Potent agonists of the inducible co-stimulatory receptor 4-1BB are too toxic for patients with advanced cancer. Here, on the basis of observations of a weak agonist of 4-1BB depleting regulatory T (T_reg) cells within the tumour microenvironment without leading to substantial restoration of dysfunctional cytotoxic T cells (CTLs), we show that effective tumour control can be achieved via concurrent T_reg cell depletion and CTL expansion through an anti-4-1BB antibody fused to interleukin-15 (IL-15) via a peptide sensitive to tumour proteases. In mouse models of advanced cancers, intraperitoneal injection of the bifunctional protein attenuated the activity of the interleukin mostly in the periphery of the primary tumour while allowing for the expansion of CTLs within the tumour microenvironment, led to more effective tumour inhibition and to lower systemic toxicity than treating the cancers with combinatorial treatment with unlinked anti-4-1BB antibody and IL-15, and reduced the resistance of tumours to checkpoint blockade. Concurrent eradication of T_reg cells and activation of tumour-infiltrating lymphocytes may represent a general strategy for the effective control of advanced metastatic tumours.

诱导型共刺激受体 4-1BB 的强效激动剂对晚期癌症患者毒性太大。在这里，基于对 4-1BB 消耗肿瘤微环境中调节性 T （T_reg） 细胞的弱激动剂的观察，而不导致功能失调的细胞毒性 T 细胞 （CTL） 的实质性恢复，我们表明可以通过同时 T_reg 细胞耗竭和 CTL 扩增来实现有效的肿瘤控制通过抗 4-1BB 抗体与白细胞介素 15 （IL-15） 融合通过对肿瘤蛋白酶敏感的肽。在晚期癌症的小鼠模型中，腹膜内注射双功能蛋白减弱了主要在原发肿瘤外围的白细胞介素的活性，同时允许 CTL 在肿瘤微环境中扩展，导致更有效的肿瘤抑制和更低的全身毒性，而不是用未连接的抗 4-1BB 抗体和 IL-15 联合治疗癌症， 并降低了肿瘤对检查点阻断的抵抗力。同时根除 T_reg 细胞和激活肿瘤浸润淋巴细胞可能代表有效控制晚期转移性肿瘤的一般策略。