肿瘤细胞治疗研究
英文原题：Clinically oriented immune heterogeneity in prostate cancer: emerging targets and strategies.
前列腺癌（PCa）长期以来被视为免疫“冷”恶性肿瘤，因为免疫检查点抑制剂（ICIs）在未经选择的患者中获益有限，尤其是在进展为转移性去势抵抗性PCa（mCRPC）或治疗相关神经内分泌PCa（NEPC）后。
前列腺癌（PCa）长期以来被视为免疫“冷”恶性肿瘤，因为免疫检查点抑制剂（ICI）在未经选择的患者中获益有限，尤其是在进展为转移性去势抵抗性PCa（mCRPC）或治疗相关神经内分泌PCa（NEPC）后。单细胞和空间分析现在揭示了患者之间、病灶之间以及从局限性疾病到转移路径上的免疫异质性。原发肿瘤形成免疫排斥腺体、髓系抑制性间质边界以及局灶性淋巴细胞富集微生态的镶嵌结构，后者伴有B细胞聚集和三级淋巴结构（TLS）。TLS高区域代表一个可干预的“热少数”，类似于炎症性、ICI应答性癌症，支持生物标志物引导的新辅助或局灶性免疫治疗。随着播散，异质性在不同部位间扩大；骨转移成为以抑制性巨噬细胞/单核细胞程序和功能障碍T细胞为主的骨髓免疫器官，通常由CCL2-CCR6轴驱动。标准治疗重塑这些生态系统，创造炎症窗口，但也促进适应性耐药。在机制上，髓系驱动、炎症偶联的重编程是逃逸的核心：IL-8/CXCR2信号和治疗诱导的衰老/SASP招募并极化抑制性髓系细胞，强化T细胞排斥和耗竭。可变的HLA I类缺失以及缺氧或代谢性“功能性冷区”增加了病灶特异性的免疫不可见性。在临床上，这些见解推动了一个异质性感知框架，将基因组应答者亚群与微环境分层相结合。屏障匹配策略包括T细胞重定向（PSMA/STEAP1衔接器、双特异性抗体、CAR-T）以及加热或调节髓系细胞的联合方案。将免疫异质性作为临床变量进行治疗，可实现PCa的持久免疫治疗。
Prostate cancer (PCa) has long been viewed as an immunologically "cold" malignancy because immune checkpoint inhibitors (ICIs) show limited benefit in unselected patients, particularly after progression to metastatic castration-resistant PCa (mCRPC) or treatment-related neuroendocrine PCa (NEPC). Single-cell and spatial profiling now reveal immune heterogeneity across patients, between lesions, and along the path from localized disease to metastasis. Primary tumors form mosaics of immune-excluded glands, myeloid-suppressed stromal borders, and focal lymphocyte-rich niches with B-cell aggregates and tertiary lymphoid structures (TLS). TLS-high regions represent an actionable "hot minority" resembling inflamed, ICI-responsive cancers, supporting biomarker-guided neoadjuvant or focal immunotherapy. With dissemination, heterogeneity expands across sites; bone metastases become marrow immune organs dominated by suppressive macrophage/monocyte programs and dysfunctional T cells, often driven by the CCL2-CCR6 axis. Standard therapies remodel these ecosystems, creating inflammatory windows yet fostering adaptive resistance. Mechanistically, myeloid-driven, inflammation-coupled rewiring is central to escape: IL-8/CXCR2 signaling and therapy-induced senescence/SASP recruit and polarize suppressive myeloid cells, reinforcing T-cell exclusion and exhaustion. Variable HLA class I loss and hypoxic or metabolic "functional cold zones" add lesion-specific immune invisibility. Clinically, these insights motivate a heterogeneity-aware framework integrating genomic responder subsets with microenvironmental stratification. Barrier-matched strategies include T-cell redirection (PSMA/STEAP1 engagers, bispecifics, CAR-T) and combinations that heat or modulate myeloid cells. Treating immune heterogeneity as a clinical variable enables durable immunotherapy in PCa.
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