Background Emerging evidence indicates that diverse bacteria colonize tumors and facilitate oncogenesis through multifaceted mechanisms, predominantly through immunosuppression of the tumor microenvironment (TME). Fusobacterium nucleatum (F.n) exemplifies this phenomenon in colorectal cancer (CRC), where it mediates immune evasion via tumor cell autophagy and upregulation of programmed death-ligand 1 (PD-L1). Effective strategies for combining precise elimination of intratumoral F.n with chemotherapy remain lacking. Methods A targeted multimodal nano-based chemoimmunotherapy was engineered by co-loading hyaluronic acid (HA)-coated silver nanoparticles (Ag NPs) and paclitaxel (PTX) into tumor-targeting cationic liposomes (Cls). The combination was mechanistically evaluated for F.n eradication capacity, antitumor effects, and remodeling of the tumor immune microenvironment. Antitumor efficacy and safety were also evaluated in vivo using a tumor-bearing mouse model. Results Intratumoral F.n subverted antitumor immunity through a dual mechanism, coupling major histocompatibility complex class I (MHC-I) degradation with PD-L1 upregulation. HA@Ag NPs/PTX Cls exerted synergistic antitumor effects through multimodal mechanisms. HA@Ag NPs/PTX Cls eliminated intratumoral bacteria, restoring microbial homeostasis, enhancing MHC-I antigen presentation, increasing production of tumor necrosis factor (TNF) and interferon (IFN), and downregulating PD-L1 to promote tumor immunorecognition. Combined with PTX-induced apoptosis, the nanotherapy inhibited both primary and metastatic tumors. Notably, bacterial clearance-triggered immune activation established long-term immunological memory, providing durable protection against tumor recurrence. These results highlighted the dual benefit of liposomes in addressing microbial dysbiosis and immune evasion in CRC. Conclusion This innovative liposomal strategy disrupts the immunosuppressive TME and synergizes with a small-molecule chemotherapeutic agent to induce tumor cell apoptosis, representing a novel approach to potentiate cancer immunotherapy.

PURPOSE:In the current study, we aimed to characterize the clinicopathological features of metastatic non-clear cell renal cell carcinoma (nccRCC) using retrospective data from our centre and to assess the clinical outcomes of patients treated with first-line immunotherapy-tyrosine kinase inhibitor (IO-TKI) therapy versus TKI monotherapy. METHODS:We conducted retrospective analysis of 105 metastatic nccRCC patients at our centre from Jan 2006 to Oct 2022. The end points included progression-free survival (PFS) and overall survival (OS). Survival analysis was performed using the Kaplan-Meier curve and multivariate Cox regression model. RESULTS:Among metastatic nccRCC patients, the most prevalent histology was papillary RCC (39.0%). The most common distant metastasis site was lung metastasis (52.4%), followed by bone metastasis (33.3%). The proportion of the favourable, intermediate and poor IMDC risk group were 19.0%, 54.3% and 26.7%, respectively. Among metastatic nccRCC patients, 26 received first-line IO-TKI therapy and 79 received first-line TKI monotherapy therapy. During the median follow-up of 22.2 months, the 1-year PFS and 3-year OS of IO-TKI group was 46.2% and 48.0%, respectively. In comparison, the 1-year PFS and 3-year OS of TKI monotherapy group was 34.9% and 33.7%, respectively. According to the Cox regression model, unclassified RCC pathology (HR = 2.027, p = 0.023) and poor IMDC risk group (HR = 2.285, p = 0.011) were identified as the independent risk factors for PFS. Poor IMDC risk group (HR = 2.638, p = 0.007) was also identified as the independent risk factors for OS. CONCLUSION:For metastatic nccRCC, unclassified RCC pathology and poor IMDC risk group were identified as independent risk factors for poor prognosis and IO-TKI showed promising efficacy in patients with metastatic nccRCC.

