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Abstract：
The introduction of novel immunotherapies has significantly transformed the treatment landscape of genitourinary (GU) cancers, even becoming the standard of care in some settings. One such type of immunotherapy, immune checkpoint inhibitors (ICIs) like nivolumab, ipilimumab, pembrolizumab, and atezolizumab play a pivotal role by disturbing signaling pathways that limit the immune system\'s ability to fight tumor cells. Despite the profound impact of these treatments, not all tumors are responsive. Recent research efforts have been focused on understanding how cancer cells manage to evade the immune response and identifying the possible mechanisms behind resistance to immunotherapy. In response, ICIs are being combined with other treatments to reduce resistance and attack cancer cells through multiple cellular pathways. Additionally, novel, targeted strategies are currently being investigated to develop innovative methods of overcoming resistance and treatment failure. This article presents a comprehensive overview of the mechanisms of immunotherapy resistance in GU cancers as currently described in the literature. It explores studies that have identified genetic markers, cytokines, and proteins that may predict resistance or response to immunotherapy. Additionally, we review current efforts to overcome this resistance, which include combination ICIs and sequential therapies, novel insights into the host immune profile, and new targeted therapies. Various approaches that combine immunotherapy with chemotherapy, targeted therapy, vaccines, and radiation have been studied in an effort to more effectively overcome resistance to immunotherapy. While each of these combination therapies has shown some efficacy in clinical trials, a deeper understanding of the immune system\'s role underscores the potential of novel targeted therapies as a particularly promising area of current research. Currently, several targeted agents are in development, along with the identification of key immune mediators involved in immunotherapy resistance. Further research is necessary to identify predictors of response.
Immunotherapy has transformed the treatment landscape for many cancer types, including genitourinary malignancies such as renal and bladder cancers.However, not all patients or tumor types, such as prostate cancer, respond to this type of treatment.Understanding the mechanisms of immunotherapy resistance is critical for developing strategies to overcome these challenges.Primary resistance, which is present at the onset of treatment, can bedue to genetic abnormalities or immune system dysregulation. These factors alter the interactions between host cells and cancer cells.Adaptive resistance develops during therapy due to dynamic changes in the levels of growth factors, cytokines, and the tumor microenvironment (TME).Acquired resistance mainly occurs at the genetic and translational levels, involving the downregulation of critical human leukocyte antigen (HLA) molecules and interference with mutational repair.Future therapies may focus on detailed genetic profiling of patients to guide treatment selection and on the use of immune profile monitoring to assist in assessing responsiveness, alongside developing novel targeted therapies and ICIs.Further research is needed to identify predictors of response to ICIs.
Immunotherapy has transformed the treatment landscape for many cancer types, including genitourinary malignancies such as renal and bladder cancers.However, not all patients or tumor types, such as prostate cancer, respond to this type of treatment.Understanding the mechanisms of immunotherapy resistance is critical for developing strategies to overcome these challenges.Primary resistance, which is present at the onset of treatment, can bedue to genetic abnormalities or immune system dysregulation. These factors alter the interactions between host cells and cancer cells.Adaptive resistance develops during therapy due to dynamic changes in the levels of growth factors, cytokines, and the tumor microenvironment (TME).Acquired resistance mainly occurs at the genetic and translational levels, involving the downregulation of critical human leukocyte antigen (HLA) molecules and interference with mutational repair.Future therapies may focus on detailed genetic profiling of patients to guide treatment selection and on the use of immune profile monitoring to assist in assessing responsiveness, alongside developing novel targeted therapies and ICIs.Further research is needed to identify predictors of response to ICIs.
摘要：
新型免疫疗法的引入极大地改变了泌尿生殖系统（GU）癌症的治疗前景，甚至成为某些环境下的护理标准。一种这样的免疫疗法，免疫检查点抑制剂（ICIs），如nivolumab，ipilimumab,pembrolizumab,阿替珠单抗通过干扰信号通路发挥关键作用，这些信号通路限制了免疫系统对抗肿瘤细胞的能力。尽管这些治疗方法产生了深远的影响，并非所有肿瘤都有反应。最近的研究工作集中在了解癌细胞如何设法逃避免疫反应，并确定对免疫疗法耐药背后的可能机制。作为回应,ICI正在与其他治疗相结合，以减少耐药性并通过多种细胞途径攻击癌细胞。此外,小说,目前正在研究有针对性的策略，以开发克服耐药性和治疗失败的创新方法。本文对目前文献中描述的GU癌症中免疫疗法耐药的机制进行了全面概述。它探索了确定遗传标记的研究，细胞因子,和可以预测对免疫疗法的抗性或反应的蛋白质。此外,我们回顾了当前克服这种阻力的努力，其中包括联合ICIs和序贯疗法，对宿主免疫谱的新见解，和新的靶向疗法。各种联合免疫疗法和化疗的方法，靶向治疗,疫苗,为了更有效地克服对免疫疗法的抗性，已经研究了辐射。虽然这些联合疗法在临床试验中都显示出一定的疗效，对免疫系统作用的更深入的了解强调了新型靶向疗法作为当前研究中一个特别有前景的领域的潜力。目前,几个目标代理正在开发中，以及与免疫疗法抗性有关的关键免疫介质的鉴定。需要进一步的研究来确定反应的预测因素。
免疫治疗改变了许多癌症类型的治疗前景。包括泌尿生殖系统恶性肿瘤，如肾癌和膀胱癌。然而,不是所有的病人或肿瘤类型,比如前列腺癌，对这种治疗的反应。了解免疫疗法抵抗的机制对于制定克服这些挑战的策略至关重要。主要阻力,在治疗开始时存在，可能是由于遗传异常或免疫系统失调。这些因素改变宿主细胞和癌细胞之间的相互作用。由于生长因子水平的动态变化，在治疗过程中会产生适应性抵抗，细胞因子,和肿瘤微环境(TME)。获得性抗性主要发生在遗传和翻译水平，涉及关键人类白细胞抗原（HLA）分子的下调和对突变修复的干扰。未来的治疗方法可能侧重于患者的详细遗传分析，以指导治疗选择，并使用免疫谱监测来帮助评估反应性。同时开发新的靶向疗法和ICIs。需要进一步的研究来确定对ICI反应的预测因素。
免疫治疗改变了许多癌症类型的治疗前景。包括泌尿生殖系统恶性肿瘤，如肾癌和膀胱癌。然而,不是所有的病人或肿瘤类型,比如前列腺癌，对这种治疗的反应。了解免疫疗法抵抗的机制对于制定克服这些挑战的策略至关重要。主要阻力,在治疗开始时存在，可能是由于遗传异常或免疫系统失调。这些因素改变宿主细胞和癌细胞之间的相互作用。由于生长因子水平的动态变化，在治疗过程中会产生适应性抵抗，细胞因子,和肿瘤微环境(TME)。获得性抗性主要发生在遗传和翻译水平，涉及关键人类白细胞抗原（HLA）分子的下调和对突变修复的干扰。未来的治疗方法可能侧重于患者的详细遗传分析，以指导治疗选择，并使用免疫谱监测来帮助评估反应性。同时开发新的靶向疗法和ICIs。需要进一步的研究来确定对ICI反应的预测因素。
