a study by Yu et al. [ 174 ], patient-derived bladder cancer organoids (BCOs) were established to evaluate CAR-T cell cytotoxicity, and 2G anti-mucin 1 (MUC1) CAR-T cells induced significant cancer cell killing and immune activation against MUC1 + BCOs. Identified as a promising therapeutic target, Nectin4 plays a pivotal role in bladder cancer initiation and progression，leading to the development of antibody-drug conjugates (ADCs) for advanced or metastatic urothelial carcinoma, such as enfortumab vedotin (EV) [ 175 , 176 ]. Utilizing a Nectin4-specific nanobody, Niu et al. [ 177 ] constructed a variable domain of heavy-chain-only antibody (VHH)-based CAR-T cell, termed VHH Nectin4 -CAR-T. In subsequent efficacy evaluations, these VHH Nectin4 -CAR-T cells displayed greater proliferation ability and powerful, targeted cytotoxicity against a variety of bladder cancer cell lines. Shen et al. [ 178 ] incorporated a mutated T cell immune receptor with Ig and ITIM domains (TIGIT) with CD28 signaling components to construct a co-receptor, which significantly improved IFN-γ production and tumor suppression of prostate stem cell antigen (PSCA)-targeted CAR-T cells against HT-1376 cells. When armed with recombinant variant surface antigen 2-cysteine-rich interdomain region A (VAR2CSA) lectins, CAR-T cells targeting oncofetal chondroitin sulfate effectively eradicated diverse tumors in vitro and rapidly inhibited tumor growth in a UM-UC-3 xenograft model, which suggested that glycosaminoglycans may be potential attractive targets for CAR-T therapy [ 179 ].

CAR-T cells targeting PD-1 in bladder cancer

A chimeric PD1-Dap10-CD3ζ (chPD1) receptor engineered by Parriott et al. [ 180 ] was reported to convert the inhibitory PD-1 signal into an activating signal for T cells. Additionally, the chPD1-expressing T-cells not only effectively lysed bladder cancer cells and secreted pro-inflammatory cytokines in vitro, but also reduced tumor burden and induced protective host antitumor memory responses in tumor-bearing mice. Compared to c-Met CAR-T cells, the bispecific c-Met/PD-1 CAR-T cells were found to have significantly enhanced proliferation, elevated expression of IL-2 and TNF-α, and increased cytotoxic activity to bladder cancer cells, suggesting improved therapeutic efficacy conferred by autocrine PD-1 antibody expression within CAR-T cells [ 181 ].

Intravesical CAR-T cells in bladder cancer

Due to the unique anatomical and physiological characteristics of the urinary bladder, intravesical treatment regimens have become standard therapies for bladder cancer. This approach can deliver therapeutic agents directly to the tumor site while minimizing systemic absorption and associated toxicities [ 182 ]. According to a recent report by Liao et al. [ 183 ], local delivery of anti-Nectin4 CAR-T cells had potent antitumor activity and instantly inhibited tumor growth in mouse bladders. Moreover, intravesical CAR-T cells were undetectable in the mice bloodstream, indicating reduced off-target effects and augmented T-cell infiltration. Likewise, intravenous administration of anti-MUC16 CAR-T cells significantly increased local antitumor activity and minimized systemic toxicity in an orthotopic HT-1376 cell model [ 184 ]. Together, these findings support the notion that intravesical CAR-T cell therapy may optimize therapeutic efficacy while limit toxicity in bladder cancer.

Combination strategies in bladder cancer

Some researchers have also made efforts to explore combination strategies of CAR-T cell therapy for bladder cancer. For instance, Grunewald et al. [ 185 ] pretreated anti-epidermal growth factor receptor (EGFR) and CD44v6 CAR-T cells with decitabine (a DNA methyltransferase inhibitor), and observed the significant tumor-specific killing of CAR T-cells against various bladder cancer cells, which was associated with key apoptotic regulators BID and BCL2L1. As a histone deacetylase inhibitor (HDACi), vorinostat was found to induce complete tumor clearance when combined with SIA-CIgG CAR-T cells in 5637 xenograft mouse models [ 173 ]. In addition, Greco et al. [ 186 ] indicated that disrupting N-glycosylation by the glucose/mannose analog 2-deoxy-D-glucose could reduce CAR-T cell exhaustion and improve their activity against bladder cancer. Chang et al. [ 187 ] revealed that utilizing the peroxisome proliferator-activated receptor γ (PPARγ) agonist rosiglitazone significantly increased bladder cancer susceptibility to Nectin4-CAR-T cells through upregulating Nectin4 expression. Notably, this combination strategy also improved the killing efficacy of Nectin4-CAR-T even in the RT112 and UMUC-1 EV-resistant cell line models, which suggests the applicability of CAR-T therapy with antigen-modulating approaches in patients with low tumor antigen expression or drug resistance.

Prostate cancer

Immunotherapy for prostate cancer

Prostate cancer is the second most common cancer in men [ 188 ]. Over the most recent 5-year period, the prevalence and mortality rates of prostate cancer has a decreased or stabilized trend in most countries, with an estimated 1,466,680 newly diagnosed cases and 396,792 deaths in 2022 [ 189 ]. For early localized prostate cancer, the standard treatments typically involve radical prostatectomy combined with chemoradiotherapy, whereas patients with locally advanced and metastatic disease are primarily managed with androgen deprivation therapy (ADT) [ 190 , 191 ]. Despite favorable initial therapeutic responses, a substantial number of patients will invariably progress to metastatic castration-resistant prostate cancer (mCRPC), with a 5-year survival rate below 30% [ 192 , 193 ]. The emergence of immunotherapy has revolutionized the therapeutic strategies of cancers, providing avenues to overcome persistent challenges in prostate cancer. Prostate cancer is commonly classified as an immunologically “cold” tumor, because of sparse TILs, low TMB, dominant immunosuppressive cell populations and the TME [ 194 ]. These features collectively contribute to its poor response to many immunotherapeutic approaches. Notwithstanding these challenges, recent advances in translational strategies have yielded some promising clinical outcomes. For example, the FDA approval of sipuleucel-T as the first-line immunotherapy for mCRPC, along with early clinical trials of several ICIs, have revealed the potential of immunotherapeutic strategies in prostate cancer [ 195 , 197 ].

