雄激素剥夺疗法（ADT）是前列腺癌的一线治疗方法。在一些男性中，他们的肿瘤可能变得难治，导致去势抵抗性前列腺癌（CRPC）的发展。尽管正在进行治疗，这仍会导致肿瘤重新生长和转移，并对患者的生存产生负面影响。众所周知，ADT 会刺激免疫抑制细胞的积累，如原肿瘤肿瘤相关巨噬细胞 (TAM)、骨髓源性抑制细胞和前列腺肿瘤中的调节性 T 细胞，以及功能低下的 T 细胞。在其他形式的癌症的化疗和放疗过程中，原肿瘤 TAM 已被证明会在肿瘤血管周围积聚，从而导致肿瘤复发。我们的目延迟CRPC。我们使用多重免疫荧光来评估ADT对小鼠和/或人类前列腺肿瘤中TAM、CD8 T细胞、CD4 T细胞和NK细胞的分布和激活状态的影响。然后，我们使用抗体包被的脂质纳米颗粒 (LNP) 在 ADT 期间选择性地将 STING 激动剂 2'3'-cGAMP (cGAMP) 靶向小鼠前列腺肿瘤中的 PV TAM。TAM 在血管周围以高密度积累，以响应ADT 和促肿瘤表型的表达标志物，包括叶酸受体-β (FR-β)、MRC1 (CD206)、CD169 和 VISTA。此外，这些 PV 肿瘤区域中存在较多数量的非活性 (PD-1-) CD8 T 细胞和数量减少的活性 (CD69 ) NK 细胞。涂有 FR-β 抗体的 LNP 选择性地将 cGAMP 递送至 ADT 治疗肿瘤中的 PV TAM，在那里它们激活 STING 并上调 IFNβ 的表达。这导致PV肿瘤区域中活性CD8 T细胞（以及CD4 T细胞和NK细胞）的密度显着增加，并显着延迟了CRPC的发病。 LNP 给药期间 CD8 T 细胞的抗体耗竭证明了这些细胞在 LNP 诱导的 CRPC 延迟中的重要作用。 总之，我们的数据表明，针对 PV TAM 的 STING 激动剂可用于延长前列腺癌 ADT 的治疗窗口.© 作者（或其雇主）2024。根据 CC BY-NC 允许重复使用。禁止商业再利用。请参阅权利和权限。英国医学杂志出版。

Androgen deprivation therapy (ADT) is a front-line treatment for prostate cancer. In some men, their tumors can become refractory leading to the development of castration-resistant prostate cancer (CRPC). This causes tumors to regrow and metastasize, despite ongoing treatment, and impacts negatively on patient survival. ADT is known to stimulate the accumulation of immunosuppressive cells like protumoral tumor-associated macrophages (TAMs), myeloid-derived suppressor cells and regulatory T cells in prostate tumors, as well as hypofunctional T cells. Protumoral TAMs have been shown to accumulate around tumor blood vessels during chemotherapy and radiotherapy in other forms of cancer, where they drive tumor relapse. Our aim was to see whether such perivascular (PV) TAMs also accumulate in ADT-treated prostate tumors prior to CRPC, and, if so, whether selectively inducing them to express a potent immunostimulant, interferon beta (IFNβ), would stimulate antitumor immunity and delay CRPC.We used multiplex immunofluorescence to assess the effects of ADT on the distribution and activation status of TAMs, CD8+T cells, CD4+T cells and NK cells in mouse and/or human prostate tumors. We then used antibody-coated, lipid nanoparticles (LNPs) to selectively target a STING agonist, 2'3'-cGAMP (cGAMP), to PV TAMs in mouse prostate tumors during ADT.TAMs accumulated at high density around blood vessels in response to ADT and expressed markers of a protumoral phenotype including folate receptor-beta (FR-β), MRC1 (CD206), CD169 and VISTA. Additionally, higher numbers of inactive (PD-1-) CD8+T cells and reduced numbers of active (CD69+) NK cells were present in these PV tumor areas. LNPs coated with an antibody to FR-β selectively delivered cGAMP to PV TAMs in ADT-treated tumors, where they activated STING and upregulated the expression of IFNβ. This resulted in a marked increase in the density of active CD8+T cells (along with CD4+T cells and NK cells) in PV tumor areas, and significantly delayed the onset of CRPC. Antibody depletion of CD8+T cells during LNP administration demonstrated the essential role of these cells in delay in CRPC induced by LNPs.Together, our data indicate that targeting a STING agonist to PV TAMs could be used to extend the treatment window for ADT in prostate cancer.© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.