445 Background: The first-line use of immunotherapy in combination with tyrosine kinase inhibitors (IO-TKIs) significantly improves the overall prognosis of patients with metastatic clear cell renal cell carcinoma (mccRCC). Nevertheless, clinically applicable biomarkers for predicting the prognosis and efficacy of first-line IO-TKIs therapy remain elusive. Methods: We retrospectively evaluated 121 mccRCC patients treated with first-line IO-TKIs to assess the prognostic value of serum immunoglobulin G (IgG), neutrophil-to-lymphocyte ratio (NLR), modified Glasgow prognostic score (mGPS), their 3-month dynamic changes, and the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk group. The Kaplan-Meier survival curves were drawn to show the differences in progression-free survival (PFS) and overall survival (OS) among various clinical subgroups. Univariate and multivariate COX analyses were used to identify the independent prognostic factors. The time-dependent ROC curves were plotted to compare the ability of each model to predict specific PFS and OS time points. Results: At a median follow-up of 31 months for the cohort (median age 60 years), the objective response rate was 63.64%. The median PFS was 18 months; however, the median OS was not reached. Baseline IgG levels were comparable across the partial response (PR)/complete response (CR), stable disease (SD), and progressive disease (PD) groups (P = 0.160). Following 3 months of treatment, PR/CR group experienced a significant decline in IgG (P < 0.001), SD group showed stable levels (P = 0.235), and PD group demonstrated a significant elevation (P < 0.001). Elevated serum IgG after 3 months of treatment was associated with worse PFS (HR = 3.92, P < 0.001) and OS (HR = 3.96, P < 0.001). High IMDC score, high baseline mGPS, and baseline NLR (≥3) predicted poorer PFS and OS. Multivariate COX analysis showed that IgG alteration and baseline mGPS were independent prognostic factors for PFS and OS in mccRCC patients receiving first-line IO-TKIs. At 16 months of PFS, IgG alteration (AUC = 0.795) exhibited superior performance compared to other predictors (baseline mGPS: AUC = 0.679, baseline NLR: AUC = 0.694, IMDC: AUC = 0.651). At 50 months of OS, IgG alteration (AUC = 0.680) demonstrated non-inferior predictive capability compared to other indicators (baseline mGPS: AUC = 0.747, baseline NLR: AUC = 0.673, IMDC: AUC = 0.574). Conclusions: Serum IgG alterations emerge as a superior independent prognostic biomarker in mccRCC patients receiving first-line IO-TKIs.

To assess the predictive power of serum immunoglobulin G (IgG) for outcomes in metastatic clear cell renal cell carcinoma (mccRCC) patients receiving first-line immunotherapy in combination with tyrosine kinase inhibitors (IO-TKIs) and to compare it with established biomarkers. We retrospectively analyzed 121 mccRCC patients receiving first-line IO-TKIs to assess prognostic value of serum IgG, neutrophil-to-lymphocyte ratio (NLR), modified Glasgow prognostic score (mGPS), and International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk score. Univariate and multivariate Cox analyses identified the independent prognostic factors. The predictive performance of each prognostic indicator was compared using Harrell’s concordance index (C-index) and time-dependent area under the curve (AUC). At 3 months after first‑line IO‑TKIs therapy, serum IgG alteration was associated with treatment response and prognosis. IgG levels decreased in patients with partial or complete response, increased in those with progressive disease, and remained stable in those with stable disease. Patients with increased IgG had worse progression‑free survival (PFS) (HR = 3.92, P < 0.001) and overall survival (OS) (HR = 3.96, P < 0.001). Multivariate Cox analysis confirmed increased IgG as an independent prognostic factor for both worse PFS and OS. In predictive performance comparison, IgG alteration achieved a C-index of 0.71 for PFS and 0.68 for OS, with time-dependent AUCs of 0.795 (16-month PFS) and 0.68 (50-month OS), comparable or superior to IMDC, NLR, and mGPS. Serum IgG alteration provides an on-treatment risk stratification tool for mccRCC patients receiving first-line IO-TKIs. Elevated IgG at 3 months predicts poor prognosis, supporting intensified monitoring and earlier therapeutic reconsideration.