CAR-T targets in prostate cancer

In prostate cancer, there is a large volume of published studies focused on modeling CAR-T cells targeting prostate tumor-associated or specific differentiation antigens, such as PSMA [ 198 , 200 ], PSCA [ 201 , 202 ], six-transmembrane epithelial antigen of the prostate 1 (STEAP1) [ 203 ], and epithelial cell adhesion molecule (EPCAM) [ 204 ]. Previous research has indicated that 2G PSMA CAR-T cells had superior efficacy and longer in vivo persistence than 1 G CAR-T cells [ 200 ], whereas 3 G CAR-T cells showed accelerated T cell exhaustion and mortality due to additional co-stimulatory domains [ 198 ]; PSCA-CAR-T cells incorporating 4-1BB domains presented improved tumor antigen recognition and antitumor durability compared to CAR-T cells with CD28 domains [ 201 ]. However, these traditional target antigens frequently showed minimal or absent expression in poorly differentiated and treatment-experienced patients, giving rise to CAR-T therapy resistance or tumor relapse risk [ 205 ]. Therefore, the identification of supplementary target antigens is necessary. For instance, an early study by Sanchez et al. [ 206 ] indicated that CAR-T cells targeting the transmembrane glycoprotein MUC1 selectively eradicated MUC1-expressing PC3 and DU-145 cells, with increased antitumor efficacy when combined with the anti-androgen medication flutamide. Prostatic acid phosphatase (PAP) is a secretory biomarker of the prostate epithelium, and its therapeutic role has been validated in sipuleucel-T [ 195 , 207 ]. Recently, Cao et al. [ 208 , 209 ] developed PAP-targeted CAR-T cells and strengthened their expansion and antitumor ability against prostate cancer through the Coupled CAR platform, which integrated cytokine-secreting CD19 CAR-T cell subsets. Ligands for the natural killer group 2 member D (NKG2D), an NK cell-activating receptor, were expressed across multiple cellular compartments within the TME [ 210 ]. Targeting the NKG2D, Jiang et al. [ 211 ] developed NKG2D-CAR-T cells, which successfully recognized and eliminated NKG2DL + prostate cancer cell lines (PC-3, DU145, and C4-2). Moreover, genetic engineering of NKG2D-CAR-T cells through IL-7 co-expression or knockdown of HDAC11 improved persistence and antitumor efficacy of CAR-T cells both in vitro and in vivo [ 211 ]. Besides, several CAR-T targets associated with tumor biological behaviors have also been explored in preclinical prostate cancer models, including carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) [ 212 ], a surface protein marker of neuroendocrine prostate cancer; mesothelin (MSLN) [ 213 ], a tumor-associated cell surface antigen involved in tumor invasion; and F77 [ 214 ], a tumor-associated carbohydrate antigen.

Engineering CAR-T cells in prostate cancer

Several engineering strategies have been developed to improve the safety and efficacy of CAR-T therapy in prostate cancer. For example, by grafting complementarity-determining regions onto human germline frameworks, humanized murine-derived scFvs enabled PSMA-CAR-T cells to mitigate immunogenicity while preserving powerful antigen specificity and cytokine secretion profiles [ 215 ]. Stepanov et al. [ 216 ] also indicated that CAR-T cells equipped with covalent small-molecule switches (Cov CAR-T) achieved regulated activity via PSMA-targeting adapters. Additionally, combining UniCAR-T cells with anti-PSCA targeting modules mediated strong antitumor activity against PSCA-positive prostate cancer cells by dissociating antigen-binding from signaling domains [ 217 ]. Certain studies observed that modifying the non-signaling spacer domains considerably influenced CAR-T cell antigen sensitivity [ 218 , 219 ]. Kennewick et al. [ 220 ] indicated that a median-length hinge-like spacer improved antigen sensitivity and specificity of PSCA-CAR-T cells compared with longer IgG4 spacers. These findings suggested that optimizing CAR construct designs could effectively reduce OTOT toxicity. Frieling et al. [ 221 ] employed Vγ9 Vδ2 T lymphocytes as vehicles to generate anti-PSCA γδ CAR-T cells, leveraging their superior cytotoxicity and responsiveness to phosphoantigens. The anti-PSCA γδ CAR-T cells demonstrated potent cytotoxic activity against prostate cancer cells in vitro and eradicated established bone metastases in mCRPC murine models, with further enhanced performance upon zoledronate administration. Notably, Liu et al. [ 222 ] engineered sonogenetic EchoBack-PSMA CAR-T cells by incorporating an ultrasensitive heat-shock promoter with an intrinsic CAR signaling feedback loop. This EchoBack technology converted ultrasound stimulation into sustained CAR activation and prolonged CAR molecule production upon focused ultrasound (FUS) exposure.

