肿瘤相关巨噬细胞（TAMs）在重新编程其他免疫细胞和协调抗肿瘤免疫中发挥关键作用。然而，TAMs和促进免疫逃逸的肿瘤细胞之间的相互作用仍不够清楚。在这里，我们揭示了白细胞介素（IL）-1β在体外肿瘤-巨噬细胞共培养系统中是最丰富的细胞因子之一，增强的IL-1β表达与人卵巢癌中CD8+ T细胞细胞毒性下降相关，表明IL-1β可能在肿瘤-TAMs相互作用中介导免疫抑制。机制上，我们证明IL-1β通过激活核因子-κb信号级联显著提高了肿瘤细胞中程序性死亡配体-1（PD-L1）的表达。具体而言，TAMs释放的IL-1β是由肿瘤细胞的厌氧代谢产物乳酸依赖激活炎症体所触发的。IL-1β通过促进C-C基序趋化因子配体2的分泌来维持和加强免疫抑制，以燃料TAMs招募。重要的是，IL-1β中和抗体在肿瘤承载小鼠模型中显著抑制了肿瘤生长，并与抗-PD-L1抗体表现出协同的抗肿瘤效力。总之，本研究介绍了TAMs和肿瘤细胞之间的以IL-1β为中心的免疫抑制循环，强调IL-1β作为候选治疗靶点，以逆转免疫抑制并增强免疫检查点阻断。©2023作者。MedComm由四川省国际医疗交流与促进协会(SCIMEA)和约翰·威立·辛普森·澳大利亚有限公司出版。

Tumor-associated macrophages (TAMs) play critical roles in reprogramming other immune cells and orchestrating antitumor immunity. However, the interplay between TAMs and tumor cells responsible for enhancing immune evasion remains insufficiently understood. Here, we revealed that interleukin (IL)-1β was among the most abundant cytokines within the in vitro tumor-macrophage coculture system, and enhanced IL-1β expression was associated with impaired cytotoxicity of CD8+ T cells in human ovarian cancer, indicating the possibility that IL-1β mediated immunosuppression during tumor-TAMs crosstalk. Mechanistically, we demonstrated that IL-1β significantly boosted programmed death-ligand 1 (PD-L1) expression in tumor cells via the activation of the nuclear factor-κb signaling cascade. Specifically, IL-1β released from TAMs was triggered by lactate, the anaerobic metabolite of tumor cells, in an inflammasome activation-dependent manner. IL-1β sustained and intensified immunosuppression by promoting C-C motif chemokine ligand 2 secretion in tumor cells to fuel TAMs recruitment. Importantly, IL-1β neutralizing antibody significantly curbed tumor growth and displayed synergistic antitumor efficacies with anti-PD-L1 antibody in tumor-bearing mouse models. Together, this study presents an IL-1β-centered immunosuppressive loop between TAMs and tumor cells, highlighting IL-1β as a candidate therapeutic target to reverse immunosuppression and potentiate immune checkpoint blockade.© 2023 The Authors. MedComm published by Sichuan International Medical Exchange & Promotion Association (SCIMEA) and John Wiley & Sons Australia, Ltd.