636 Background: Upper Tract Urothelial Carcinoma (UTUC) presents a challenging prognosis even after Radical Nephroureterectomy (RNU), and postoperative renal insufficiency further limits the options for adjuvant therapy. The efficacy of neoadjuvant chemotherapy for UTUC remains uncertain as past studies have not shown satisfactory results and have mostly been retrospective. There is an urgent need for a more promising regimen. This phase II study aims to investigate the efficacy and safety of a combination of chemotherapy (Gemcitabine/Cisplatin) and PD-1 inhibitor (Toripalimab) as neoadjuvant treatment (NT) in UTUC patients. Methods: We planned to enroll 34 UTUC patients with either cT1N0M0 (high grade) or cT2-3N0M0, confirmed by ureterorenoscopy biopsy and imaging. The treatment regimen included three or four cycles of NT (Gemcitabine, 800mg/m 2 , days 1 and 8/Cisplatin, 60mg/m 2 , day 1/Toripalimab, 240mg, day 1 of a 21-day cycle), followed by RNU and pelvic lymphadenectomy. The primary outcome was the pathological complete response (pCR) rate, with secondary outcomes including significant downstaging (≤pT1) rate, disease control rate (DCR), and safety. Results: To date, 17 patients have been accrued since August 1st, 2020, and recruitment is ongoing. Fifteen patients have completed treatments and were preliminarily analyzed, with two patients still undergoing treatment. The median age was 66.0 years, with 53.3% being male. The majority of patients had unifocal tumors, with a median maximum diameter of 2.8cm (0.4-5.8). All patients experienced obstructed hydronephrosis. Clinical T staging was confirmed by multi-parameter MRI, indicating two T2 and thirteen T3 patients. Ureterorenoscopy biopsy revealed 13 high-grade and two low-grade urothelial carcinoma patients. All patients were classified as high-risk UTUC. Twelve patients completed 4 cycles, and three underwent 3 cycles. The median interval time from initiation of NT to RNU and from the end of NT to RNU was 18.3 (11.4-22.7) weeks and 6.3 (0.1-11.6) weeks respectively. The pCR rate was 20.0% (3/15), the ≤pT1 rate was 53.3% (8/15), and the DCR was 100%. No grade 4-5 chemotherapy-related adverse events were recorded, but 26.7% (4/15) experienced grade 2 myelosuppression, 20% (3/15) grade 3, and 6.7% (1/15) grade 4. Two patients experienced immune-related adverse events after 4 cycles, including hypothyroidism (grade 2) and adrenal insufficiency (grade 2). No surgery-related complications or readmissions within one month were reported. With a median follow-up of 25.6 months, all patients remained alive and tumor-free. Conclusions: Preliminary analyses suggest that the combination of chemotherapy and a PD-1 inhibitor as NT exhibits promising pCR rate for UTUC. The treatment was manageable in terms of safety, with immune-related adverse events potentially leading to prolonged treatment periods. Clinical trial information: NCT04099589 .