Targeting immunosuppression in prostate cancer

Given that immunosuppressive cytokines and ligands impair effector T-cell recruitment and activation, targeting immune checkpoints or cytokines is considered a promising strategy to enhance T-cell responses in prostate cancer [ 223 ]. Several studies have thus linked PD-1/PD-L1 axis inhibition with CAR-T cell therapy, including engineering CAR-T cells targeting PD-L1 [ 224 ], combination therapy with anti-PD-1 antibodies [ 225 ], OAV engineered to express PD-L1 blocking mini-antibodies [ 226 ], CAR-T cell modification via shRNA-mediated gene silencing [ 227 ], and the development of chimeric PD-1 receptors converting inhibitory PD-1 signals into activation signals [ 180 ]. CAR-T cells directly targeting the immune checkpoint B7–H3 have also been reported to kill B7–H3-positive prostate cancer cells and suppress DU145 xenografts growth in mice [ 228 ]. Additionally, intrinsic inhibition of the checkpoint receptor adrenoceptor beta 2 (ADRB2) substantially improved CAR-T cell proliferation and cytotoxicity against prostate cancer cells and increased CD8 + /CD4 + T cell ratio through ZAP-70/NF-κB pathway activation [ 229 ]. TGF-β has been shown to promote neoangiogenesis and tumor metastasis, as well as contribute to an immunosuppressive TME in prostate cancer [ 230 ]. To block TGF-β signaling, dominant-negative TGF-β receptor II (dnTGF-βRII) was encompassed into anti-PSMA CAR-T cells or anti-STEAP2-CAR-T cells (AZD0754) [ 231 , 232 ]. When co-cultured with antigen-positive prostate cancer cells, dnTGF-βRII-armored CAR-T cells showed higher proliferative capacity and significantly eradicated tumor burdens in mice with xenograft or metastatic tumors [ 232 ]. In line with these results, Narayan et al. [ 97 ] initiated a clinical trial ( NCT03089203 ) administering dnTGF-βRII-anti-PSMA CAR-T cells to patients with refractory mCRPC. Results showed that 4 of 13 patients achieved a ≥ 30% decline in PSA levels, 5 patients maintained stable disease (SD) at 3-month imaging assessments, and 5 of 13 patients experienced Grade ≥2 CRS. Tang et al. [ 233 ] incorporated a truncated extracellular TIM3 domain into CAR constructs, generating dnTGFβRII-truncated TIM3-PSMA CAR-T (DT-PSMA-CAR-T) cells. Notably, DT-PSMA-CAR-T cells effectively eradicated PSMA-positive LNCaP cells under immunosuppressive conditions characterized by elevated TGF-β levels, neutralized TIM3-mediated suppression, and successfully eliminated tumors in mice engrafted with PC3 cells. However, other studies have noticed that TGF-β could increase IL-7 production and induced T-cell differentiation into the Th17 phenotype, whereas IL-7 improved tumor-specific T cell survival in vivo [ 234 ]. Therefore, Weimin et al. [ 235 ] designed an inverted chimeric cytokine receptor (ICR), composed of a TGF-β extracellular domain and IL-7 receptor ICD. This design redirected immunosuppressive TGF-β signals to activate IL-7 signaling pathways, promoting PSMA-CAR-T cell survival and proliferation. The pro-inflammatory cytokine IL-23 activates androgen receptor signaling in prostate cancer, promoting tumor cell proliferation and progression [ 236 ]. To counteract IL-23-mediated immunosuppression, Wang et al. [ 237 ] designed PSMA-duo-CAR-T cells secreting IL-23 antibodies, demonstrating enhanced proliferation and antitumor capabilities compared to conventional CAR-T cells. Conversely, the local application or CAR-T cell secretion of IL-12 could augment the efficacy of STEAP1- or PD-L1-targeted CAR-T cells in disseminated prostate cancer via reversing tumor stromal and modulating immune cell activity [ 203 , 238 ].

Combination strategies in prostate cancer

Docetaxel was found to significantly strengthen the therapeutic effects of PSMA-CAR-T cells in both prostate cancer xenograft and liver metastasis mouse models, primarily by reducing MDSCs and immune checkpoint molecules in the TME, such as PD-1, CTLA-4 and lymphocyte-activation gene 3 (LAG-3) [ 239 , 240 ]. Murad et al. [ 241 ] observed that cyclophosphamide pretreatment reprogrammed the immunosuppressive microenvironment and improved the efficacy of PSCA-CAR-T cells in mPCa models, while PSCA-CAR-T cell monotherapy showed minimal antitumor activity. In exploring the synergistic effects of CAR-T cells and chemotherapeutic agents, Porter et al. [ 242 ] found that carboplatin synergized with CAR-T cells targeting Lewis Y (Ley, an oncofetal glycolipid antigen) via inducing a cascade of pro-inflammatory immune responses that facilitated CAR-T cell activation, infiltration, and persistence in prostate cancer. In addition, the use of the EZH2 inhibitor tazemetostat or the EZH1/2 inhibitor valemetostat was reported to promote the proliferation and antitumor efficacy of anti-CD19 CAR-T cells in multiple malignancies, including prostate cancer [ 243 ]. Fang et al. [ 244 ] incorporated the chemokine CXCL9 and IL-15 genes into an OAV to construct the armored virus Ad-CXCL9–IL15, which not only markedly improved the infiltration and survival of B7–H3-CAR-T T cells but also prolonged the survival of prostate cancer–bearing mice receiving combination therapy. Additional combination strategies with CAR-T cell therapy under active investigation. For instance, the fractionated irradiation could sensitize prostate cancer stem cells to B7–H3 CAR-T cells by upregulating B7–H3 expression [ 245 ], whereas short-term febrile temperature exposure increased IFN-γ production in STEAP1 CAR-T cells [ 246 ].

CAR-T clinical studies in prostate cancer

Previous early phase I dose-escalation trials have assessed the safety and efficiency of anti-PSMA CAR-T cell therapy in prostate cancer. In one study, two of four patients in the low-dose cohort (10 7 cells/kg) achieved a SD for 6 and 16 months, while all three patients in the high-dose cohort (1.5 or 3 × 10 7 cells/kg) developed high fever accompanied by elevated inflammatory cytokines [ 247 ]. Another trial reported a PR in two of five patients, with prostate-specific antigen (PSA) reductions of 50 and 70%, and no anti-PSMA-related toxicities were observed [ 248 ]. Consistent with these findings, Dorff et al. [ 249 ] conducted a phase I trial, which evaluated PSCA-CAR-T cell therapy in men with mCRPC ( NCT03873805 ). Preliminary data from 14 participants indicated one dose-limiting toxicity (DLT), Grade 3 cystitis, along with early signs of therapeutic benefit, including > 30% PSA reductions in 4 of 14 patients and radiographic improvement in some cases. A multi-institutional phase I trial by Stein et al. [ 250 ] evaluated the safety and efficacy of autologous PSCA-directed CAR-T cells (BPX-601) in mCRPC, which incorporated an inducible MyD88/CD40 (iMC) on-switch. This iMC on-switch could be activated by rimiducid to deliver robust activation, expansion, and survival signals to CAR-T cells. Although two DLTs and two treatment-related deaths in the highest-dose cohort led to trial termination, the antitumor activity observed with BPX-601 plus rimiducid was encouraging. Five of nine patients experienced a ≥ 50% decline in PSA, including one patient with stable nodal disease lasting over one year and another whose bone scans showed stable to improving findings for six months. These data suggest that pharmacological activation of CAR-T cells using inducible molecules is theoretically feasible, although further dose-optimization studies are required (Fig. 2 ). Fig. 2 Main targets of CAR-T cells for urological cancers（renal, bladder, and prostate cancers）and common combination strategies. In renal, bladder, and prostate cancers, several conventional tumor antigens, including CAIX, CD70, PSCA, and PSMA, have been extensively investigated as targets for CAR-T cell therapy, while more novel targets (such as DNAJB8, Nectin4 and NKG2D) are under active investigation. Combination strategies have shown potential to produce synergistic antitumor responses and enhance CAR-T therapeutic efficacy, including chemotherapy drugs, molecular targeted drugs, signal pathway agonists/inhibitors, and oncolytic adenoviruses, etc

