Diffuse pleural mesothelioma (PM) is a rare thoracic malignancy with historically limited treatment options and poor outcomes. Despite the recent breakthrough of dual immune checkpoint blockade (ICB)—notably the combination of anti-PD-1 and anti-CTLA-4 therapies—clinical responses remain variable and overall survival gains modest. Consequently, there is an urgent need for multidimensional biomarkers and adaptive trial designs to unravel the complexity of PM immune biology. This review provides a comprehensive overview of current evidence on how histological subtypes (epithelioid vs. non-epithelioid) influence ICB efficacy, highlighting distinct genetic landscapes (e.g., BAP1, CDKN2A, NF2 mutations) and tumor microenvironment (TME) features, including immune infiltration patterns and PD-L1 or VISTA expression, that underlie differential responses. We further examine intrinsic tumor factors—such as mutational burden and checkpoint ligand expression—and extrinsic determinants, including immune cell composition, stromal architecture, patient immune status, and microbiota, as modulators of immunotherapy outcomes. We also discuss the rationale behind emerging strategies designed to enhance ICB efficacy, currently under clinical evaluation. These include combination regimens with chemotherapy, radiotherapy, surgery, epigenetic modulators, anti-angiogenic agents, and novel immunotherapies such as next-generation checkpoint inhibitors (LAG-3, VISTA), immune-suppressive cell–targeting agents, vaccines, cell-based therapies, and oncolytic viruses. Collectively, these advancements underscore the importance of integrating histological classification with molecular and microenvironmental profiling to refine patient selection and guide the development of combination strategies aimed at transforming “cold” mesotheliomas into “hot,” immune-responsive tumors, thereby enhancing the efficacy of ICB.
弥漫性胸膜间皮瘤是一种罕见的胸部恶性肿瘤，历史上治疗选择有限且预后不良。尽管近期双免疫检查点阻断疗法取得突破——尤其是抗PD-1与抗CTLA-4联合治疗——但临床反应仍存在差异，总生存获益有限。因此，迫切需要多维生物标志物和适应性试验设计来解析胸膜间皮瘤免疫生物学的复杂性。本综述全面概述了当前关于组织学亚型（上皮样与非上皮样）如何影响免疫检查点阻断疗效的证据，重点阐明了导致不同治疗反应的独特遗传特征（如BAP1、CDKN2A、NF2突变）和肿瘤微环境特征，包括免疫浸润模式及PD-L1或VISTA表达。我们进一步探讨了内在肿瘤因素（如突变负荷和检查点配体表达）与外在决定因素（包括免疫细胞组成、基质结构、患者免疫状态及微生物群）作为免疫治疗结果的调节因子。同时分析了当前处于临床评估阶段、旨在增强免疫检查点阻断疗效的新兴策略理论基础，包括与化疗、放疗、手术、表观遗传调节剂、抗血管生成药物及新型免疫疗法（如新一代检查点抑制剂LAG-3、VISTA）、免疫抑制细胞靶向剂、疫苗、细胞疗法和溶瘤病毒的联合方案。这些进展共同强调了将组织学分类与分子及微环境特征整合的重要性，以优化患者选择，指导旨在将“冷”间皮瘤转化为“热”免疫应答性肿瘤的联合策略开发，从而提升免疫检查点阻断疗效。
肿瘤(癌症)患者之家