852 Background: Urachal carcinoma (UrC) is an extremely rare cancer, and there is still a lack of standard drug treatment models for advanced UrC. Antibody-drug conjugate (ADC) therapy represents a promising cancer treatment method. However, the efficacy of ADC on UrC remains unclear due to the scarcity of knowledge about the immunohistochemical features of relevant targets. This study focused on the immunohistochemical features of UrC based on ADC therapeutic targets and its relationship with overall survival (OS), providing a basis for UrC treatment. Methods: A total of 45 postoperative pathological specimens confirmed to be UrC were collected. Using immunohistochemistry, protein expression levels of ADC targets HER2, Nectin-4, Claudin18.2, Trop2, Mesothelin, and the immunotherapy target PD-L1 were assessed, with the proportion of high expression (2+ or 3+) of target proteins evaluated. 38 cases with complete clinical information were screened to evaluate the relationship between the expression of target proteins and OS. Results: Among the ADC therapeutic targets, Trop2 had the highest high expression rate (55.6%) in UrC tissues, followed by Mesothelin (46.7%), Claudin18.2 (31.1%), Nectin-4 (22.2%), and HER2 (15.6%). The high expression rate of PD-L1 was 15.6%. The median age of UrC patients was 53.5 years. Sheldon stage I, III and IV patients accounted for 2.6%, 89.5% and 7.9%, respectively. Survival analysis revealed that the five-year survival rate was 85.7% in the low Trop2 expression group and 49.2% in the high expression group. High expression of Trop2 was associated with poor OS (P=0.031). Conclusions: The target proteins of ADC are expressed in UrC tissue. Trop2 exhibits a significant high expression rate, and UrC patients with high Trop2 expression have a worse prognosis. Trop2 could be a pivotal target for future ADC treatment of UrC.

504 Background: Non-clear cell renal cell carcinoma (nccRCC) is a clinicopathological heterogeneous disease that comprises a complex mixture of different pathology subtypes, accounting for approximately 20% of all RCC cases. Due to its heterogeneity and rarity, standard treatment strategy for metastatic nccRCC remain poorly defined. Methods: We conducted retrospective analysis of 105 metastatic nccRCC patients at our center from June 2010 to April 2022. Demographic, clinicopathological, and systemic therapy data were collected. The data of 872 metastatic ccRCC patients were also collected for comparison.The end points included progression-free survival (PFS) and overall survival (OS). Results: Among 105 metastatic nccRCC patients, the most prevalent histology was papillary RCC (pRCC, 39.0%). The second most common histological type was translocation RCC (tRCC, 29.5%), followed by unclassified RCC (24.8%). The median age of metastatic nccRCC patients was 50 years old. 68.6% patients had advanced primary tumor stage of T3/4, and 48.6% patients had regional lymph node metastasis. The most common distant metastasis site was lung metastasis (52.4%), followed by bone metastasis (33.3%), and 21.0% patients had liver metastasis. The proportion of the favorable, intermediate, and poor IMDC risk group were 19.0%, 54.3%, and 26.7%, respectively. Among metastatic nccRCC patients, 26 received first-line IO-TKI therapy, 79 received first-line TKI monotherapy therapy. During the median follow-up of 22.2 months, there was no statistical significance between the prognosis of IO-TKI and TKI monotherapy group (PFS: 10.9 months vs. 8.6 months, P = 0.23; OS: 23.3 months vs. 24.0 months, P = 0.39). The PFS of tRCC was significantly longer than pRCC and unclassified RCC (P＜0.001). According to the Cox regression model, unclassified RCC pathology (HR=2.027，P=0.023) and poor IMDC risk group (HR=2.285，P=0.011) were identified as the independent risk factors for PFS. Poor IMDC risk group was also identified as the independent risk factors for OS (HR=2.638，P=0.007). Compared to metastatic ccRCC, the metastatic nccRCC patients were younger, with more advanced T and N stage, having a higher proportion for liver metastasis. The outcome of metastatic nccRCC was also poorer than metastatic ccRCC patients (P＜0.001), with a median OS of 24.0 months and 38.0 months, respectively. Conclusions: Compared to metastatic ccRCC, the prognosis of the patients with metastatic nccRCC was poorer, and the metastatic nccRCC patients were younger, with more advanced T and N stage, having a higher proportion for liver metastasis. Unclassified RCC pathology and poor IMDC risk group were the independent risk factors for poor prognosis. For metastatic nccRCC, the efficacy of IO-TKI was not superior than TKI monotherapy.Therefore, it is of great significance to investigate novel therapeutic targets for metastatic nccRCC.