Clinical trials of CAR-T cell therapy for urological cancers

Table 2 summarizes CAR-T cell therapy clinical trials for renal, bladder, and prostate cancers registered on ClinicalTrials.gov (extended details and statistical summary of these trials is available in Supplementary Tables). These trials primarily investigated established or emerging CAR-T target antigens, and structurally optimized or genetically engineered CAR-T products. Most studies were conducted in the United States and China, with other countries including Australia, Canada, Germany, Malaysia, and Netherlands. Three registered CAR-T cell clinical trials targeted bladder cancer. One terminated trial ( NCT03960060 ) investigated the therapeutic outcomes of ROR2-targeted CAR-T cells (CCT301-59) but has not yet reported results. The other two ongoing trials are evaluating the safety and therapeutic efficacy of HER2-specific CAR-T cells combined with the OAV CAdVEC ( NCT03740256 ), and PSMA- or FRα-specific 4SCAR-T cells ( NCT03185468 ). In recent years, the number of CAR-T clinical trials for renal cancer have expanded rapidly. Among these, three trials were terminated, and one trial was completed. An early-phase study ( NCT01218867 ) enrolled 24 patients with metastatic renal cancer and other tumors. The five-year follow-up data revealed tumor progression in most patients treated with VEGFR2-CAR-T cells, with only one PR and five severe adverse events reported. Results of the COBALT-RCC trial ( NCT04438083 ) have been previously reported, whereas outcomes remain unavailable for trials investigating ROR2-targeted CAR-T cells (CCT301-59), AXL-targeted CAR-T cells ( NCT03393936 ), and CD70-targeted CAR-T cells (CTX131, NCT05795595 ). Currently, CD70 represents the most prominent target in renal cancer CAR-T trials, while other antigens under investigation include EGFR, MUC1-C, CAIX, and c-Met. Regarding prostate cancer, CAR-T trials are numerous and show a distinct upward trend. Among these, four trials were terminated, one completed, and one suspended, all targeting PSMA. Although results for NCT04227275 and NCT0427287 have been reported, outcomes are still pending for trials investigating dually armored CAR-T cells (TmPSMA-02, NCT05489991 ), PD-1-modified PSMA-CAR-T cells ( NCT04768608 ), UniCAR02-T with TMpPSMA ( NCT04633148 ), and P-PSMA-101 CAR-T cells with rimiducid ( NCT04249947 ). Current prostate cancer CAR-T trials predominantly focus on conventional targets PSMA and PSCA, whereas other antigens include STEAP1/2, EpCAM, KLK2, and NKG2DL. Table 2 CAR-T cell therapy clinical trials for renal, bladder, and prostate cancers ID Start Date Phase N Target Nation Sites Sponsor Funder Type Status BCa NCT03960060 2019.05 I 9 ROR2 CN Single Shanghai PerHum Therapeutics Co., Ltd. Industry/Other Terminated BCa NCT03740256 2020.12 I 45 HER2 US Single Baylor College of Medicine Other Recruiting BCa NCT03185468 2025.08 I/II 20 PSMA, Fra CN Multiple Shenzhen Geno-Immune Medical Institute Other Recruiting RCa NCT07181720 2025.09 I 90 CD70 CN Single Chongqing Precision Biotech Co., Ltd Industry Recruiting RCa NCT07113977 2025.08 I 30 CD70 CN / Wei Guan Individual Not yet recruiting RCa NCT06586658 2024.09 I 9 CD70 CN Single Shanghai Changzheng Hospital Other/Industry Recruiting RCa NCT06480565 2024.12 I/II 60 CD70 US Single Adicet Therapeutics Industry Active RCa NCT06383507 2024.04 I 18 CD70 CN Single Zhejiang University Other Not yet recruiting RCa NCT06010875 2023.11 I 48 CD70 CN Single Chongqing Precision Biotech Co., Ltd Industry/Other Recruiting RCa NCT05795595 2023.03 I/II 19 CD70 US Multiple CRISPR Therapeutics AG Industry Completed RCa NCT05518253 2022.05 I 30 CD70 CN Single Weijia Fang, MD Other/Industry Recruiting RCa NCT05468190 2022.7.17 I 48 CD70 CN Single Chongqing Precision Biotech Co., Ltd Industry Unknown RCa NCT05420545 2021.12 I 36 CD70 CN Single Chongqing Precision Biotech Co., Ltd Industry Unknown RCa NCT05420519 2021.12 I 24 CD70 CN Single Chongqing Precision Biotech Co., Ltd Industry Unknown RCa NCT04696731 2021.02 I 120 CD70 US Multiple Allogene Therapeutics Industry Active RCa NCT04438083 2020.06 I 19 CD70 US, AU, CA, NL Multiple CRISPR Therapeutics Industry Terminated RCa NCT02830724 2017.04 I/II 124 CD70 US Single National Cancer Institute (NCI) NIH Recruiting RCa NCT06682793 2025.05 I/II 240 EGFR US Multiple A2 Biotherapeutics Inc. Industry Recruiting RCa NCT05672459 2023.06 I/II 117 HLA-G US Single M.D. Anderson Cancer Center Other/Industry Recruiting RCa NCT05239143 2022.02 I 180 MUC1-C US Multiple Poseida Therapeutics, Inc. Industry Active RCa NCT04969354 2021.10 I 20 CAIX CN Single The Affiliated Hospital of Xuzhou Medical University Other Recruiting RCa NCT03638206 2018.03 I/II 73 C-met CN Single Shenzhen BinDeBio Ltd. Industry/Other Unknown RCa NCT03393936 2018.03 I/II 66 AXL, ROR2 CN Single Shanghai PerHum Therapeutics Co., Ltd. Industry/Other Terminated RCa NCT01218867 2010.11 I/II 24 VEGFR2 US Single National Cancer Institute (NCI) NIH Terminated PCa NCT07240857 2025.12 I 18 PSMA CN / Zhejiang University Other/Industry Not yet recruiting PCa NCT06895811 2025.03 I 3 PSMA CN Single Shanghai Changzheng Hospital Other/Industry Recruiting PCa NCT06228404 2024.03 I 18 PSMA CN Single Shanghai Changzheng Hospital Other/Industry Recruiting PCa NCT06046040 2024.01 I 18 PSMA US Single University of Pennsylvania Other Active PCa NCT05489991 2022.09 I/II 1 PSMA US Single Tceleron Therapeutics, Inc. Industry Terminated PCa NCT05354375 2022.12 I 20 PSMA CN Single The Affiliated Hospital of Xuzhou Medical University Other Recruiting PCa NCT04768608 2021.12 I 3 PSMA CN Single Zhejiang University Industry/Other Completed PCa NCT04633148 2020.11 I 16 PSMA DE Multiple AvenCell Europe GmbH Industry/Other Terminated PCa NCT04429451 2020.01 I/II 100 PSMA CN Single Shenzhen Geno-Immune Medical Institute Other Unknown PCa NCT04249947 2020.02 I 40 PSMA US Multiple Poseida Therapeutics, Inc. Industry Terminated PCa NCT04227275 2019.11 I 16 PSMA US Multiple Tceleron Therapeutics, Inc. Industry Terminated PCa NCT03089203 2017.03 I 23 PSMA US Single University of Pennsylvania Other Active PCa NCT01140373 2010.06 I 13 PSMA US Single Memorial Sloan Kettering Cancer Center Other Active Pca NCT05805371 2024.07 I 21 PSCA US Single City of Hope Medical Center Other/NIH Recruiting PCa NCT03873805 2019.08 I 14 PSCA US Single City of Hope Medical Center Other/NIH Active PCa NCT02744287 2016.11 I/II 151 PSCA US Multiple Bellicum Pharmaceuticals Industry Suspended PCa NCT05732948 2018.08 I 12 PSCA, PSMA CN Single Shanghai Unicar-Therapy Bio-medicine Technology Co., Ltd Industry/Other Unknown PCa NCT06267729 2024.03 I/II 60 STEAP2 US, AU Multiple AstraZeneca Industry Recruiting PCa NCT06236139 2024.11 I/II 48 STEAP1 US Single Fred Hutchinson Cancer Center Other/Industry Recruiting PCa NCT05022849 2021.09 I 15 KLK2 US Multiple Janssen Research & Development, LLC Industry Active PCa NCT04107142 2019.12 I 10 NKG2DL MY Single CytoMed Therapeutics Pte Ltd Industry Unknown PCa NCT03013712 2017.01 I/II 60 EpCAM CN Single First Affiliated Hospital of Chengdu Medical College Other Unknown BCa, bladder cancer; RCa, renal cancer; PCa, prostate cancer; AU, Australia; CA, Canada; CN, China; DE, Germany; MY, Malaysia; NL, Netherlands; US, United States; NCI, National Cancer Institute; NIH, National Institutes of Health; Other, Other of Funder Type includes individuals, universities, and organizations

