前列腺癌 (PCa) 很少对免疫检查点阻断 (ICB) 疗法产生反应。癌症相关成纤维细胞（CAF）是免疫“冷”肿瘤微环境的关键组成部分，被认为是增强免疫治疗反应的有希望的靶标。在本研究中，我们旨在揭示调节 CAF 可塑性的机制，以确定将 CAF 从促肿瘤表型转变为抗肿瘤表型的潜在策略，并增强 ICB 在 PCa 中的疗效。四个 PCa 单细胞 RNA 测序数据集的整合定义了促肿瘤和抗肿瘤 CAF，RNA 测序、流式细胞术和 PCa 类器官模型证明了两种 CAF 亚型的功能。细胞外基质相关CAF（ECM-CAF）促进胶原沉积和癌细胞进展，淋巴细胞相关CAF（Lym-CAF）表现出抗肿瘤表型并诱导CD8 T细胞的浸润和激活。 YAP1 活性调节 ECM-CAF 表型，YAP1 沉默促进向 Lym-CAF 的转换。 NF-κB p65是Lym-CAF亚群中的核心转录因子，YAP1抑制p65的核转位。体内 ECM-CAF 中 YAP1 的选择性耗竭促进了 CD8 T 细胞浸润和激活，并增强了 PCa 中抗 PD-1 治疗的治疗效果。总体而言，这项研究揭示了 PCa 中 CAF 特性的调节机制，并强调了改变 CAF 亚型以抑制肿瘤生长并增加对 ICB 敏感性的治疗策略。

Prostate cancer (PCa) rarely responds to immune-checkpoint blockade (ICB) therapies. Cancer-associated fibroblasts (CAFs) are critical components of the immunologically "cold" tumor microenvironment and are considered a promising target to enhance the immunotherapy response. In this study, we aimed to reveal the mechanisms regulating CAF plasticity to identify potential strategies to switch CAFs from pro-tumorigenic to anti-tumor phenotypes and enhance ICB efficacy in PCa. Integration of four PCa single-cell RNA-sequencing datasets defined pro-tumorigenic and anti-tumor CAFs, and RNA-seq, flow cytometry, and a PCa organoid model demonstrated the functions of two CAF subtypes. Extracellular matrix-associated CAFs (ECM-CAF) promoted collagen deposition and cancer cell progression, and lymphocyte-associated CAFs (Lym-CAF) exhibited an anti-tumor phenotype and induced the infiltration and activation of CD8+ T cells. YAP1 activity regulated the ECM-CAF phenotype, and YAP1 silencing promoted switching to Lym-CAFs. NF-κB p65 was the core transcription factor in the Lym-CAF subset, and YAP1 inhibited nuclear translocation of p65. Selective depletion of YAP1 in ECM-CAFs in vivo promoted CD8+ T-cell infiltration and activation and enhanced the therapeutic effects of anti- PD-1 treatment in PCa. Overall, this study revealed a mechanism regulating CAF identity in PCa and highlighted a therapeutic strategy for altering the CAF subtype to suppress tumor growth and increase sensitivity to ICB.