787 Background: Patients treated with bladder-preserving therapy for muscle-invasive bladder cancer are at risk of developing recurrent non-muscle-invasive bladder cancer. This study aims to evaluate the efficacy and adverse events of postoperative Bacillus Calmette-Guerin (BCG) instillation in patients with superficial recurrence following bladder-preserving therapy for muscle-invasive bladder cancer. Methods: We retrospectively analyzed 120 patients diagnosed with non-muscle-invasive bladder cancer who underwent transurethral resection followed by BCG instillation. The 19 patients with prior muscle-invasive bladder cancer were categorized as the NMIBC-M group, while the remaining 101 patients formed the NMIBC group. All patients completed a six-cycle BCG course. Results: Both groups showed no significant differences in baseline characteristics, except for the number of BCG instillations (15.5 vs. 9, p = 0.010). Overall survival, recurrence-free survival, metastasis, bladder preservation, and adverse event profiles were comparable between groups. However, patients in the group with prior muscle-invasive bladder cancer reported lower rates of urinary retention (28.7% vs. 0.0%, p = 0.017) and fever (30.7% vs. 5.3%, p = 0.044). Conclusions: Postoperative BCG instillation in patients with superficial recurrence following bladder-preserving therapy for muscle-invasive bladder cancer showed comparable efficacy and side effects to those without muscle-invasive bladder cancer history.

BACKGROUND:Urachal carcinoma (UrC), a rare malignancy originating from urachal remnants, currently lacks standardized therapeutic options for advanced stages. While antibody-drug conjugate (ADC) therapy has emerged as a transformative approach in oncology, its clinical application in UrC remains investigational due to the paucity of data regarding target antigen expression profiles. This study systematically characterized the immunohistochemical landscape of UrC through the lens of established ADC targets and evaluated their prognostic implications, thereby informing future therapeutic development. PATIENTS AND METHODS:We retrospectively analyzed 41 histologically confirmed UrC specimens with complete clinical information. Immunohistochemical evaluation was performed for 6 therapeutic targets: HER2, Nectin-4, Claudin18.2, Trop2, Mesothelin, and PD-L1. Standardized scoring system was used to quantify the level of target expression and to determine the rate of high expression for each target. Survival outcomes were assessed through Kaplan-Meier method and Cox proportional hazards modeling. RESULTS:With a median follow-up of 99 months, the cohort exhibited a 5-year overall survival (OS) rate of 62.4% (95% CI, 48.5%-80.3%). Analysis of ADC target protein expression showed that Trop2 had the highest rate of high expression (58.5%), followed by Mesothelin (43.9%), Claudin18.2 (34.1%), Nectin-4 (24.4%), HER2 (9.8%), and PD-L1 (4.9%). Survival analysis demonstrated significantly reduced 5-year overall survival (OS) in the Trop2-high group (47.1% vs. 87.5%, P = 0.01). Multivariate Cox regression analysis identified both Trop2 and Sheldon stage as independent prognostic determinants. CONCLUSION:Our findings confirm that UrC has the potential to be treated by ADC. Trop2 has the highest high expression rate in UrC and is associated with a worse prognosis, which may be a potential target for ADC therapy for UrC.

There is a lack of clinical evidence on whether further clinical strategies are needed after TURBT combined with immediate bladder instillation. This study intends to establish a reliable quantitative assay for active urinary cancer cells (AUCC) and to investigate the clinical efficacy of continuous saline bladder irrigation (CSBI) as a feasible option by analyzing the perioperative AUCC changes in TURBT. An AUCC assay was developed and its reliability was verified by single-cell whole genome sequencing. Bladder cancer patients (N = 324) diagnosed by cystoscopy and pathologic biopsy and control individuals (N = 92) were included from 2021 to 2023 in the study. Enrolled patients with non-muscle invasive bladder cancer (NMIBC) underwent TURBT followed by immediate bladder instillation of epirubicin, after subgroups received CSBI or not, and AUCCs were tested on the first and fifth postoperative day. The patients were followed up for two years for postoperative recurrence. The AUCC assay achieved good detection accuracy, with a sensitivity of 0.821 and specificity of 0.902. AUCC increased on the first day after TURBT in combination with immediate bladder instillation, regardless of whether or not the patient received CSBI. However, AUCCs decreased more rapidly on the fifth day in patients treated with CSBI, and patients with concomitant risk factors benefited more from CSBI. The two-year follow-up results showed that high-risk patients with complex surgeries could benefit significantly from CSBI. We pioneered a quantitative assay for AUCC and provided laboratory evidence that TURBT causes tumor cell dissemination and CSBI can be a further clinical strategy to reduce the risk of potential recurrence.