Limited efficacy and treatment-related adverse events frequently result in the early termination of CAR‑T trials in urological cancers [ 41 , 251 , 252 ]. Notably, a considerable number of urological cancer CAR‑T trials led by Chinese companies (five of eight) remain listed with an “unknown” status or lack updated information. These are mostly single‑center studies encompassing multiple cancer types and imposing specific enrollment quotas (Table S1 ). Several factors contribute to the suboptimal outcomes observed in urological cancer CAR‑T trials. First, recruiting sufficient participants at a single site is challenging, especially for large-scale or multi-cancer studies. Second, many ongoing or recently registered trials began after 2020, typically requiring three to five years or longer to collect and integrate initial data (Table S2 ). This timeline demands sustained follow-up and timely data processing by investigators; otherwise, delays in data availability become inevitable. Third, the substantial costs associated with CAR‑T development and clinical implementation remain prohibitive [ 253 , 254 ]. Given these financial and operational risks, small- to mid-sized academic institutions and companies often lack sufficient resources to withstand clinical trial failures. Additionally, there is a persistent scarcity of publicly accessible clinical trial data, limiting motivation among researchers to pursue and track long-term studies, as the academic community usually cannot afford to publish negative findings [ 255 , 256 ]. Concurrently, companies may be hesitant to report CAR‑T projects with high investment significant investments and uncertain returns, for considering the balance between scientific transparency against transparency, commercial confidentiality, and data protection requirements [ 257 ].

As CAR‑T technologies develop, establishing standardized clinical trial protocols is critical to ensure participant safety and accurate efficacy analysis in urological cancers [ 258 , 259 ]. Concurrently, regulatory agencies are encouraged to strengthen their oversight of trial conduct and the reporting of study outcomes [ 260 ]. Leading centers with adequate scale and expertise can serve as coordinating hubs to centralize patients and technical resources, while multi-center collaborations broaden participant diversity and improve trial feasibility [ 260 ]. This hub-and-spoke model provides a more representative and operationally efficient framework for clinical researches. Regarding financing, blended funding mechanisms can diversify risk and encourage engagement from multiple stakeholders, which accelerates the translation of foundational research into clinical applications [ 261 , 262 ]. Finally, the construction of dedicated data platforms and open-access databases will facilitate the sharing and secondary analysis of negative trial results [ 263 , 264 ]. It is also important to gradually foster academic consensus that negative outcomes have inherent scientific and referential values, especially those derived from large-scale, long-term, innovatively designed studies, or investigations employing cutting-edge technologies. Advances in genetic engineering and CAR modification have introduced further strategies, such as universal CAR-T (UCAR-T) platforms, logic-gated CAR-T, gene-edited CAR-T cells (such as PD-1/TGF-β–modified constructs), and γδ T cell-based CAR-T. Moreover, several trials have explored combination approaches, including CAR-T therapy combined with cyclophosphamide/fludarabine-based lymphodepletion, rimiducid as a costimulatory dimerizer, and engineered OAVs. In general, an increasing number of trials are anticipated to expand eligible patient populations for validated CAR-T targets, develop next-generation CAR-T cells with improved safety and efficacy profiles, and integrate CAR-T therapy with other cutting-edge cancer treatments.

