Patients with advanced metastatic castration-resistant prostate cancer (mCRPC) are refractory to immune checkpoint inhibitors (ICIs)^1,2, partly because there are immunosuppressive myeloid cells in tumours^3,4. However, the heterogeneity of myeloid cells has made them difficult to target, making blockade of the colony stimulating factor-1 receptor (CSF1R) clinically ineffective. Here we use single-cell profiling on patient biopsies across the disease continuum and find that a distinct population of tumour-associated macrophages with elevated levels of SPP1 transcripts (SPP1^hi-TAMs) becomes enriched with the progression of prostate cancer to mCRPC. In syngeneic mouse modelling, an analogous macrophage population suppresses CD8⁺ T cell activity in vitro and promotes ICI resistance in vivo. Furthermore, Spp1^hi-TAMs are not responsive to anti-CSF1R antibody treatment. Pathway analysis identifies adenosine signalling as a potential mechanism for SPP1^hi-TAM-mediated immunotherapeutic resistance. Indeed, pharmacological inhibition of adenosine A2A receptors (A2ARs) significantly reverses Spp1^hi-TAM-mediated immunosuppression in CD8⁺ T cells in vitro and enhances CRPC responsiveness to programmed cell death protein 1 (PD-1) blockade in vivo. Consistent with preclinical results, inhibition of A2ARs using ciforadenant in combination with programmed death 1 ligand 1 (PD-L1) blockade using atezolizumab induces clinical responses in patients with mCRPC. Moreover, inhibiting A2ARs results in a significant decrease in SPP1^hi-TAM abundance in CRPC, indicating that this pathway is involved in both induction and downstream immunosuppression. Collectively, these findings establish SPP1^hi-TAMs as key mediators of ICI resistance in mCRPC through adenosine signalling, emphasizing their importance as both a therapeutic target and a potential biomarker for predicting treatment efficacy.

晚期转移性去势抵抗性前列腺癌 （mCRPC） 患者对免疫检查点抑制剂 （ICI） ^1,2 难治，部分原因是肿瘤中存在免疫抑制性髓系细胞^3,4。然而，髓系细胞的异质性使其难以靶向，使得阻断集落刺激因子-1 受体 （CSF1R） 在临床上无效。在这里，我们对整个疾病连续体的患者活检使用单细胞分析，发现随着前列腺癌进展为 mCRPC，SPP1 转录本 （SPP1^hi-TAM） 水平升高的不同肿瘤相关巨噬细胞群变得丰富。在同基因小鼠模型中，类似的巨噬细胞群在体外抑制 CD8⁺ T 细胞活性，并在体内促进 ICI 耐药。此外，Spp1 hi-TAMs 对抗 CSF1R 抗体治疗无反应。通路分析确定腺苷信号传导是 SPP1^hi-TAM 介导的免疫治疗耐药的潜在机制。事实上，腺苷 A2A 受体 （A2ARs） 的药理学抑制在体外显着逆转 CD8⁺ T 细胞中 Spp1^hi-TAM 介导的免疫抑制，并增强 CRPC 对体内程序性细胞死亡蛋白 1 （PD-1） 阻断的反应性。与临床前结果一致，使用 ciforadenant 联合使用 atezolizumab 的程序性死亡 1 配体 1 （PD-L1） 阻断抑制 A2ARs 可诱导 mCRPC 患者的临床反应。 此外，抑制 A2ARs 导致 CRPC 中 SPP1^hi-TAM 丰度显着降低，表明该途径参与诱导和下游免疫抑制。总的来说，这些发现通过腺苷信号传导将 SPP1 hi-TAMs 确立为 mCRPC 中 ICI 耐药的关键介质，强调了它们作为治疗靶点和预测治疗效果的潜在生物标志物的重要性。