Background: Colorectal cancer (CRC) is one of the common malignant tumors. Chemotherapeutic agents represented by doxorubicin (DOX) are common adjuvant therapies for patients with advanced CRC. However, DOX suffers from dose-dependent cardiotoxicity and myelosuppression due to a lack of targeting and specificity, which severely limits its clinical application. Methods: Herein, we constructed a zeolitic imidazolate framework-8 (ZIF-8) modified by a novel peptide (LT peptide) to deliver the chemotherapeutic drug doxorubicin (DOX) for the targeted treatment of CRC. Results: In this study, LT-PEG@DOX@ZIF-8 nanoparticles were prepared by a simple method with suitable particle size and zeta potential, which were also capable of pH-responsive drug release. In vitro assays exhibited that LT-PEG@DOX@ZIF-8 nanoparticles were effectively taken up by C26 cells, significantly inhibited cell proliferation, and induced apoptosis. Furthermore, in mice models with colorectal tumors, LT-PEG@DOX@ZIF-8 nanoparticles also displayed specific tumor aggregation and exerted anti-tumor effects to prolong the survival of the mice. Conclusions: In conclusion, LT-PEG@DOX@ZIF-8 provides a promising strategy for the delivery of DOX to effectively treat CRC.

563 Background: The measurement of serum fibrinogen (FIB) levels is often overlooked in metastatic clear cell renal cell carcinoma (mccRCC). This study aims to investigate the prognostic value of preoperative serum FIB levels in mccRCC patients undergoing cytoreductive nephrectomy (CN) followed by systemic therapy. Methods: This retrospective study analyzed 209 mccRCC patients who underwent CN from 2010 to 2022. The optimal cutoff value of preoperative serum FIB levels was determined via receiver operating characteristic (ROC) curve. Survival outcomes were evaluated by the Kaplan-Meier method and Cox proportional hazards models. The predictive ability was evaluated by ROC curve. Propensity Score Matching (PSM) was performed to equate demographic and clinical characteristics. Results: An optimal cutoff value of 4.39 g/L for the FIB levels was determined and patients were categorized into high and low FIB groups. With a median follow-up time of 61.1 months, patients in the low FIB group exhibited significantly higher median OS compared with the high FIB group (53.1 vs 27.9 months, p < 0.001). The ROC curve demonstrated that the serum FIB predicted a 36-month overall survival with an AUC of 0.652, while the AUC for the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk category was 0.558. After PSM matching, high FIB levels remained significantly associated with poorer OS (24.0 vs 50.2 months; p = 0.019). Conclusions: Serum FIB level is a significant prognostic factor for mccRCC patients undergoing CN followed by systemic therapy. This finding underscores the potential of FIB as a biomarker that could be integrated into the prognostic model for preoperative risk stratification and management strategies.