Perspective and conclusion

The past decade has witnessed the remarkable advancement of CAR-T cell therapy in hematologic malignancies and its continued expansion toward broader clinical applications. However, the therapeutic value of CAR-T cells remains limited in urological cancers, including renal, bladder, and prostate cancers. Currently, the primary factors restricting CAR-T efficacy in urological cancers include: (1) Tumor heterogeneity and antigen escape: Renal, bladder, and prostate cancers exhibit substantial molecular and genetic heterogeneity, with distinct cellular subclones harboring diverse mutations and molecular profiles [ 265 , 266 ]. For instance, renal cancer frequently involves VHL mutations, leading to constitutive activation of hypoxia-inducible factor signaling [ 267 ]. Bladder cancer typically carries a high somatic mutation burden, with recurrent alterations in TP53 , FGFR3 , and PIK3CA [ 268 ]. In prostate cancer, progression is closely linked to androgen receptor signaling, whereas mutations in TP53 , PTEN , and RB1 are associated with aggressive phenotypes [ 193 , 269 , 270 ]. Moreover, the expression levels of therapeutic targets, such as VEGF in renal cancer [ 271 ], PD‑L1 in bladder cancer [ 272 ], and PSMA in prostate cancer [ 205 ], can vary significantly within tumors. This molecular and genomic heterogeneity contributes markedly to disease progression and facilitates antigen escape from CAR-T cell–mediated targeting. (2) Limited trafficking and infiltration: Extensive of ECM remodeling, driven by excessive matrix deposition, fibrous cross-linking, and cancer-associated fibroblasts (CAFs) activity, creates a dense physical barrier that restricts immune cell penetration and infiltration [ 273 , 274 ]. This phenomenon is exemplified in bladder cancer, where the urothelium is surrounded by an extremely dense ECM [ 275 ]. In addition, aberrant tumor vasculature characterized by structurally and functionally disorganized blood vessels, impairs T-cell extravasation and migration into the tumor parenchyma [ 276 , 278 ]. Dysregulated expression of VEGF further uncouples angiogenesis from immune cell infiltration [ 279 ]. For example, RCC features pronounced hypoxia and pathological angiogenesis, substantially impeding immune cell activity [ 280 , 281 ]. (3) Immunosuppressive TME: The TME in urological cancers encompasses diverse cellular and acellular components, including immune cells, stromal cells, endothelial cells, and ECM. Together, these elements establish a tumor-supportive niche that promotes progression, metastasis, and immune evasion [ 282 , 284 ]. Key immunosuppressive cell populations, such as Tregs and MDSCs, impair T-cell function by the secretion of suppressive mediators (e.g., TGF-β, arginase-1, and nitric oxide synthase) and expressing immune checkpoint molecules; while CAFs and TAMs produce growth factors, cytokines, and matrix metalloproteinases, further driving ECM remodeling, angiogenesis, and local metabolic reprogramming [ 285 , 287 ]. Additionally, urological cancer cells can secrete immunosuppressive factors including TGF-β, IL-10, IL-6, and PD-L1, directly suppressing T-cell activity and promoting immunosuppressive cell expansion and differentiation [ 288 , 289 ]. Further reinforcing this network, urological cancer cells undergo metabolic reprogramming, involving aerobic glycolysis (the Warburg effect), enhanced glutaminolysis, and elevated amino acid and lipid metabolism [ 290 , 291 ]. Through these metabolism adaptations, urological cancer cells deplete essential nutrients, exacerbate local hypoxia, and promote metabolic byproducts accumulation [ 291 , 292 ]. Consequently, these metabolic adaptations not only support tumor proliferation but also significantly impair antitumor immunity [ 293 , 294 ]. For example, T-cell cytotoxicity notably diminished in microenvironments with low glucose or elevated lactate levels [ 295 ]. (4) Treatment-related toxicities: CAR-T cell therapy is associated with several clinically significant toxicities. Cytokine release syndrome, the most common complication, results from excessive cytokine secretion by activated T cells, typically presenting with fever, hypotension, and systemic inflammatory manifestations that may escalate to life-threatening severity [ 296 ]. Immune effector cell–associated neurotoxicity syndrome (ICANS) predominantly impacts the central nervous system, with manifestations ranging from mild confusion to severe cerebral edema [ 297 ]. On-target/off-tumor toxicity can involve multiple organ systems, including the gastrointestinal tract, hematopoietic system, and lungs [ 298 ]. For example, early-phase CAIX-CAR-T trials in renal cell carcinoma reported cholestatic liver toxicity attributed to target expression on biliary epithelium [ 127 ]. Additional adverse events encompass cytopenia, allergic reactions, graft-versus-host disease (GvHD), secondary infections, etc. [ 299 ]. (5) High cost: The substantial expense of CAR-T therapy arises from complex, multi-step manufacturing processes involving personalized autologous treatment design, viral or non-viral gene transfer, T-cell expansion, and the associated transportation, storage, and equipment maintenance required throughout the treatment course [ 253 ] (Fig. 3 ). Fig. 3 Major obstacles limiting the therapeutic efficacy of CAR-T cell therapy in urological cancers. Key challenges include tumor heterogeneity and antigen escape through reduced or lost target expression; insufficient trafficking and tumor infiltration; an immunosuppressive tumor microenvironment (TME) containing inhibitory factors (e.g., PD-L1, TGF-β, B7–H3) and cells (e.g., myeloid-derived suppressor cells [MDSCs], tumor-associated macrophages [TAMs], regulatory T cells [Tregs]); treatment-related toxicities such as cytokine release syndrome (CRS), Immune effector cell-associated neurotoxicity syndrome (ICANS), and on-target/off-tumor (OTOT) effects; and the substantial technical and economic burden of CAR-T cell manufacturing and clinical application

