Patients with metastatic castration-resistant prostate cancer (mCRPC) face poor prognoses due to tumor heterogeneity and drug resistance. Antibody-drug conjugates (ADCs) have been under development for over two decades for mCRPC treatment. Several clinical trials have demonstrated promising antitumor activity and acceptable safety profiles for ADCs in this setting. Among prostate-specific membrane antigen (PSMA)-targeted ADCs, ARX517 demonstrates superior safety and more significant prostate-specific antigen (PSA) reductions compared to earlier agents such as MLN2704, PSMA-ADC, and MEDI3726. ADCs targeting B7-H3, such as MGC018 and DB-1311, have also shown antitumor activity. ADCs targeting other antigens, including six-transmembrane epithelial antigen of the prostate (STEAP)1 (DSTP3086S), trophoblast cell surface antigen (TROP)2 (sacituzumab govitecan), and solute carrier (SLC) 44A4 (ASG-5ME), have shown preliminary antitumor activity in early trials but face challenges with insufficient efficacy or toxicity. Tisotumab vedotin (targeting tissue factor) has shown no significant therapeutic response in mCRPC. Meanwhile, disitamab vedotin (HER2-targeted), ABBV-969 and DXC008 (both dual PSMA/STEAP1-targeted) are currently under evaluation. Notably, an international multicenter phase Ⅲ clinical trial (NCT06925737) for mCRPC has been initiated in May 2025 for evaluating B7-H3-targeted ADC ifinatamab deruxtecan. This review summarizes recent advances in ADCs targeting key antigens in mCRPC (including PSMA, B7-H3, STEAP1, TROP2, SLC44A4, and others) and explores combination strategies, offering insights to inform the clinical management of mCRPC.
Humans ; Prostatic Neoplasms, Castration-Resistant/pathology* ; Male ; Immunoconjugates/therapeutic use* ; Glutamate Carboxypeptidase II/immunology* ; Antibodies, Monoclonal, Humanized/therapeutic use* ; B7 Antigens/immunology* ; Neoplasm Metastasis ; Prostate-Specific Antigen ; Antigens, Neoplasm/immunology* ; Antigens, Surface ; Camptothecin/analogs & derivatives* ; Oxidoreductases

Immune checkpoint blockade therapy has demonstrated remarkable efficacy in treating various malignancies; however, its clinical application remains challenged by low response rates and immune-related adverse events. Immunoglobulin superfamily member 11 (IGSF11), an inhibitory immune checkpoint molecule, serves as a specific ligand for the V-domain immunoglobulin suppressor of T cell activation (VISTA). Through the IGSF11/VISTA axis, it suppresses T cell function and represents a promising novel target for cancer immunotherapy. IGSF11 is widely expressed across multiple tumor types, though its regulatory mechanisms vary depending on the malignancy. Studies have confirmed that blocking the IGSF11-VISTA interaction or specifically inhibiting IGSF11 exerts antitumor effects. While IGSF11 is closely associated with patient prognosis, its prognostic significance differs among cancer types. This review systematically summarizes the structural characteristics of IGSF11, its regulatory mechanisms, interaction with VISTA, and functional role within the tumor microenvironment.
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Humans ; Immunotherapy ; Neoplasms/metabolism* ; B7 Antigens/chemistry* ; Animals ; Molecular Targeted Therapy ; Tumor Microenvironment