Breast cancer as a “cold” tumor presents an immunosuppressive microenvironment and inferior T-lymphocyte infiltration, leading to poor efficacy of immune checkpoint blockade (ICB) therapies. It is urgent to develop new effective combination treatment strategies. Pyroptosis is an inflammatory form of programmed cell death mediated by Caspase-1/GSDMD pathway, which can cause immunogenic cell death (ICD) and boost the immunogenicity of tumor. In this study, an immune activator (siRNAPD-L1@HA-ZIF-8) was proposed based on metal-organic framework (ZIF-8) nanosystem carrying Zn2+ and PD-L1 siRNA to improve anti-tumor immunotherapy through evoking pyroptosis combined with immune checkpoint blockade. We found that siRNAPD-L1@HA-ZIF-8 could disintegrate under low pH and release massive amounts of Zn2+, leading to elevated intracellular osmolarity and ROS, eventually resulting in pyroptosis. Zn2+ overload-triggered pyroptosis caused ICD effect and promoted the maturation of dendritic cells and infiltration of T-lymphocytes, which reprogramed the immunoecology of tumor from “cold” to “hot” state. Meanwhile, the co-delivered PD-L1 siRNA decreased the expression of PD-L1 protein on the tumor surface, relieving immune evasion and recovering the recognition and killing ability of cytotoxic T-lymphocytes, further boosting the immune response. This research not only confirmed the potential of ZIF-8 intrinsically as an immune activator that induces pyroptosis in combination with encapsulated PD-L1 siRNA-mediated ICB therapy for the first time, but also adequately revealed the immune responses mechanism by multiple techniques. This study will provide new strategies for pyroptosis-mediated treatments for augmented anti-tumor immunotherapy and greatly inspire the further development of immune activators based on Zn2+ overload-triggered pyroptotic pathway.

Immune checkpoint inhibition (ICI) has become the mainstay of immunotherapy for the treatment of renal cell carcinoma (RCC). However, only a small portion of patients exhibit a positive response to PD-1/PD-L1 blockade therapy and the key reason is that RCC belongs to a vascular-rich tumor for promoting immunosuppression. Specifically, the dysfunctional tumor vasculature hinders effector T cell infiltration and induces immunosuppressive tumor microenvironment via the release of cytokine, which attenuates the therapeutic efficacy of ICI. Therefore, regulating abnormal tumor vasculature may be a promising strategy to overcome the immunosuppressive microenvironment and enhance ICI therapy. Here, we propose an NGR peptide-modified actively targeted liposome (Axi/siRNAPD-L1@NGR-Lipo) to encapsulate the anti-angiogenic agents Axitinib and PD-L1 siRNA to promote tumor vasculature normalization and relieve immune evasion for enhanced anti-tumor immunotherapy. With NGR-mediated tumor homing and active targeting, Axi/siRNAPD-L1@NGR-Lipo could act on tumor vascular endothelial cells to inhibit neo-angiogenesis, increase pericyte coverage and vascular perfusion, and normalize the structure and function of tumor blood vessels. Meanwhile, it also enhanced immune effector T cells and NK cells infiltration and reduced the proportion of immunosuppressive T cells including MDSC cells and Tregs, thus improving the tumor immunosuppressive microenvironment. Moreover, Axi/siRNAPD-L1@NGR-Lipo reduced the expression of PD-L1 protein in tumor cells, restored the recognition and killing ability of cytotoxic T cells, and relieved immune evasion. As expected, Axi/siRNAPD-L1@NGR-Lipo displayed superior anti-tumor and anti-metastatic efficacy in mice bearing RCC. Overall, this study demonstrated the important potential of regulating abnormal tumor vasculature to reshape the immunosuppressive microenvironment and boost ICI therapy, which represents a promising avenue for the synergistic anti-tumor with cancer immunotherapy.

In the original publication [...].