Researchers are actively exploring innovative strategies to enhance CAR-T cell therapy efficacy in renal, bladder, and prostate cancers. (1) Expansion and identification of potential targets: Researchers are integrating multi-omics data, including transcriptomics, proteomics, and metabolomics, to systematically characterize molecular subtypes of renal, bladder, and prostate cancers [ 300 , 301 ]. Combined with tissue and liquid biopsies, these approaches will facilitate the identification of novel biomarkers [ 302 ]. Current efforts also focus on discovering targetable antigens derived from somatic mutations, aberrant glycosylation patterns, tumor-stromal interactions, and others [ 144 , 145 , 173 , 208 , 303 ]. For instance, a recent study identified regulator of calcineurin 1 isoform 4 (RCAN1.4) as a novel immunogenic target in glioblastoma and developed targeted TCR-T cells, which supply valuable insights for exploring tumor antigens [ 304 ]. (2) Optimizing CAR structure and T-cell function: Tandem or multi-target CAR designs are under development to broaden antigen recognition [ 137 , 181 ]. Precision engineering of antigen-binding domains, transmembrane regions, and gene-delivery systems can enhance CAR-T cell specificity and persistence [ 177 , 220 ]. Concurrently, strategies aimed at modulating T-cell expansion and memory formation are being explored to strengthen CAR-T therapeutic performance and minimize off-target effects [ 139 , 221 ]. (3) Improving CAR-T cell trafficking and infiltration: Adenoviral vectors expressing chemokines can be used to guide CAR-T cell migration toward tumor sites [ 244 ]. Local administration strategies, such as intravesical instillation for bladder cancer and focused ultrasound–mediated delivery for prostate cancer, can help overcome physiological barriers, increase local therapeutic concentrations, and minimize systemic exposure [ 184 , 222 ]. Recently, Tang et al. [ 305 ] developed CAR-T cells decorated with immunomagnetic beads (M-CAR-T), enabling precise tumor targeting and localized T-cell activation. (4) Reversing the immunosuppressive TME: Engineering CAR-T cells to secrete immunostimulatory cytokines (e.g., IL-7 [ 211 ] and IL-12 [ 238 ]), employing gene-editing strategies, and combining therapies targeting immune checkpoints (e.g., PD-1 [ 181 , 227 ], PD-L1 [ 306 ], and TIGIT [ 178 ]) represent promising approaches. Another approach strategy involves expressing dominant-negative receptors in CAR-T cells; for example, integrating TGF-β variants into STEAP2- or PSMA-targeted CAR-T cells can attenuate inhibitory signaling in prostate cancer [ 97 , 231 ]. In addition, some therapeutic agents or CAR-NKT cells were found to selectively deplete immunosuppressive populations, such as TAMs and MDSCs [ 139 , 150 , 239 ]. Notably, two recent studies have introduced innovative CAR-T cell designs: one demonstrated CAR-T cells secreting a fusion protein simultaneously targeting PD-L1 and delivering IL-12 [ 224 ]; another reported IL-36γ-armored CAR-T cells remodeling the immunosuppressive TME by reprogramming neutrophils and enhancing endogenous T-cell immune responses multiple tumor-associated antigens [ 307 ]. (5) Controllable CAR-T strategies: Systematic dose-escalation studies are vital for balance CAR-T efficacy and toxicity. Incorporating molecularly regulated safety switches allows real-time and reversible control over CAR-T cell activity, offering critical safeguards against adverse events [ 217 , 250 ]. To mitigate immune rejection and GvHD in allogeneic CAR-T therapy, Wu et al. [ 308 ] employed SPPL3-targeted knockout to remodel cell-surface glycans on allogeneic CD19-CAR-T cells. This glycan-shielding technique preserved functional TCRs while improving immunological tolerance and proliferative ability. The safety and durability of this approach were subsequently verified in a clinical cohort of nine patients with B-cell lymphoma ( NCT06014073 ), supporting glycan-based immunomodulation as a promising strategy for developing safer and more durable allogeneic CAR-T therapies. Regulated local cytokine delivery is another viable approach, exemplified by CRISPR-edited armored CAR-T cells engineered to secrete IL-2 and IL-12 upon targeting tumor-specific endogenous genes [ 309 ]. Recently developed in vivo CAR-T generation technologies aim to selectively transport CAR constructs to patient T cells using engineered delivery systems, including viral vectors, lipid nanoparticles (LNPs), and polymer-based nanocarriers [ 310 ]. For example, Hunter et al. [ 311 ] indicated that targeted LNPs could reprogram CD8 + T cells, increasing their antitumor efficacy and safety in leukemia xenograft mouse models. Unlike conventional ex vivo manufacturing, in vivo approaches circumvent complicated cell-processing procedures and substantially reduce manufacturing costs. Through localized delivery and in situ functional modulation, this strategy holds significant potential to address manufacturing and application drawbacks associated with traditional CAR-T platforms. Notably, artificial intelligence (AI) provides great assistance in processing and integrating complex information. With AI support, researchers have identified novel therapeutic targets from multi-omics data [ 312 ], predicted patient prognosis and complications using machine-learning models [ 313 , 314 ], and generated synthetic datasets to simulate clinical trials [ 315 ]. In addition, AI-driven platforms, facilitate refined CAR structural optimization and sequence design [ 316 , 317 ]. Recent AI advancements have also spurred the development of automated smart-manufacturing hospitals for CAR-T production [ 318 , 319 ]. Furthermore, AI-based analyses of clinical and pathological datasets will provide increasingly precise and personalized CAR-T therapeutic strategies for patients with urological cancers [ 320 , 321 ].

In summary, numerous preclinical studies have indicated the antitumor efficacy of CAR-T cell therapy, and clinical trials in urological cancers continue to progress. However, current research still faces several limitations. Due to molecular and genomic heterogeneity inherent in urological cancers, CAR-T cells targeting a single antigen are insufficient to eliminate all cancer cells. Therefore, integrating multi-omics approaches and acquiring samples from multiple sources, including tumor tissues and liquid biopsies, is essential [ 302 ]. Such comprehensive analyses can identify biomarkers reflecting of tumor heterogeneity, thus promoting the development of CAR-T cells with broader therapeutic applicability. Additionally, conventional functional studies using cell lines and immunodeficient mouse models fail to fully capture the complex three-dimensional structures and TME characteristics of urological cancers [ 322 ]. Advanced experimental models, such as tumor spheroids, patient-derived organoids, and biomimetic tumor microenvironment systems, are increasingly utilized to address these limitations [ 174 , 323 ]. Furthermore, humanized mouse models reconstituted with functional immune system are also widely regarded as a valuable platform for evaluating CAR-T therapeutic efficacy and related adverse events [ 133 , 324 ]. Real-time tracking of CAR-T cell biodistribution and activation status in animal models has become achievable through the integration of in vivo imaging modalities such as fluorescence imaging, bioluminescence imaging, and magnetic resonance imaging [ 325 ]. These techniques substantially expand our understanding of CAR-T cell dynamics and therapeutic behavior in living systems. At present, CAR-T clinical trials for urological cancers remain in the early stages with relatively small sample sizes; thus, large-scale, multi-center studies are necessary for future clinical translation. Moreover, clinical trial population typically comprise older patients with advanced or metastatic disease, who have diverse prior treatments and declining organ function, influencing treatment response and potentially increasing adverse events [ 326 , 327 ]. Socioeconomic barriers are also significant challenges, affecting both patient enrollment and retention in clinical trials [ 328 ]. Beyond conventional αβ T cells and their subsets (e.g., γδ T cells and NKT cells), CAR engineering has been expanded to other immune cell types to complement CAR-T cell functions. For example, CAR-macrophages (CAR-M) derived from engineered macrophages exhibit enhanced tumor-specific phagocytosis and inflammatory cytokine secretion, promote macrophage polarization toward the immunostimulatory M1 phenotype, and synergize with T cells through improved antigen presentation [ 329 , 330 ]. As critical components of the innate immune system, NK cells can also be equipped with CAR constructs to accomplish precise tumor targeting and potent cytotoxicity [ 331 , 332 ]. CAR-NK cells can be produced from umbilical cord blood or induced pluripotent stem cells (iPSCs), which permits large-scale manufacturing production and cryopreservation for future “off-the-shelf” clinical applications [ 332 , 333 ]. Compared with allogeneic CAR-T cells, which carry risks of graft-versus-host disease and host rejection, CAR-NK cells are associated with a substantially lower incidences of CRS and other immune-related toxicities [ 334 ]. In addition, a recent study introduced an alternative approach to CAR engineering by utilizing mast cells (MCs) sensitized with tumor antigen–specific IgE [ 335 ]. The IgE-MCs were observed to serve as targeted carriers for the delivery of OAVs, while also secreting chemokines and inflammatory mediators that recruited and activated CD8 + T cells. Collectively, these advances highlight the expanding landscape of cell-based immunotherapies and their promising potential for treating urological cancers.