OBJECTIVES: Sepsis remains a major global health challenge, yet specific diagnostic biomarkers are still lacking. This study aims to investigate the causal relationship between B7 homologue 3 (B7-H3) and sepsis susceptibility, severity, and clinical outcomes using Mendelian randomization (MR) analysis, in order to evaluate its potential as a biomarker. METHODS: Genetic data related to sepsis (including overall sepsis, sepsis-related mortality with 28 days, severe sepsis, and severe sepsis with 28-day mortality) were extracted from genome-wide association study (GWAS) datasets. Single nucleotide polymorphisms (SNPs) associated with B7-H3 were selected as instrumental variables. The inverse-variance weighted (IVW) was used as the primary approach for causal effect estimation, while weighted median (WME) and MR-Egger regression served as supplementary methods. Additionally, a constrained maximum likelihood-model average (cML-MA) approach was employed to enhance the reliability of causal effect estimation. Cochran's Q test was conducted to assess heterogeneity, and MR-PRESSO along with the MR-Egger intercept method were used to detect horizontal pleiotropy. Sensitivity analyses were performed using the leave-one-out method. A reverse MR analysis was performed with sepsis as the exposure and B7-H3 as the outcome to exclude potential reverse causation. RESULTS: IVW analysis indicated a significant positive causal association between B7-H3 and sepsis susceptibility, severity, and clinical outcomes. A genetically predicted 1-standard deviation (SD) increase in B7-H3 levels was associated with a 10.4% increased risk of sepsis (OR=1.104, 95% CI 1.021 to 1.194, P=0.013), a 26.2% increased risk of sepsis-related 28-day mortality (OR=1.262, 95% CI 1.078 to 1.476, P=0.004), a 22.3% increased risk of severe sepsis (OR=1.223, 95% CI 1.023 to 1.463, P=0.027), and a 60.2% increased risk of severe sepsis with 28-day mortality (OR=1.602, 95% CI 1.119 to 2.294, P=0.010). The causal effect direction remained consistent across IVW, WME, MR-Egger, and cML-MA analyses, reinforcing the robustness and reliability of the results. Cochran's Q test showed no heterogeneity (P>0.05), while MR-PRESSO and MR-Egger intercept tests indicated no evidence of horizontal pleiotropy (both P>0.05). The leave-one-out analysis showed that removing individual SNPs did not significantly alter the causal estimates. Reverse MR analysis showed no causal association between sepsis and B7-H3. CONCLUSIONS B7-H3 may serve as an important biomarker for sepsis, as it is closely associated with sepsis susceptibility, severity, and clinical outcomes.
Sepsis/mortality* ; Humans ; Mendelian Randomization Analysis ; Polymorphism, Single Nucleotide ; B7 Antigens/genetics* ; Prognosis ; Genome-Wide Association Study ; Biomarkers ; Genetic Predisposition to Disease

OBJECTIVE: To observe the effects of drug-containing serum of Xijiao Dihuang combined prescription(XJDH) on the related functions of dendritic cells(DCs) induced in vitro, and to explore the mechanisms underlying the effectiveness of XJDH treatment on primary immune thrombocytopenia(ITP). METHODS: Peripheral blood samples were colle-ted from 6 healthy volunteers. Mononuclear cells were isolated by density gradient centrifugation, and CD14⁺ mononuclear cells were collected by the magnetic separation technique. CD14+ mononuclear cells were induced into immature DCs by recombinant human granulocyte-macrophage colony stimulating factor (GM-CSF) and recombinant human interleukin 4 (IL-4). Immature DCs were divided into three groups: control group, model group and XJDH group. CCK-8 assay was used to determine the intervention concentration and time of drug-containing serum. Lipopolysaccharide(LPS) with the final concentration of 1 μg/ml was added to model group and XJDH group respectively for 24 h to induce DCs maturation. Normal rat serum was added to control group and model group, and XJDH was added to XJDH group for 24 h. Flow cytometry was used to detect the levels of CD80, CD83 and HLA-DR on the surface of DCs. Western blot was used to detect the expression of TLR4 and NF-κB, and levels of IL-6, IL-12 and TNF-α in cell supernatant was detected by ELISA. RESULTS: Compared with the control group, LPS stimulation increased the expression of CD80, CD83 and HLA-DR, with subsequent increasing expression of TLR4 and NF-κB, as well as IL-6, IL-12 and TNF-α increased(P<0.05). In comparison with model group, the expression of DCs surface molecules CD80, CD83 and HLA-DR, DCs' expression of TLR4 and NF-κB protein, and the levels of IL-6, IL-12 and TNF-α in the cell supernatant of XJDH group decreased after the intervention of XJDH (P<0.05). CONCLUSION Drug containing serum of Xijiao Dihuang combined prescription can down-regulate TLR4/NF-κB signaling pathway related protein expression, inhibit DCs maturation, and reduce proinflammatory factor secretion, which may be one of the mechanisms of drug-containing serum of Xijiao Dihuang combined prescription in the treatment of immune thrombocytopenia.
Animals ; B7-1 Antigen/pharmacology* ; Cell Differentiation ; Dendritic Cells ; HLA-DR Antigens/pharmacology* ; Humans ; Interleukin-12/pharmacology* ; Interleukin-6 ; Lipopolysaccharides/pharmacology* ; Medicine, Chinese Traditional ; NF-kappa B ; Prescriptions ; Purpura, Thrombocytopenic, Idiopathic ; Rats ; Toll-Like Receptor 4 ; Tumor Necrosis Factor-alpha/pharmacology*

