Advanced prostate cancer (PCa) remains lethal despite standard therapies, and immune checkpoint inhibitors offer limited benefit in its “immune-cold” microenvironment. T-cell engagers (TCEs)—bispecific antibodies linking CD3 on T-cells to tumor-associated antigens (TAAs)—provide potent, MHC-independent cytotoxicity, overcoming a key resistance mechanism. While early PSMA-targeted TCEs established proof-of-concept, recent data, notably for six transmembrane epithelial antigen of the prostate 1 (STEAP1)-targeting agents like Xaluritamig, demonstrate more substantial objective responses, highlighting progress through improved target selection and molecular design. This review synthesizes the evolving landscape of TCEs targeting PSMA, STEAP1, and DLL3 in PCa. We critically evaluate emerging clinical evidence, arguing that realizing the significant therapeutic potential of TCEs requires overcoming key challenges, including cytokine release syndrome (CRS), limited response durability, and antigen escape. We contend that future success hinges on sophisticated engineering strategies (e.g., affinity tuning, masking, multispecific constructs) and rationally designed combination therapies tailored to disease-specific hurdles. Strategies for toxicity mitigation, the crucial role of biomarker-driven patient selection, and potential integration with existing treatments are also discussed. Accumulating evidence supports TCEs becoming a new therapeutic pillar for advanced PCa, but achieving this demands sustained innovation focused on optimizing efficacy and safety. This review critically connects molecular engineering advancements with clinical realities and future imperatives.
尽管标准疗法不断进步，晚期前列腺癌（PCa）仍具有致命性，而免疫检查点抑制剂在其“免疫冷”微环境中获益有限。T细胞衔接器（TCEs）——一种将T细胞上的CD3与肿瘤相关抗原（TAAs）连接的双特异性抗体——提供了强大且不依赖于MHC的细胞毒性，从而克服了一个关键耐药机制。早期靶向前列腺特异性膜抗原（PSMA）的TCEs已确立概念验证，而近期数据，特别是针对前列腺六次跨膜上皮抗原1（STEAP1）的靶向药物（如Xaluritamig），显示出更显著的客观缓解，凸显了通过改进靶点选择和分子设计所取得的进展。本综述综合评述了靶向PSMA、STEAP1和DLL3的TCEs在前列腺癌领域不断发展的格局。我们批判性地评估了新出现的临床证据，认为要实现TCEs的重大治疗潜力，必须克服关键挑战，包括细胞因子释放综合征（CRS）、缓解持久性有限以及抗原逃逸。我们认为，未来的成功取决于精密的工程策略（例如亲和力调节、掩蔽技术、多特异性构建体）以及针对疾病特异性障碍合理设计的联合疗法。本文还讨论了减轻毒性的策略、生物标志物驱动的患者选择的关键作用，以及与现有治疗手段的潜在整合。越来越多的证据支持TCEs成为晚期前列腺癌的新治疗支柱，但实现这一目标需要持续创新，专注于优化疗效和安全性。本综述批判性地将分子工程进展与临床现实及未来需求联系起来。
T-Cell Engager Therapy in Prostate Cancer: Molecular Insights into a New Frontier in Immunotherapy
肿瘤(癌症)患者之家