In conclusion, accumulating preclinical and clinical evidence supports the therapeutic potential of CAR-T cell therapy in renal, bladder, and prostate cancers. Although its translation into routine clinical practice in urological cancers remains in progress, future research needs to prioritize the rational design of combinatorial strategies, optimizing the balance between efficacy and toxicity, validating findings in larger and more diverse patient cohorts, and developing more precise, individualized treatment regimens.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary Material 1: Table S1 Extended details of CAR-T cell therapy clinical trials for renal, bladder, and prostate cancers Supplementary Material 2: Table S2 Statistical summary of CAR-T cell therapy clinical trials for renal, bladder, and prostate cancers Table S1 provides expanded details of the clinical trials listed in the main text Table 2, including trial estimated start/completion dates and investigational products. Table S2 presents a statistical summary and categorizations (e.g., start date, enrollment and funder types) of the clinical trials listed in Table 2.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Kai Chen, Yifan Wang and Pu Zhang contributed equally to this work.

Acknowledgements

We appreciated the Biorender ( http://www.biorender.com ) for their assistance in drawing.

Author contributions

K.C., Y.W., and P.Z. contributed equally to this paper. K.C. conceived and designed the study. K.C., Y.W., and P.Z. were responsible for investigation, data curation, formal analysis, visualization, and writing the original draft. Y.H., D.W., and K.Y. assisted in investigation, data curation, and visualization. L.L., Q.H., and W.W. assisted in data curation, and visualization. L.W., Q.Z., and D.F., provided resources, and supervised the project. All authors reviewed, edited and approved the final manuscript.

Funding

This program was supported by the Jiaxing Medical Key Subject Funding of Zhejiang Province (2023-ZC-013), National Health Commission of the People’s Republic of China-Zhejiang Province Jointly Constructed Project, Zhejiang Province Medical and Health Science and Technology Plan (WKJ-ZJ-2517), and Clinical-Basic Joint Research Project of Zhejiang Provincial People’s Hospital Affiliated with Hangzhou Medical College (C-2025-YXLH09). The funders had no role in the study design, data collection or analysis, preparation of the manuscript, or the decision to publish.

Data availability

The original clinical trial data analyzed in this review are publicly available in the ClinicalTrials.gov repository ( https://clinicaltrials.gov/ ). The specific datasets generated and analyzed during the current study are included within the article and its supplementary information file (see Supplementary Tables).

Declarations

Ethics approval and consent to participate

Not applicable.

Competing interests

The authors declare no competing interests.

Abbreviations

Antibody-drug conjugates

Adrenoceptor beta 2

Androgen deprivation therapy

Artificial intelligence

Bacillus calmette-guérin

B-cell lymphoma 2-like 1

Patient-derived bladder cancer organoids

BH3 interacting domain death agonist

Cancer-associated fibroblasts

Carbonic anhydrase ix

Chimeric antigen receptor

Carcinoembryonic antigen

Carcinoembryonic antigen-related cell adhesion molecule 5

Costimulatory molecules

Complete response

Cytokine release syndrome

Cancer stem-like cells

Cytotoxic T lymphocyte-associated antigen-4

Dose-limiting toxicity

Extracellular matrix

Epidermal growth factor receptor

Epithelial cell adhesion molecule

Enfortumab vedotin

Fc receptor γ

Food and Drug Administration

Focused ultrasound

Anglioside gd2

Graft-versus-host disease

Histone deacetylase inhibitor

Hypoxia-inducible factor 1α

Immune effector cell–associated neurotoxicity syndrome

Immune checkpoint inhibitors

Inverted chimeric cytokine receptor

Interferon

Immunoglobulin

Interleukin

Induced pluripotent stem cells

Lymphocyte-activation gene 3

Lewis y

Lipid nanoparticles

Mast cells

Metastatic castration-resistant prostate cancer

Myeloid-derived suppressor cells

Major histocompatibility complex

Muscle-invasive bladder cancer

Mesothelin

Mammalian target of rapamycin

Mucin

Neoadjuvant chemotherapy

Nuclear factor of the activated t cell

Natural killer

Natural killer group 2 member D

Non-muscle invasive bladder cancer

Oncolytic adenovirus

Overall survival

On-target/off-tumor

Oncolytic viruses

Prostatic acid phosphatase

Poly (adp-ribose) polymerase inhibitors

Programmed cell death-1

Programmed cell death ligand-1

Peroxisome proliferator-activated receptor γ

Partial response

Prostate-specific antigen

Prostate stem cell antigen

Prostate-specific membrane antigen

Regulator of calcineurin 1 isoform 4

Renal cell carcinoma

Receptor tyrosine kinase-like orphan receptor 2

Single-chain variable fragment

Stable disease

Sialylated cancer-derived igg

Six-transmembrane epithelial antigen of the prostate 1

Tumor-associated macrophages

T-cell receptor

Transforming growth factor

T cell immune receptor with Ig and ITIM domains

Tumor-infiltrating lymphocytes

Tyrosine kinase inhibitors

Tumor mutational burdens

Tumor microenvironment

Targeting modules

Tumour necrosis factor

Tumor necrosis factor receptor superfamily

Trinitrophenyl

regulatory T cells

T cells redirected for antigen-unrestricted cytokine-activated killing

Variant surface antigen 2-cysteine-rich interdomain region A

Vascular endothelial growth factor

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