Hansen Stian Bakke, Unal Bilal, Kuzu Omer Faruk, Saatcioglu Fahri
Department of Biosciences, University of Oslo, Oslo, Norway.
Institute for Cancer Genetics and Informatics, Oslo University Hospital, Oslo, Norway.
Theranostics. 2024 Oct 21;14(18):6913-6934. doi: 10.7150/thno.100555. eCollection 2024.
Prostate cancer (PCa) is the most common non-cutaneous cancer in men and a major cause of cancer-related deaths. Whereas localized PCa can be cured by surgery and radiotherapy, metastatic disease can be treated, but is not curable. Inhibition of androgen signaling remains the main therapeutic intervention for treatment of metastatic PCa, in addition to chemotherapy, radionuclide therapy and emerging targeted therapies. Although initial responses are favorable, resistance to these therapies invariably arise with development of castration resistant PCa (CRPC) and lethal phenotypes. Recent findings have implicated the crosstalk between PCa cells and the tumor microenvironment (TME) as a key factor for disease progression and metastasis, and the immune system is becoming an increasingly attractive target for therapy. Given the striking success of immune checkpoint inhibitors (ICIs) in various cancer types, preclinical and clinical studies have begun to explore their potential in PCa. It has become clear that the PCa TME is largely immunosuppressive, and ICI therapy does not have efficacy for PCa. Intense effort is therefore being made in the field to understand the mechanisms of suppression and to turn the immunosuppressive TME into an immune active one that would enable ICI efficacy. Herein we examine this recent body of knowledge and how the mutational landscape of PCa integrates with an immunosuppressive TME to circumvent ICI-mediated T-cell activity and tumor killing. We then review the emerging potential success of combinatorial ICI approaches, utility of careful patient selection, and potential novel strategies to improve the efficacy of ICI for PCa therapy.
前列腺癌（PCa）是男性中最常见的非皮肤癌，也是癌症相关死亡的主要原因。虽然局限性PCa可以通过手术和放疗治愈，但转移性疾病可以治疗，但无法治愈。除化疗、放射性核素治疗和新兴的靶向治疗外，抑制雄激素信号仍然是治疗转移性PCa的主要治疗手段。尽管初始反应良好，但随着去势抵抗性PCa（CRPC）和致死性表型的发展，这些治疗方法总会出现耐药性。最近的研究发现，PCa细胞与肿瘤微环境（TME）之间的相互作用是疾病进展和转移的关键因素，免疫系统正日益成为一个有吸引力的治疗靶点。鉴于免疫检查点抑制剂（ICIs）在各种癌症类型中取得了显著成功，临床前和临床研究已开始探索其在PCa中的潜力。很明显，PCa的TME在很大程度上具有免疫抑制作用，ICI治疗对PCa无效。因此，该领域正在进行大量努力，以了解抑制机制，并将免疫抑制性TME转变为具有免疫活性的TME，从而使ICI发挥疗效。在此，我们研究了这一最新知识体系，以及PCa的突变图谱如何与免疫抑制性TME整合，以规避ICI介导的T细胞活性和肿瘤杀伤。然后，我们回顾了联合ICI方法的新兴潜在成功、谨慎选择患者的效用，以及提高ICI治疗PCa疗效的潜在新策略。