We constructed the CS1-targeted second- and third-generation CAR-T cells with genetic engineered 4-1BB or/and ICOS as a costimulatory signaling molecule by use of lentiviral platform. The CS1-targeted second-generation CAR-T cells with ICOS or 4-1BB had similar anti-neoplastic activity. When effector/target ratio was 1:1, the CAR-T cells with ICOS showed better killing effect on IM9-lucgfp cells than those with 4-1BB. However, The CS1-targeted third-generation CAR-T cells exihibited lower cytolytic capacity against IM9-lucgfp cells than the CS1-targeted second-generation CAR-T cells when the ratio of effector/target was 1:1, 2:1 or 5:1. When the ratio of effector/target was 10:1, the killing efficacy of both the second- and third-generation CAR-T cells against IM9-lucgfp cells was more than 85%, significantly higher than that of the control T cells. Taken together, both the CS1-targeted second- and third-generation CAR-T cells with ICOS or/and 4-1BB could efficiently kill CS1-positive multiple myeloma cells, but the CS1-targeted second-generation CAR-T cells had more potent killing effect on CS1-positive multiple myeloma cells than the CS1-targeted third-generation CAR-T cells.
4-1BB Ligand/metabolism* ; Cell Line, Tumor ; Genetic Engineering ; Humans ; Inducible T-Cell Co-Stimulator Protein/metabolism* ; Multiple Myeloma/therapy* ; Signal Transduction ; T-Lymphocytes/chemistry* ; Xenograft Model Antitumor Assays

OBJECTIVE: To study the expression of multiple negative costimulatory molecules on peripheral blood T cells in patients with acute myeloid leukemia (AML) and its affection on prognosis. METHODS: The peripheral blood samples from patients with newly diagnosed AML, complete remission (CR), and no-remission (NR) were collected, the expression levels PD-1、VISTA and TIM-3 in CD4 and CD8 T cells were detected by flow cytometry , and the clinical data of patients were analyzed. RESULTS: The expression levels of PD-1、VISTA and TIM-3 of CD4 and CD8 T cells in the newly diagnosed AML patients were significantly higher than those in control group (P＜0.05). The expression levels of PD-1、TIM-3 and VISTA of CD4 and CD8 T cells in the CR group were significantly lower than those in newly diagnosed and the NR group (P＜0.05). The TIM-3 expression level positively correlated with VISTA expression level of CD4 and CD8 T cells in newly diagnosed AML patients (r=0.85 and 0.73). The VISTA and PD-1 expression level of CD4 T cells in newly diagnosed AML, NR after first induction chemotherapy and high risk patients significantly increased (P＜0.05), the TIM-3 expression level of CD8 T cells in high risk group significantly increased (P＜0.05), and the VISTA expression level of CD8 T cells in CBFβ-MYH11 mutation-positive group significantly decreased (P＜0.05). CONCLUSION The expression of PD-1、TIM-3 and VISTA in AML peripheral blood T cells may be involved in the immune escape of AML and can be the targets of treatment for acute myeloid leukemia patients.
B7 Antigens ; CD8-Positive T-Lymphocytes ; Flow Cytometry ; Hepatitis A Virus Cellular Receptor 2 ; Humans ; Leukemia, Myeloid, Acute ; Programmed Cell Death 1 Receptor

Immune checkpoint blockade targeting PD-1 and PD-L1 has resulted in unprecedented clinical benefit for cancer patients. Anti-PD-1/PD-L1 therapy has become the standard treatment for diverse cancer types as monotherapy or in combination with other anti-cancer therapies, and its indications are expanding. However, many patients do not benefit from anti-PD-1/PD-L1 therapy due to primary and/or acquired resistance, which is a major obstacle to broadening the clinical applicability of anti-PD-1/PD-L1 therapy. In addition, hyperprogressive disease, an acceleration of tumor growth following anti-PD-1/PD-L1 therapy, has been proposed as a new response pattern associated with deleterious prognosis. Anti-PD-1/PD-L1 therapy can also cause a unique pattern of adverse events termed immune-related adverse events, sometimes leading to treatment discontinuation and fatal outcomes. Investigations have been carried out to predict and monitor treatment outcomes using peripheral blood as an alternative to tissue biopsy. This review summarizes recent studies utilizing peripheral blood immune cells to predict various outcomes in cancer patients treated with anti-PD-1/PD-L1 therapy.
Acceleration ; Antigens, CD274 ; Biomarkers ; Biopsy ; Drug-Related Side Effects and Adverse Reactions ; Fatal Outcome ; Humans ; Prognosis ; Programmed Cell Death 1 Receptor