763 Background: Oncolytic virus therapy represents a novel approach in cancer treatment, showing promising results in non-muscle-invasive bladder cancer (NMIBC). OH2 injection is a recombinant oncolytic virus, derived from genetically modified HSV-2 strain HG52, which is confirmed efficacy in certain malignant tumors. This clinical trial aims to evaluate the safety and preliminary efficacy of using OH2 injection solution for intravesical irrigation to prevent recurrence in patients with high-risk NMIBC who have failed first-line preventive irrigation therapy. Methods: This study included pathology confirmed high-risk NMIBC patients who had undergone TURBT after failing first-line preventive bladder irrigation therapy and had been confirmed to be free of tumor residue. To be eligible for enrollment, patients needed to have adequate organ function, an ECOG performance status of 2 or less, and be ineligible for or refused radical cystectomy. Those with muscle invasive or locally advanced metastatic bladder cancer were excluded. Following enrollment, patients received OH2 with normal saline intravesical irrigation. The irrigation was given every two weeks for 5 times, followed the sixth irrigation after 3 weeks, then once a month till a year. We evaluated the 6-month and 12-month recurrence-free survival (RFS) rates and safety following the administration of oncolytic virus irrigation during the induction and maintenance treatment. Results: Thirty patients were planned to enroll in this clinical trial. The data of 9 high risk NMIBC patients could be analyzed at this time. Most of the patients (6 out of 9) received BCG treatment before. The 6-month RFS rate was 66.7%, the 12-month RFS rate was 55.6%, and the median RFS was 353 days. One patient who failed after the BCG treatment had the long RFS nearly 2 years. In terms of safety, adverse effects observed were consistent with the known safety profile of the agent. The most common complain included transient genitourinary symptoms which might be due to TURBT. The symptoms did not worsen during the treatment process. No significant adverse effects related to OH2 irrigation was observed. Conclusions: OH2 injection is independently developed domestically and is the first in China to be used for intravesical irrigation therapy for recurrent high-risk NMIBC, particularly in patients who have failed BCG therapy. According to our data, OH2 injection intravesical irrigation is safe. The long term efficacy deserves further research. Clinical trial information: NCT05232136 .

Background and objective: Systemic treatments involving immunotherapy-tyrosine kinase inhibitor (IO-TKI) combinations and TKI monotherapy have significantly improved outcomes for patients with metastatic clear-cell renal cell carcinoma (mccRCC). However, there are no biomarkers for predicting the efficacy of these treatments. Our aim was to investigate the prognostic and therapeutic significance of serum immunoglobulin G (IgG) in patients with mccRCC patients receiving systemic therapy. Methods: We included 318 patients with mccRCC who received TKI or IO-TKI therapy. Patients were classified into groups according to whether they had an increase or decrease in serum IgG after systemic treatment. The association between baseline serum IgG and the objective response rate (ORR) was compared between the groups using a t test. The association of the change in serum IgG with progression-free survival (PFS) and overall survival (OS) was evaluated via Cox proportional-hazards regression, and survival curves were generated using the Kaplan-Meier method. Key findings and limitations: Baseline serum IgG was not significantly associated with ORR (p = 0.055). After 3-mo systemic therapy, 133 patients (42%) exhibited an increase in serum IgG. The group with an IgG increase had significantly poorer median PFS (5.6 vs 16.2 mo; hazard ratio [HR] 3.36, 95% confidence interval [CI] 2.58-4.36; p < 0.001) and OS (26.0 vs 52.2 mo; HR 2.26, 95% CI 1.66-3.08; p < 0.001) than the group with an IgG decrease. Multivariable analysis revealed that an increase in serum IgG after 3-mo systemic therapy was an independent risk factor for both PFS (HR 3.28, 95% CI 2.51-4.30; p < 0.001) and OS (HR 1.94, 95% CI 1.41-2.68; p < 0.001). An increase in serum IgG after 1-mo treatment (n = 160) was also significantly associated with poorer median PFS (7.9 vs 13.7 mo; HR 1.62, 95% CI 1.13-2.32; p = 0.008) and OS (32.6 vs 50.5 mo; HR 1.68, 95% CI 1.09-2.59; p = 0.017). Conclusions and clinical implications: The change in serum IgG after 3-mo systemic therapy can predict the therapeutic effect and prognosis for patients with mccRCC. This predictive value was observed as early as 1 mo after treatment initiation. Our findings highlight the potential of serum IgG as a predictive biomarker in this setting. Further validation is required in large prospective studies.