OBJECTIVE: Programmed cell death-ligand 1 (PD-L1) is expressed in tumor cells and has been shown to predict clinical outcomes of several types of malignancies. The aim of this study was to investigate the effects of carbon-ion (C-ion) beam irradiation on PD-L1 expression in human uterine cervical adeno/adenosquamous carcinoma (UCAA) cells and clinical samples and to identify the prognostic factors for outcomes after C-ion radiotherapy (CIRT).METHODS: The effects of C-ion irradiation on PD-L1 expression in human UCAA and cervical squamous cell carcinoma cells were examined by flow cytometry. We examined PD-L1 expression in UCAA biopsy specimens from 33 patients before CIRT started (pre-CIRT) and after 12 Gy (relative biological effectiveness [RBE]) irradiation (post-12Gy-C) in 4 fractions of CIRT to investigate the correlation between PD-L1 status and clinical outcomes.RESULTS: The PD-L1 expression was upregulated by C-ion beam in a dose-dependent manner in HeLa and SiHa cells through phosphorylated Chk1. The overall frequencies of pre-CIRT and post-12Gy-C PD-L1 positivity were 45% (15/33) and 67% (22/33), respectively. The post-12Gy-C PD-L1 expression was significantly elevated compared to the pre-CIRT PD-L1 expression. There was no significant relationship between the pre-CIRT PD-L1 status and clinical outcomes, such as local control (LC), progression-free survival (PFS), and overall survival (OS). However, the post-12Gy-C PD-L1 expression had better correlation with PFS, but not with LC and OS.CONCLUSION: CIRT can induce PD-L1 expression in UCAA and we propose that PD-L1 expression after starting CIRT may become as a predictive prognostic marker in CIRT for UCAA.
Antigens, CD274 ; Biopsy ; Carcinoma, Squamous Cell ; Disease-Free Survival ; Flow Cytometry ; Heavy Ion Radiotherapy ; Humans ; Radiotherapy ; Treatment Outcome ; Uterine Cervical Neoplasms

CD80 is mainly expressed on Ag-presenting cells (APCs) as a costimulatory molecule but is also detected on T cells. However, the origin and physiological role of CD80 on CD8⁺ T cells remain unclear. In the present study, we demonstrated that effector and memory CD8⁺ T cells, but not naïve CD8⁺ T cells, displayed CD80 molecules on their surfaces after acute lymphocytic choriomeningitis virus infection. Using adoptive transfer of CD80-knockout (KO) CD8⁺ T cells into a wild type or CD80-KO recipient, we demonstrated that the effector CD8⁺ T cells displayed CD80 by both intrinsic expression and extrinsic acquisition, while memory CD8⁺ T cells displayed CD80 only by extrinsic acquisition. Interestingly, the extrinsic acquisition of CD80 by CD8⁺ T cells was observed only in the lymphoid organs but not in the periphery, indicating the trogocytosis of CD80 molecules via interaction between CD8⁺ T cells and APCs. We compared the recall immune responses by memory CD8⁺ T cells that either extrinsically acquired CD80 or were deficient in CD80, and found that CD80, presented by memory CD8⁺ T cells, played a role in limiting their expansion and IL-2 production upon exposure to secondary challenge. Our study presents the in vivo dynamics of the extrinsic acquisition of CD80 by Ag-specific CD8⁺ T cells and its role in the regulation of recall immune responses in memory CD8+ T cells.
Adoptive Transfer ; Antigens, CD80 ; Interleukin-2 ; Lymphocytic choriomeningitis virus ; Memory ; T-Lymphocytes

PURPOSE: The efficacy of nivolumab in metastatic renal cell carcinoma (mRCC) has been proven. However, the nivolumab experience in Korean patients with mRCC is still poorly reported. We report initial experiences with the efficacy and safety of nivolumab in patients with mRCC. MATERIALS AND METHODS: We retrospectively reviewed records for 25 patients with mRCC who had failed targeted therapy and were treated by nivolumab (2 mg/kg, every 2 weeks) at a single institution. The primary endpoint was objective response rate (ORR), and secondary endpoints were progression-free survival (PFS), safety profiles, and ORR in a programmed cell death receptor ligand 1 (PD-L1) expression subgroup. RESULTS: The median age was 60 years and 16 patients (64%) were male. Objective responses were achieved in 8 patients (32.0%) (complete response, 1; partial response, 7). Median PFS was 3.0 months (95% confidence interval, 1.46–4.53). Treatment-related adverse events (AEs) of any grade were observed in 19 patients (76.0%) with 6 (24.0%) experiencing grade 3 to 4 treatment-related AEs. In subgroups by PD-L1 expression levels classified as 1% or greater and less than 1%, ORR was 50% and 0%, respectively. CONCLUSIONS: This study showed the efficacy and safety of initial experiences with nivolumab in Korean patients with mRCC who had failed targeted therapy. Our results were comparable to recent clinical trials on nivolumab in mRCC.
Antigens, CD274 ; Carcinoma, Renal Cell ; Cell Death ; Disease-Free Survival ; Humans ; Male ; Neoplasm Metastasis ; Retrospective Studies ; Treatment Outcome